JPH0853403A - New compound and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound, having pharmacological activities such as inhibiting activities against collagenases and useful for treating and/or preventing diseases mediated by the collagenases. CONSTITUTION:This compound is expressed by formula I (R<1> is H or a hydroxy- protecting group; R<2> is H, a lower alkyl or an amino-protecting group; R<3> is H or 2-thuenylthuo; R<4> is 2-pyridyl or its N-oxide, 4-pyridyl, phenyl or 4- methoxyphenyl; R<5> is hydroxy, a lower alkoxy or amino having a substituent group, with the proviso that R<4> is 2-pyridyl or its N-oxide or 4-pyridyl when R<1> and R<2> are each H) or its pharmaceutically permissible salt, e.g. [(2R,3 S)-4-(hydroxylamino)-2-isobutyl-3-(2-thienylthiomethyl)succinyl]-L-2-p yridylalanine- N-methylamide. The compound is obtained by reacting a compound of formula II or its reactive derivative or salt with a compound of formula III or lts reactive derivative or salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound and a pharmaceutically acceptable salt thereof. More specifically, the present invention provides a novel compound useful as a collagenase inhibitor and a pharmaceutically acceptable salt thereof, a method for producing the same,
It relates to a pharmaceutical composition containing the same, a method for treating and / or preventing a collagenase-mediated disease. One object of the present invention is to provide new and useful compounds having pharmacological activity such as collagenase inhibitory activity and pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a method for producing the above compound and salts thereof.

Still another object of the present invention is to provide a pharmaceutical composition containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient. Another object of this invention is to provide a method of using it for the treatment and / or prevention of collagenase mediated diseases. In another aspect, one object of this invention is to provide hydroxamic acid protecting groups, protected hydroxamic acid derivatives and salts thereof. Another object in this aspect is to provide a process for preparing the protected hydroxamic acid derivatives and salts thereof.

[0003]

The object compound of the present invention is represented by the following general formula (I).

[Wherein R ¹ is hydrogen or a hydroxy protecting group, R ² is hydrogen, a lower alkyl group or an amino protecting group,
R ³ is hydrogen or a 2-thienylthio group, R ⁴ is a 2-pyridyl group or its N-oxide, 4-pyridyl group, phenyl group or 4-methoxyphenyl group, R ⁵ is a hydroxy group, a lower alkoxy group or an amino having a substituent. Group, respectively. However, when R ¹ and R ² are each hydrogen, R ⁴ is a 2-pyridyl group or its N-oxide. ]

Another object compound of the present invention is represented by the following general formula (IA). [In the formula, R ¹ _a means an acyl group, R ² _a means an acyloxymethyl group, and R means an organic group, respectively. ] Further, the target compound (I) having the most potent activity is
It can be expressed by the following formula. (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are respectively as defined above. According to the present invention, the novel compound (I) and a salt thereof can be produced by the following production method. it can.

Manufacturing method 1

Manufacturing method 2

Manufacturing method 3

Manufacturing method 4

Manufacturing method 5

Manufacturing method 6 (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, R ¹ _a is a hydroxy protecting group, R ² _b is hydrogen or an amino protecting group, and R ⁵ _a is A hydroxy group or a lower alkoxy group, R ⁵ _b is a substituted amino group, R ⁵ _c is a lower alkoxy group, and R ⁶ _a is a hydroxy protecting group.)

Compound (IA) is a useful protected hydroxamic acid derivative because it exhibits greater oral absorbability than the corresponding free acid derivative and can be converted into a free hydroxamic acid derivative in the human or animal body. Preferred examples of R ¹ a and R ² b (or R ² a) for the purpose are a lower alkanoyl group and hydrogen, respectively.
A lower alkanoyl group and a lower alkanoyloxymethyl group can be mentioned, and most particularly preferable examples include a pivaloyl group and hydrogen, or a pivaloyl group and a pivaloyloxymethyl group, respectively. Compound (IA) can be produced by the following formula.

(Wherein R, R ¹ _a and R ² _a are each as defined above.) This reaction can be carried out in substantially the same manner as the reaction of the production method 4, and therefore, For details of this reaction, refer to the explanation of the production method 4 below. In this regard, preferred introducing agents for the hydroxamic acid protecting group used in Process 4 include lower alkanoyloxymethyl halides (eg pivaloyloxymethyl chloride) used in the presence of a base (eg potassium carbonate). And tetra (lower) alkylammonium halides (eg tetrabutylammonium iodide), lower alkanoic anhydrides (eg acetic anhydride, pivalic anhydride etc.) and trialkylamines (eg N, N-diisopropyl-N-ethylamine etc.) ) And the like in combination with a base. The starting material compound (II) used in Production Method 1 is novel and can be produced according to the following formula or by a conventional method.

Manufacturing method A

Production method B

(In the formulae, R ⁴ and R ⁵ are as defined above.) Suitable pharmaceutically acceptable salts of the target compound (I) are:
Conventional non-toxic salts, such as organic acid salts (eg acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate). Salt) and acid addition salts such as inorganic acid salts (eg hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate etc.) or amino acids (eg arginine, aspartic acid, glutamic acid etc.) ) And other bases, alkali metal salts (eg sodium salt, potassium salt, etc.), alkaline earth metal salts (tatoba calcium salt, magnesium salt, etc.), ammonium salt, organic base salts (eg trimethylamine salt, triethylamine salt) , Pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.) Can be mentioned. In the above and subsequent description of this specification, suitable examples and explanations of various definitions included in the scope of the present invention are explained in detail below. Unless otherwise specified, "lower" means
1 to 6 carbon atoms (or 2 to 6 in the case of a lower alkenyl group), preferably 1 to 4 (or
In the case of a lower alkenyl group, it means 2 to 4),
"Higher" means having more than 6 carbon atoms, preferably 7 to 12.

Suitable "hydroxy protecting groups" are customary
Hydroxy protecting groups such as the following acyl, mono or
Or di- or triphenyl (lower) alkyl (eg
Benzyl, benzhydryl, trityl, phenethyl, na
Such as ar (lower) alkyl such as futylmethyl);
Tri (lower) alkylsilyl (eg trimethylsilyl)
, Triethylsilyl, isopropyldimethylsilyl,
tert-butyldimethylsilyl, diisopropylmethyl
Rusilyl), triarylsilyl (eg trif
Phenylsilyl), trial (lower) alkylsilyl
Tri-substituted silanes such as tribenzylsilyl, etc.
Lill etc. can be mentioned. Defined like this
The preferred "hydroxy protecting group" is C
₆-C_TenAroyl, C₆-C_TenAr (lower) alkyl and
And lower alkanoyl can be mentioned, and the most preferable
Among them, benzyl, acetyl and pivaloyl
Can be mentioned.

Suitable "acyl group" includes aliphatic acyl, aromatic acyl, heterocyclic acyl, and aliphatic acyl substituted with aromatic group or heterocyclic group, such as carboxylic acid, carbonic acid, carbamic acid. And an acyl derived from an acid such as sulfonic acid.

The aliphatic acyl is a saturated or unsaturated acyclic or cyclic one, for example, carbamoyl, lower alkanoyl (eg formyl, acetyl,
Propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkanesulfonyl (eg, mesyl, ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, te)
rt-butoxycarbonyl etc.), lower alkenoyl (eg acryloyl, methacryloyl, crotonoyl etc.), (C ₃ -C ₇ ) cycloalkanecarbonyl (eg cyclohexanecarbonyl etc.), (C ₃ -C ₇ ).
Cycloalkyl (lower) alkanoyl (eg cycloalkylacetyl etc.), amidino, lower alkoxalyl (eg methoxallyl, etoxaryl, tert-
Protected carboxycarbonyl such as butoxalyl, lower or higher alkylcarbamoyl (eg methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, 2-methylbutylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, heptylcarbamoyl, octylcarbamoyl). , Nonylcarbamoyl), di (lower) alkylcarbamoyl [eg dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, dihexylcarbamoyl etc.), C ₃ -C ₇ cycloalkylcarbamoyl (eg cyclopropyl) Carbamoyl, cyclobutylcarbamoyl, Clopentylcarbamoyl, cyclohexylcarbamoyl, cycloheptylcarbamoyl, etc.), N-lower alkyl-N- (C ₃ -C ₇ ) cycloalkylcarbamoyl (eg N-methyl-N-cyclopropylcarbamoyl, N-methyl-N-cyclohexylcarbonyl, N- Ethyl-N-cyclohexylcarbamoyl, N-propyl-N-hexylcarbamoyl and the like), di (C ₃ -C ₇ ) cyclohexylcarbamoyl (eg dicyclopropylcarbamoyl, dicyclopentylcarbamoyl, dicyclohexylcarbamoyl), N- [di (lower) alkyl Carbamoyl (C ₃ -C ₇ ) cycloalkyl] carbamoyl (eg N-
(1 over dimethylcarbamoyl-cyclohexyl) carbamoyl, etc.), N-[di (lower) alkylcarbamoyl (lower) alkyl (C ₃ over C ₇₎ cycloalkyl] carbamoyl (e.g. N-[1 chromatography (dimethylcarbamoylmethyl) cyclohexyl] carbamoyl Etc.), N- [carbamoyl (lower) alkyl] carbamoyl (eg N- [1-carbamoyl-2-methylbutyl] carbamoyl etc.), N- [N- (lower) alkylcarbamoyl] carbamoyl (eg N- (1-isopropylcarbamoyl-2 -Methylbutyl) carbamoyl etc.),
N- [N, N-lower alkylenecarbamoyl (lower) alkyl] carbamoyl (eg N- [2-methyl-1
-(Piperidinocarbonyl) butyl] carbamoyl etc., N- [N, N-di (lower) alkylcarbamoyl (lower) alkyl] carbamoyl (eg N- (dimethylcarbamoylmethyl) carbamoyl, N- [1- (dimethyl) Carbamoyl) ethyl] carbamoyl, N-
[1- (Dimethylcarbamoyl) -2-methylpropyl] carbamoyl, N- [2,2-dimethyl-1- (dimethylcarbamoyl) propyl] carbamoyl, N-
[2-methyl-1- (dimethylcarbamoyl) butyl]
Carbamoyl, N- [2-methyl-1- (diethylcarbamoyl) butyl] carbamoyl, N- [3-methyl-1- (dimethylcarbamoyl) butyl] carbamoyl,
N- (1-dimethylcarbamoylpentyl) carbamoyl etc.), N- (lower) alkyl-N- [N, N-di (lower) alkylcarbamoyl] (lower) alkylcarbamoyl (for example, N-methyl-N- [1-dimethylcarbamoyl) -2-methylbutyl] carbamoyl, N-methyl-N- [1-dimethylcarbamoyl-3-methylbutyl] carbamoyl, etc.) and the like.

Examples of the aromatic acyl include C ₆ -C ₁₀ aroyl (eg, benzoyl, toluoyl, xyloyl, etc.), C ₆ -C ₁₀ arenesulfonyl (eg, benzenesulfonyl, tosyl, etc.), C ₆ -C ₁₀ arylcarbamoyl (eg, Phenylcarbamoyl etc.), C ₆
-C ₁₀ aryloxalyl (eg, phenyloxalyl, etc.) and the like can be mentioned.

Examples of the heterocyclic acyl include heterocyclic carbonyl (eg, furoyl, tenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, etc.), lower alkyleneaminocarbonyl. (For example, aziridine-1-ylcarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl, octahydroazosin-1-ylcarbonyl, tetrahydroquinolinecarbonyl, tetrahydroisoquinolinecarbonyl, dihydropyridinecarbonyl, tetrahydropyridinecarbonyl, etc.), heterogeneous Ring carbamoyl (eg pyridi Lucarbamoyl, piperidylcarbamoyl, etc.) and the like.

Examples of the aliphatic acyl substituted with an aromatic group include (C ₆ -C ₁₀ ) alk (lower) alkanoyl such as phenyl (lower) alkanoyl (eg, phenylacetyl, phenylpropionyl, phenylhexanoyl), phenyl. Al (lower) alkoxycarbonyl such as (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.), phenoxy (lower) alkanoyl (eg, phenoxyacetyl, phenoxypropionyl, etc.), phenyl (lower) alkoxaryl (eg, benzyloxalyl, etc.) ) And the like, al (lower) alkoxaryl, phenyl (lower) alkenoyl (eg, cinnamoyl, etc.) and other al (lower) alkenoyl, al (lower) alkylsulfonyl (eg, Jirusuruhoniru, etc.) and the like.

Examples of the aliphatic acyl substituted with a heterocyclic group include heterocyclic (lower) alkanoyl (eg, thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl). , Thiadiazolylpropionyl, pyridylacetyl, etc.), heterocyclic lower alkylcarbamoyl (eg, pyridylmethylcarbamoyl, etc.) and the like.

These acyl groups may be further substituted with one or more, more preferably 1 to 3, suitable substituents, and such substituents include carboxy, lower alkyl (eg, Methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), halogen (eg chlorine, bromine,
Iodine, fluorine), carbamoyl, amino, lower alkanoylamino (eg formamide, acetamide,
Protected amino such as propionamide), lower alkoxycarbonylamino (such as tert-butoxycarbonylamino), lower alkylsulfonyl (such as methylsulfonyl), arylsulfonyl (such as phenylsulfonyl, tosyl), ar (lower) Alkyl (eg benzyl etc.), lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc.),
Examples thereof include carboxy, protected carboxy as described below, carboxy (lower) alkyl (eg, carboxymethyl, carboxyethyl, etc.), protected carboxy (lower) alkyl (eg, tert-butoxycarbonylmethyl, etc.) and the like.

Suitable "lower alkyl groups" or lower alkyl moieties, unless otherwise indicated, are straight or branched ones, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, Hexyl and the like can be mentioned, and the most preferable example is methyl as R ⁶ . Suitable “amino protecting group” is the above acyl,
Conventional ones such as acyloxymethyl can be mentioned, more preferably lower alkanoyl and lower alkanoyloxymethyl, most preferably pivaloyloxymethyl.

Suitable acyl moieties of the above-mentioned "acyloxymethyl" may include the same ones as shown above, more preferred examples are lower alkanoyl, and most preferred acyloxymethyl is pivaloyl. Oxymethyl can be mentioned.

Suitable "lower alkoxy group" or lower group
Unless otherwise specified, the lucoxy moiety is a straight chain or
Is branched, for example, methoxy, ethoxy, propo
Xy, isopropoxy, butoxy, isobutoxy, te
rt-butoxy, pentyloxy, hexyloxy, etc.
The most preferable example is R ^FiveWhen
Then methoxy can be mentioned.

Suitable "substituted amino group" and the substituted amino moiety in the substituted amine include lower alkylamino, lower alkoxyamino, hydroxy (lower) alkylamino, and optionally substituted cyclo (lower) alkylamino. , Optionally substituted heterocyclic amino, optionally substituted nitrogen-containing heterocyclic group, formula: —NH—AX
—CO—R ⁶ (wherein R ⁶ is a lower alkyl group, a lower alkoxy group, an aryloxy group, a mono- or di (lower) alkylamino group, N- (lower) alkyl-N- [hydroxy (lower) alkyl] Amino group, optionally substituted arylamino group, optionally substituted nitrogen-containing heterocyclic group, optionally substituted cyclo (lower) alkyl (lower) alkyl group; A is lower alkylene group; X Is
It means an oxa group, an imino group or a lower alkylimino group, respectively. And a group represented by).

Preferred "lower alkylamino group" is C ₁ -C ₄ alkylamino, and most preferred is methylamino. As preferable "lower alkoxyamino group",
Mention may be made of C ₁ -C ₄ alkoxyamino.

Examples of preferable "hydroxy (lower) alkylamino group" include the following amino groups substituted with hydroxy (lower) alkyl, and more preferable examples are hydroxy (C ₁ -C ₄ ) alkyl. Is most preferably 2-hydroxyethylamino. A preferable “optionally substituted cyclo (lower) alkylamino group” means an amino group substituted with the following cyclo (lower) alkyl, and the aforementioned cyclo (lower) alkyl is hydroxy, lower alkyl or the like. It is optionally substituted with one or more, preferably one or two suitable substituents, and more preferred examples include cyclo (C ₃ -C ₆ ) alkylamino optionally substituted with hydroxy. The most preferable one is 4-hydroxycyclohexylamino.

Suitable "cyclo (lower) alkyl group" may be cyclo (C ₃ -C ₆ ) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the most preferred example is cyclohexyl. be able to.

The preferable “optionally substituted heterocyclic amino group” means an amino group substituted with the following heterocyclic group, and the above-mentioned heterocyclic group is the following protected carboxy, hydroxy, Optionally substituted with one or more, preferably one or two appropriate substituents such as halogen, and more preferred examples include heterocyclic amino optionally substituted with lower alkoxycarbonyl. The heterocyclic group is a 5- to 7-membered unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, and the most preferable example is 1-ethoxycarbonylpiperidin-4-ylamino. be able to. Suitable "heterocyclic group" may be a saturated or unsaturated monocyclic or polycyclic heterocyclic group having at least one hetero atom such as oxygen atom, sulfur atom or nitrogen atom.

Preferred heterocyclic groups are 3- to 8-membered (more preferably 5- to 7-membered) unsaturated heteromonocyclic groups having 1 to 4 nitrogen atoms, such as azepinyl (eg, 1H-azepinyl), pyrrolyl, Pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,
2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and the like), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl and the like); 3 to 8 members having 1 to 4 nitrogen atoms ( More preferably 5 to 7 membered) saturated heteromonocyclic groups such as perhydroazepinyl (eg perhydro-1H-azepinyl etc.), pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl etc .;

7 to 1 having 1 to 4 nitrogen atoms
2-membered unsaturated fused heterocyclic groups such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; 7 to 12 having 1 to 4 nitrogen atoms
Membered saturated fused heterocyclic group, for example, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.
2] Nonanyl and the like;

A 3- to 8-membered (more preferably 5- to 7-membered) unsaturated heteromonocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,
Isoxazolyl, oxadiazolyl (eg 1,
2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); 3 to 8 members having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (More preferably a 5- to 7-membered saturated heteromonocyclic group such as morpholinyl, sydnonyl, etc .; a 7- to 12-membered unsaturated condensed heterocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzo. Oxazolyl, benzoxazodiazolyl, etc .; 3- to 8-membered (more preferably 5- to 7-membered) unsaturated heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl , Thiadiazolyl (eg 1,2,3-thiadiazolyl, 1,
2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc .; 3 to 8 members having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (more preferably 5) To 7-membered) saturated heteromonocyclic groups such as thiazolidinyl; 7- to 12-membered unsaturated condensed heterocyclic groups having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl and benzothiadiazolyl. A 3- to 8-membered (more preferably 5- to 7-membered) unsaturated heteromonocyclic group having one oxygen atom, such as furyl;

3- to 8-membered (more preferably 5- to 7-membered) having one oxygen atom and one or two sulfur atom
Unsaturated heteromonocyclic groups such as dihydrooxathiynyl; 7 to 12-membered unsaturated condensed heterocyclic groups having 1 to 2 sulfur atoms, such as benzothienyl, benzodithynyl, etc .; 1 oxygen atom and 1 sulfur atom. And 7 to 12-membered unsaturated condensed heterocyclic group having 2 to 2, for example, benzoxathiynyl and the like; Preferred "optionally substituted nitrogen-containing heterocyclic group" is a saturated or unsaturated monocyclic group having at least one nitrogen atom and optionally other heteroatoms such as oxygen atom and sulfur atom. Or a polycyclic heterocyclic group, said heterocyclic group being attached to the adjacent group at a ring nitrogen atom.

Suitable nitrogen-containing heterocyclic groups are 3- to 8-membered, preferably 5- to 7-membered, unsaturated heteromonocyclic groups having 1 to 4 nitrogen atoms, such as pyrrol (-1
-) Yl, pyrrolin (-1-) yl, imidazole (-1-) yl, pyrazol (-1-) yl, tetrahydropyridin (-1-) yl (for example 1,2,3,6-tetrahydropyridine (- 1-) yl), triazolyl (eg 4H-1,2,4-triazole (-4
-) Yl, 1H-1,2,3-triazole (-1-)
1,2H-1,2,3-triazol (-2-) yl, etc.), tetrazolyl (eg, 1H-tetrazole (-1-) yl, 2H-tetrazole (-2-) yl), dihydrotriazinyl (eg 4, 5-dihydro-1,2,4-triazin (-4-) yl, 2,5-dihydro-1,2,4-triazin (-2-) yl, etc.), pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydropyridyl (eg 1,2,2,4) 3,6
-Tetrahydropyridin (-1-) yl etc.) and the like;

3 to 8 having 1 to 4 nitrogen atoms
Members, preferably 5- to 7-membered saturated heteromonocyclic groups such as azetidin (-1-) yl, pyrrolidin (-1-) yl, imidazolidin (-1-) (or -3-) yl, piperidine (- 1-) yl, pyrazolidine (-1
-) Yl, piperazine (-1) -yl, etc .; oxygen atom 1
To 2 and 3 to 8 membered, preferably 5 to 7 membered, unsaturated heteromonocyclic group having 1 to 3 nitrogen atoms,
For example, oxazinyl (eg, 4H-1,4-oxazin (-4-) yl, etc.), oxadiazinyl (eg, 4H-1,2,4-oxadiazin (-4-) yl, etc.), etc .; 1 or 2 oxygen atoms and 1 nitrogen atom A 3- to 8-membered, preferably 5- to 7-membered saturated heteromonocyclic group having 3 to 3 groups, such as morpholin (-4-) yl;

3 to 8 member, preferably 5 to 7, having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms.
Membered unsaturated heteromonocyclic groups such as thiazolinyl (eg 1,3-thiazolin (-3-) yl, 1,2-thiazolin (-2-) yl), etc .; 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms. 3 to 8-membered, preferably 5 to 7-membered, saturated heteromonocyclic group having a number of groups such as thiazolidinyl (eg 1,3-thiazolidine (-3-))
Yl, 1,2-thiazolidin (-2-) yl, etc.); and the above-mentioned nitrogen-containing heterocyclic group is
Optionally substituted with one or more suitable substituents, such as lower alkanoyl (eg acetyl etc.), lower alkylaminocarbonyl (eg methylaminocarbonyl etc.), lower alkoxycarbonyl (eg ethoxycarbonyl etc.), hydroxy and the like.

Preferred examples of the “optionally substituted nitrogen-containing heterocyclic group” as defined above include a 5- to 7-membered one having 1 to 4 nitrogen atoms and / or 1 to 2 oxygen atoms. Mention may be made of saturated or unsaturated heteromonocyclic groups which may be substituted by one or two suitable substituents such as lower alkanoyl, lower alkylaminocarbonyl, lower alkoxycarbonyl and hydroxy. As most preferable examples of R ⁶ , heptahydroazepin-1-yl and morpholino can be mentioned.

Suitable "aryl group" or aryl moiety may include C ₆ -C ₁₀ aryl such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like. Phenoxy can be mentioned as a preferable aryloxy. A suitable “mono- or di (lower) alkylamino group” means an amino group substituted with one or two of the above lower alkyl groups, and more preferable examples include di (lower) alkylamino. Dimethylamino can be mentioned as a preferable example.

Suitable "N- (lower) alkyl-N- [hydroxy (lower) alkyl] amino group" is N-
Methyl-N- (hydroxyethyl) amino and the like can be mentioned, and more preferable examples include N- (C ₁ -C ₄
Chromatography) Alkyl N- [hydroxy (C ₁ over C ₄₎ alkyl] and an amino.

Suitable "optionally substituted arylamino group" may include C ₆ -C ₁₀ arylamino such as phenylamino, tolylamino, xylylamino, mesitylamino and naphthylamino, each of which is 1 or more, preferably 1 or 2
Optionally substituted with a suitable substituent, for example, halo (lower) alkyl below, and more preferred examples include:
Mention may be made of phenylamino which may be substituted by trihalo (C ₁ -C ₄ ) alkyl, most preferably 4-trifluoromethylphenylamino.

Preferred "halo (lower) alkyl group" is
It means the above lower alkyl substituted by one or more, preferably 1 to 3 halogens, and more preferred examples include trihalo (lower) alkyl,
Most preferred is trifluoromethyl. Suitable "optionally substituted cyclo (lower) alkyl (lower) alkyl group" may include lower alkyl substituted with cyclo (lower) alkyl, wherein cyclo (lower) alkyl is 1 Optionally substituted with one or more, preferably one or two suitable substituents such as hydroxy and the like,
More preferred examples include cyclo (C ₃ -C ₆ ) alkyl (C ₁ -C ₄ ) alkyl optionally substituted with hydroxy.

Suitable "lower alkylene group" is a straight or branched one, for example, methylene, ethylene,
Propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like can be mentioned, with methylene being the most preferable example.
Suitable "lower alkylimino group" may be a conventional one, for example, methylimino, ethylimino, propylimino, isopropylimino, butylimino, pentylimino, hexylimino and the like. More preferred examples are C ₁ -C. Methylimino can be mentioned as the most preferable _4- alkylimino.

The thus defined "formula: NH-AX"
-CO-R ⁶ "is a preferable example of a lower alkanoylamino (lower) alkylamino, di (lower) alkylcarbamoyloxy (lower) alkylamino, N ', N'-dimethylureido (lower). Alkylamino, [N′-trihalo (lower) alkylphenylureido] (lower) alkylamino, heptahydroazepin-1-ylcarbonylamino (lower) alkylamino,
Morpholinocarbonylamino (lower) alkylamino and [N-methyl-N-morpholinocarbonylamino]
(Lower) alkylamino can be mentioned, and the most preferable ones are 2- (acetylamino) ethylamino, 2- (dimethylcarbamoyloxy) ethylamino, and 2- (N ', N'-dimethylureido) ethylamino. 2- [N '-(4-trifluoromethylphenyl)
Ureido] ethylamino, 2- (heptahydroazepin-1-ylcarbonylamino) ethylamino, 2- (morpholinocarbonylamino) ethylamino and 2- (N-methyl-N-morpholinocarbonylamino) ethylamino may be mentioned. .

Preferred examples of R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as follows. R ¹ is hydrogen or a hydroxy protecting group, R ² is hydrogen, a lower alkyl group or an amino protecting group, R ³ is hydrogen or a 2-thienylthio group, R ⁴ is a 2-pyridyl group or its N-oxide, 4-pyridyl group,
Phenyl group or 4-methoxyphenyl group, R ⁵ is hydroxy group, lower alkoxy group, lower alkylamino group,
Lower alkoxyamino group, N- (lower) alkyl-N-
(Lower) alkoxyamino group, mono- or di-hydroxy (lower) alkylamino group, protected mono- or di-hydroxy (lower) alkylamino group, optionally substituted cyclo (lower) alkylamino group, Optionally substituted cyclo (lower) alkyl (lower) alkylamino group, optionally substituted heterocyclic amino group, optionally substituted nitrogen-containing heterocyclic group, optionally substituted aryl (lower ) Alkylamino group, optionally substituted heterocyclic (lower) alkyl, halo (lower) alkylamino group, N '-(lower) alkanoylhydrazino group, formula: NH-A-X-CO-R ⁶ A group represented by the formula (wherein R ⁶ is a lower alkyl group, a lower alkoxy group, an aryloxy group, a mono- or di (lower) alkylamino group,
N- (lower) alkyl-N- [hydroxy (lower) alkyl] amino group, optionally substituted arylamino group, optionally substituted nitrogen-containing heterocyclic group, optionally substituted cyclo (lower) An alkyl (lower) alkyl group, A is a lower alkylene group, X is an oxa group, an imino group or a lower alkylimino group. However, when R ¹ and R ² are each hydrogen, R ⁴ is a 2-pyridyl group or its N-oxide or 4-pyridyl group. R ¹ , R ² , R ^{3 of} the target compound (I),
More preferable examples of R ⁴ and R ⁵ are as follows.

R ¹ is hydrogen, C ₆ -C ₁₀ aroyl group, C ₆ -C ₁₀ ar (lower) alkyl group or lower alkanoyl group, R ² is hydrogen, lower alkyl group, lower alkanoyl group or lower alkanoyloxymethyl group , R ³ is hydrogen or 2-thienylthio group, R ⁴ is 2-pyridyl group or its N-oxide, phenyl group or 4-methoxyphenyl group, R ⁵ is hydroxy group; lower alkoxy group; lower alkylamino group; lower alkoxyamino group A hydroxy (lower) alkylamino group; a cyclo (C ₃ -C ₆ ) alkylamino group which may be substituted with a hydroxy group;
The heterocyclic amino group which may be substituted with a lower alkoxycarbonyl group, and the above-mentioned heterocyclic group include a nitrogen atom of 1 to 4
A 5- to 7-membered unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, optionally substituted by a group consisting of lower alkanoyl, lower alkylaminocarbonyl, lower alkoxycarbonyl and hydroxy, and 1 to 4 nitrogen atoms and / or oxygen atoms. 5- to 7-membered saturated or unsaturated heteromonocyclic group having 1 or 2; lower alkanoylamino (lower) alkylamino, lower alkoxycarbonylamino (lower) alkylamino, phenoxycarbonylamino (lower) alkylamino, [N ', N'-di (lower) alkylureido] (lower) alkylamino, [N- (lower) alkyl-N', N'-di (lower) alkylureido] (lower) alkylamino, [di (lower) alkyl Carbamoyloxy] (lower) alkylamino, [N-
(Lower) alkyl-N-hydroxy (lower) alkylcarbamoyloxy] (lower) alkylamino, [phenylcarbamoyloxy] (lower) alkylamino,
[N′-phenyl [optionally substituted with trihalo (lower) alkyl] ureido] (lower) alkylamino,
Piperidinocarbonyloxy (lower) alkylamino,
Morpholino carbonyloxy (lower) alkylamino,
Morpholino carbonylamino (lower) alkylamino,
[N- (lower) alkyl-N- (morpholinocarbonyl) amino] (lower) alkylamino and (heptahydroazepin-1-ylcarbonyl) amino (lower) alkylamino.

However, when R ¹ and R ² are each hydrogen, R ⁴ is a 2-pyridyl group or its N-oxide. Suitable “organic group” for R is
It may be any organic group which can be linked to the hydroxamoyl moiety of "HO-NH-CO-", for example the residue of compound (I), ie the group of the formula:

Others of such compounds which may be protected by the hydroxamic acid protecting group are described in the documents below. 1) Japanese Patent Publication Heisei 4-149170 2) European Patent Publication No. 236872, 2
74453, 489579 and 497192 3) British Patent Publication No. 2268934 4) US Patent No. 5256657 5) International Patent Publication No. WO90 / 05716, W
O90 / 05719, WO91 / 02716, WO91
/ 08222, WO92 / 09282, WO92 / 09
556, WO92 / 09563, WO92 / 0956
4, WO92 / 09565, WO92 / 13831, W
O92 / 17460, WO92 / 22523, WO93
/ 09090, WO93 / 09097, WO93 / 24
475, WO94 / 02446 and WO94 / 024
47 The method for producing the object compound (I) will be described in detail below.

Production Method 1 The object compound (I) or its salt is obtained by reacting the compound (II) or its reactive derivative at the carboxy group or its salt with the compound (III) or its reactive derivative at the amino group or its salt. It can be manufactured by Suitable reactive derivative at the amino group of compound (III) includes Schiff base type imino produced by reacting compound (III) with carbonyl compound such as aldehyde and ketone, or tautomeric enamine type isomer thereof; compound A silyl derivative formed by reacting (III) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea; compound (I
Examples thereof include derivatives produced by reacting II) with phosphorus trichloride or phosgene.

Suitable salt of the compound (III) and its reactive derivative may be the acid addition salt shown for the compound (I). Suitable reactive derivative at the carboxy group of the compound (II) may include acid halide, acid anhydride, active amide, active ester and the like. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid (for example, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid,
Halogenated phosphoric acid, etc., dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (eg methanesulfonic acid, etc.), aliphatic carboxylic acid (eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentane) Acids, 2-ethylbutyric acid, trichloroacetic acid, etc.) or mixed acid anhydrides with acids such as aromatic carboxylic acids (eg benzoic acid, etc.); symmetrical acid anhydrides; imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles An active amide; or an active ester (eg, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH
-] Ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester,
p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc., or N-hydroxy compound (for example, N, N-dimethylhydroxylamine, 1
-Hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.) and the like. These reactive derivatives can be arbitrarily selected from these depending on the type of compound (II) used.

Suitable salts of the compound (II) and its reactive derivative may be the same as those shown for the compound (I). This reaction is usually carried out in a conventional solvent such as water, alcohol (eg methanol, ethanol etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. Or in any other organic solvent that does not adversely affect the reaction. These conventional solvents may be used as a mixture with water.

When the compound (II) is used in the form of a free acid or a salt thereof in this reaction, this reaction is preferably carried out in the presence of a conventional condensing agent, and examples of the condensing agent include N. , N'-dicyclohexylcarbodiimide; N-cyclohexyl- [N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'
-Diethylcarbodiimide; N, N'-diisopropylcarbodiimide; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene -N-
Cyclohexyl imine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite,
Ethyl polyphosphate; Isopropyl polyphosphate; Phosphorus oxychloride (phosphoryl chloride); Phosphorus trichloride; Diphenylphosphoryl azide; Thionyl chloride; Oxalyl chloride; Lower alkyl haloformates [eg ethyl chloroformate, isopropyl chloroformate]; Triphenylphosphine; 2-Ethyl-7-hydroxybenzoisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole;
1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. , Etc. can be mentioned.

This reaction is carried out using alkali metal bicarbonates, tri (lower) alkylamines (eg triethylamine,
It can also be carried out in the presence of an inorganic or organic base such as N, N-diisopropyl-N-ethylamine), pyridine, N- (lower) alkylmorpholine or N, N-di (lower) alkylbenzylamine. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Production Method 2 The object compound (Ib) or a salt thereof is the compound (I-b).
It can be prepared by reacting a) or a reactive derivative thereof in the carboxy group or a salt thereof with a reactive derivative thereof in a substituted amine or amino group or a salt thereof.

Suitable salts of the compound (Ia) and its reactive derivative include those shown for the compound (II). Suitable salts of the substituted amine and its reactive derivative may be those mentioned for compound (III). When the acyl group of the symbol "R ¹ " is derived from carbamic acid, the starting substituted amine is usually used in the form of isocyanate.

This reaction can be carried out in substantially the same manner as in Production Method 1. Therefore, the reaction mode and reaction conditions (eg, reactive derivative, solvent, base reaction temperature, etc.) of this reaction are the same as those described in Production Method 1. You can refer to it.

Production Method 3 The object compound (Id) or its salt is the compound (I-d).
It can be prepared by subjecting c) or a salt thereof to elimination reaction of a hydroxamic acid protecting group. Compound (I-
Suitable salts of c) and (Id) may include those shown for compound (I). This reaction is carried out according to a conventional method such as solvolysis including hydrolysis and reduction. This solvolysis is preferably carried out in the presence of a base or an acid such as a Lewis acid.

Suitable bases include alkali metals (eg sodium, potassium etc.), alkaline earth metals (eg magnesium, calcium etc.), their hydroxides, carbonates or bicarbonates, hydrazine, trialkylamines ( (Eg, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]. Mention may be made of inorganic and organic bases such as undec-7-ene.

Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). Hydrogen fluoride). The elimination reaction using a Lewis acid such as trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.) is preferably carried out in the presence of a cation scavenger (eg, anisole, phenol, etc.).

This reaction is usually detrimental to conventional solvents such as water, alcohols (eg methanol, ethanol, etc.), methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, N, N-dimethylformamide, mixtures or reactions thereof. In any other solvent that does not Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. Examples of the reduction method applicable to the elimination reaction include chemical reduction and catalytic reduction.

Suitable reducing agents used in the chemical reduction include metals (eg tin, zinc, iron etc.) or metal compounds (eg chromium chloride, chromium acetate etc.) and organic or inorganic acids (eg formic acid, acetic acid etc.). , Propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts used for catalytic reduction include conventional catalysts such as platinum catalysts (eg platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg palladium sponge, palladium black). , Palladium oxide, palladium-carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, etc.), nickel catalysts (eg reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalysts (eg reduced cobalt, Raney cobalt etc.), iron catalysts ( For example, reduced iron, Raney iron, etc., copper catalysts (eg reduced copper,
Raney copper, Ullmann copper, etc.) and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, for example water, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof. Furthermore, if the above acids used for chemical reduction are liquids, they can also be used as solvents. Further, suitable solvents used for catalytic reduction may include the above-mentioned solvents, and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof. The reaction temperature for this reduction is not particularly limited, and the reaction is usually performed under cooling or heating.

Production Method 4 The object compound (Ic) or a salt thereof can be produced by introducing a hydroxamic acid-protecting group into the compound (Id) or a salt thereof. Suitable hydroxamic acid-protecting group introducing agents used in this reaction include conventional acylating agents capable of introducing the hydroxamic acid-protecting group such as ar (lower) alkanoyl, lower alkanoyloxymethyl and acyl. You can

Suitable examples include ar (lower) alkanoyl halides (eg benzyl chloride), lower alkanoyloxymethyl halides (eg pivaloyloxymethyl chloride), carboxylic acids, carbonic acids, sulfonic acids and their Mention may be made of reactive derivatives such as acid halides, acid anhydrides, active amides, active esters and the like. Preferred examples of such a reactive derivative include acid chloride; acid bromide; substituted phosphoric acid (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, Sulfuric acid, alkyl carbonate (eg, methyl carbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic carboxylic acid (eg, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (eg, benzoic acid, etc.) Mixed acid anhydrides with acids such as; symmetric acid anhydrides; activated acid amides and activated esters with heterocyclic compounds containing imino functional groups such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole; p-nitrophenyl ester, 2,4-dinitrof Nyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyridyl ester, piperidinyl ester, 8-quinolylthioester Etc.) or N, N-dimethylhydroxylamine, N-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc. -Esters with hydroxy compounds can be mentioned.

When a lower alkanoyloxymethyl halide is used in this reaction, this reaction can be carried out in the presence of a tetra (lower) alkylammonium halide such as tetrabutylammonium iodide.

This reaction can be carried out in the presence of an organic or inorganic base, for example, an alkali metal (eg lithium, sodium, potassium etc.), an alkaline earth metal (eg calcium etc.), an alkali metal hydride (eg For example, sodium hydride), alkaline earth metal hydrides (such as calcium hydride), alkali metal hydroxides (such as sodium hydroxide and potassium hydroxide), alkali metal carbonates (such as sodium carbonate and potassium carbonate) ), Alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate, etc.),
Alkali metal alkoxides (eg sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.), alkali metal alkanates (eg sodium acetate etc.), trialkylamines (eg triethylamine, N, N-diisopropyl-N-ethylamine etc.) , Pyridine compounds (eg, pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline and the like.

In this reaction, when the hydroxamic acid protecting group-introducing agent is used in the form of a free acid or a salt thereof, the reaction is preferably carried out in the presence of a condensing agent. , Carbodiimide compounds (eg, N, N′-dicyclohexylcarbodiimide, N-
Cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N
-Ethyl-N '-(3-dimethylaminopropyl) carbodiimide, etc., ketene imine compounds (for example, N,
N′-carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); olefin or acetylene ether compound (for example, ethoxyacetylene, β-chlorovinylethyl ether),
N-hydroxybenzotriazole derivative (for example, 1
-(4-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole etc. sulfonic acid ester, trialkyl phosphite or triphenylphosphine and carbon tetrachloride, disulfide or diazene dicarboxylate (eg diethyl diazene dicarboxylate etc.) ), A phosphorus compound (for example, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphoryl chloride, phosphorus trichloride, etc.), thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5. -Phenylisoxazolium-3-sulfonate, N, N-di (lower) alkylformamide (eg, dimethylformamide, etc.), N-methylformamide, and other amide compounds are thionyl chloride, phosphorus oxychloride,
Examples thereof include a reagent prepared by reacting with a halogen compound such as phosgene (so-called “Vilsmeier reagent”).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, acetone, methylene chloride, alcohol (eg methanol, ethanol etc.), tetrahydrofuran, pyridine, N, N-dimethylformamide etc. If the hydroxamic acid protecting group introducing agent is a liquid, it can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Production Method 5 The object compound (If) or a salt thereof is the compound (I-f).
It can be prepared by subjecting e) or a salt thereof to elimination reaction of the carboxy protecting group of R ⁵ _c . Compound (I
Suitable salts of -e) and (If) may include those shown for compound (I). This elimination reaction can be carried out according to a conventional method in peptide chemistry such as solvolysis and reduction. For details thereof, refer to the description of the production method 3.

Production Method 6 Compound (I-h) or a salt thereof can be produced by oxidizing the 2-pyridyl group of compound (I-g) or a salt thereof. Compounds (I-g) and (I-
Suitable salts of h) may be the same as those shown for compound (I). Suitable oxidizing agents for the pyridyl group used in this reaction include those which can convert the pyridyl group to pyridyl oxide, such as potassium permanganate, chromium compounds (for example, chromium trioxide, chromic acid, sodium chromate, Dichromic acid, sodium dichromate, pyridinium dichromate, etc.), m
Examples thereof include chloroperbenzoic acid.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, acetone, dioxane,
Dimethylformamide, methylene chloride, chloroform,
Done in pyridine or the like, or mixtures thereof. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. The compound obtained by the above-mentioned production method can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography or reprecipitation. The target compound (I) can be converted into its salt by a conventional method. Compound (I) and other compounds are based on an asymmetric carbon atom.
May contain one or more stereoisomers,
All such isomers and mixtures thereof are also within the scope of the present invention. Collagenase induces collagen degradation in vertebrates and, in addition to its normal function in connective tissue metabolism and wound healing, is associated with many pathological conditions, such as joint destruction in the case of rheumatoid arthritis, periodontal disease. Disease, corneal ulcer, tumor metastasis, osteoarthritis, recumbent restenosis after percutaneous transluminal coronary canal injury, osteoporosis, psoriasis, chronic active hepatitis, autoimmune keratitis, etc. The compounds of this invention are useful in the treatment and / or prevention of such pathological conditions.

When administered for therapy, the peptide compound (I) of the present invention and pharmaceutically acceptable salts thereof are suitable for oral administration, parenteral administration or external use, with one of the compounds as an active ingredient. It is used in the form of a pharmaceutical preparation containing it as a mixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient. The above pharmaceutical preparations include capsules, tablets, dragees, granules, solutions, suspensions,
It may be an emulsion, a sublingual tablet, a suppository, an ointment and the like. If necessary, the above-mentioned preparations may be mixed with auxiliaries, stabilizers, wetting or emulsifying agents, buffers and other conventional additives.

The dose of compound (I) will vary depending on the age and symptoms of the patient, but in general, when administered intravenously, an amount of active ingredient in the range of 0.01 to 100 mg per day will be used for human body weight. Per kg, for intramuscular administration, the amount of active ingredient in the range of 0.05 to 100 mg per 1 kg of human body weight per kg; for oral administration, the amount of active ingredient in the range of 0.1 to 100 mg per day. It may be administered per kg of human body weight for the treatment of collagenase-mediated diseases. In order to show the efficacy of the target compound (I), the pharmacological test data of representative compounds of the compound (I) are shown below.

Collagenase Inhibitory Activity 1. Test method Human collagenase was tested for interleukin-1β (1n
g / ml) of human dermal fibroblast medium stimulated. Latent collagenase was activated by incubating trypsin (200 μg / ml) for 60 minutes at 37 ° C. to activate soybean trypsin inhibitor (800 μg / ml).
ml) was added to stop the reaction. Collagenase activity was confirmed using FTTC-labeled calf skin type I collagen. FITC collagen (2.5mg / m
l) at 37 ° C. for 120 minutes in 50 mM Tris buffer (5
mM CaCl ₂ , 200 mM NaCl and 0.0
Test compound was incubated with active collagenase in 2% NaN ₃ , containing pH 7.5). Isometric 7
0% ethanol-200 mM Tris buffer (pH 9.
After 5) was added to stop the enzymatic reaction, the reaction mixture was centrifuged and the collagenase activity was estimated by measuring the fluorescence intensity of the supernatant at 495 nm (excitation) and 520 nm (emission).

2. Test Compound Compound A (Compound of Example 26) 3. Test results

In these examples, IUPAC-IUB
In addition to the abbreviations adopted by, the following abbreviations are used. Ac: Acetyl DMF: Dimethylformamide DMSO: Dimethyl sulfoxide Et: Ethyl HOBT: N-Hydroxybenzotriazole Me: Methyl WSCD: 1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide THF: Tetrahydrofuran TLC: Thin layer chromatography mCP. m-chloroperbenzoic acid

[0079]

The present invention will be described in more detail with reference to the following production examples and examples. Production Example 1-1) Concentrated sulfuric acid (11 ml) of D-leucine (35 g) and water (4
A solution of sodium nitrite (28g) in water (150ml) is added dropwise to the solution in 00ml) at 5 ° C. The solution is stirred at room temperature for 3 hours and poured into saturated saline (400 ml) and ethyl acetate (400 ml). The organic layers are combined and dried over magnesium sulfate. After the solvent was distilled off, the residue was triturated with n-hexane to obtain (R) -2-hydroxy-4-methylpentanoic acid (24 g) as a white powder. TLC: Rf 0.45 (chloroform: methanol:
Acetic acid = 8: 2: 1) NMR (DMSO-d6, δ): 0.87 (3H, d,
J = 6.5 Hz), 0.88 (3H, d, J = 6.6H)
z), 1.32-1.51 (3H, m), 3.93.
(1H, dd, J = 8.4, 5.2Hz), 5.06
(1H, br s), 12.32 (1H, br s)

Production Example 1-2) (R) -2-hydroxy-4-methylpentanoic acid (28
g) in DMF (500 ml) solution, potassium carbonate (1
8 g) and benzyl bromide (25.2 ml) are added. The mixture is stirred at room temperature for 1 hour and poured into saturated brine-diethyl ether. The organic layers are combined and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate) to obtain benzyl (R) -2-hydroxy-4-methylpentanoate (44.5 g) as a colorless oil. TLC: Rf 0.50 (hexane: EtOAc = 1
0: 1) NMR (CDCl ₃ , δ): 0.93 (3H, d, J
= 6.7 Hz), 0.94 (3H, d, J = 6.6H
z), 1.48-1.65 (3H, m), 2.63.
(1H, d, J = 6.0 Hz), 4.24 (1H,
m), 5.21 (2H, s), 7.28-7.46 (5
H, m)

Production Example 1-3) A solution of trifluan anhydride (trifluoromethanesulfonic anhydride) was added to a solution of benzyl (R) -2-hydroxy-4-methylpentanoate (37.8 g) and 2,6 lutidine (20 ml) in methylene chloride (380 ml). Thing) (50 g) at 0 ° C
Drop by. The solution is stirred at 0 ° C. for 0.5 hours and poured into saturated saline solution. The extracted organic layer is dried over magnesium sulfate and the solvent is concentrated to 200 ml. To a suspension of sodium hydride (7.5g) in THF (200ml) was added di-ter-butyl malonate (37g) in THF (300g).
ml) solution is added at 10 ° C. Then, the triflate solution (200 ml) is added dropwise at 0 ° C. The solution is stirred for 0.5 hours and poured successively into saturated saline and ethyl acetate. The extracted organic layer is dried over magnesium sulfate and the solvent is distilled off in vacuum. The residue was purified by silica gel column chromatography (eluent: chloroform) to give (R) -2- (di-
Benzyl tert-butoxycarbonyl) methyl-4-methylpentanoate (65.5 g) is obtained as a pale yellow oil. TLC: Rf 0.40 (hexane: ethyl acetate = 1
0: 1) NMR (CDCl ₃ , δ): 0.83 (3H, d, J
= 6 Hz), 0.91 (3H, d, J = 6 Hz), 1.
21 (1H, m), 1.43 (9H, s), 1.46
(9H, s), 1.54 (2H, m), 3.10 (1
H, ddd, J = 10, 10, 4 Hz), 3.53 (1
H, d, J = 10 Hz), 5.10 (1H, d, J =
12.5Hz), 5.18 (1H, d, J = 12.5H
z), 7.27-7.38 (5H, m)

Production Example 1-4) A solution of benzyl (R) -2- (di-tert-butoxycarbonyl) methyl-4-methylpentanoate (65 g) in methanol (150 ml) was treated with 10% palladium-carbon (6.5 g). Hydrogenate under 4 atmospheres of hydrogen.
The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give (R) -2- (di-tert-butoxycarbonyl) methyl-4-methylpentanoic acid (50 g) as a colorless oil. TLC: Rf 0.45 (chloroform: methanol =
10: 1) NMR (CDCl ₃ , δ): 0.90 (3H, d, J =
6Hz), 0.95 (3HdJ = 6Hz), 1.22
(1H, m), 1.45 (9H, s), 1.48 (9
H, s), 1.61 (1H, m), 1.70 (1H,
m), 3.07 (1H, ddd, J = 10, 10, 4
Hz), 3.49 (1H, d, J = 10Hz)

Production Example 1-5) DMF of (R) -2- (di-tert-butoxycarbonyl) methyl-4-methylpentanoic acid (63.5 g)
(500 ml) solution, HOBT (28.6 g), W
SCD (32.8 g), L-2-pyridylalanine methyl ester dihydrochloride (53.5 g) and N, N-diisopropyl-N-ethylamine (55.1 g) are added at 0 ° C. The mixture is stirred at room temperature for 15 hours. The reaction mixture was poured into saturated saline (1.4 l), and ethyl acetate (500 m
Extract with lx2). The extract is washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 1) to give [(R) -4-tert-butoxy-3-ter.
t-butoxycarbonyl-2-isobutylsuccinyl]
-L-o-pyridylalanine methyl ester (85.9
g) is obtained. Mass spectrum (FB ⁺ ): 493.4 (M ⁺ + H) [α] ¹⁹ _D = + 58.3 ° (C 1.01, chloroform) NMR (DMSO-d6, δ): 0.77 (3H,
d, J = 6.6 Hz), 0.86 (3H, d, J = 6.
4 Hz), 0.96 (1H, ddd, J = 10.2,
3.2, 3.0 Hz), 1.30 (9H, s), 1.3
9 (9H, s), 1.32-1.62 (2H, m),
2.80 (1H, ddd, J = 10.7, 3.2, 3.
2 Hz), 3.08 (1H, dd, J = 14.4, 8.
0 Hz), 3.14 (1H, dd, J = 14.4, 7.
0Hz), 3.25 (1H, d, J = 10.7Hz),
3.52 (3H, s), 4.72 (1H, ddd, J =
8.0, 7.1, 7.0 Hz), 7.22 (1H, d
d, J = 7.6, 4.9 Hz), 7.28 (1H, d,
J = 7.7 Hz), 7.69 (1H, ddd, J = 7.
7, 7.6, 1.7 Hz), 8.47 (1H, dd, J
= 4.9, 1.7 Hz), 8.53 (1H, d, J =
7.1 Hz)

Production Example 1-6) [(R) -4-tert-butoxy-3-tert-butoxycarbonyl-2-isobutylsuccinyl] -L-
To a solution of 2-pyridylalanine methyl ester (85.6g) in methylene chloride (350ml) is added trifluoroacetic acid (250ml) at 0 ° C. Bring the reaction mixture to room temperature for 1 hour.
Stir for 5 hours. The solvent was distilled off from the mixture and the residue was triturated with ethyl acetate-diethyl ether (1: 1, 800 ml) to give [(R) -4-hydroxy-3-carboxy-2-isobutylsuccinyl] -L-2-pyridylalanine methyl ester.・ Trifluoroacetate (68.2)
g) is obtained. Melting point: 132-135 ° C Mass spectrum (FB ⁺ ): 381.3 (M ⁺ + H) [α] D20 = + 17.1 ° (C 1.00, methanol) NMR (DMSO-d6, δ): 0.78 (3H, d,
J = 6.5 Hz), 0.84 (3 Hd, J = 6.4 H)
z), 1.03 (1H, m), 1.32-1.58 (2
H, m), 2.84 (1H, ddd, J = 10.8, 1
0.4, 3.4 Hz), 3.19 (1H, dd, J = 1)
4.7, 8.7 Hz), 3.31 (1H, d, J = 1)
0.8 Hz), 3.33 (1H, dd, J = 14.7,
6.2 Hz), 3.56 (3 H, s), 4.80 (1
H, ddd, J = 8.7, 7.7, 6.2 Hz), 7.
20-7.33 (2H, m), 8.08 (1H, d
d, J = 7.2, 7.1 Hz), 8.62 (1H, d,
J = 7.7 Hz), 8.65 (1H, d, J = 4.4H)
z)

Production Example 1-7) A solution of [(R) -4-hydroxy-3-carboxy-2-isobutylsuccinyl] -L-2-pyridylalanine methyl ester trifluoroacetate (67.8 g) in ethanol (3 l) was added. Formaldehyde aqueous solution (37w
/ V%, 103 ml) at once at room temperature. Then piperidine (29 ml) is added dropwise and the solution is stirred for 4 hours at room temperature. The solvent is distilled off in a vacuum. The residue is dissolved in chloroform (400 ml), washed with aqueous citric acid solution, dried over magnesium sulphate and evaporated. The residue was triturated with diethyl ether to give [(R) -4-hydroxy-2-isobutyl-3-methylenesuccinyl] -L-2.
-Pyridylalanine methyl ester (35.5 g) is obtained. Melting point: 118-120 ° C Mass spectrum (FB ⁺ ): 349.3 (M ⁺ + H) [α] ²⁰ _D = + 2.9 ° (C 1.00, methanol) NMR (DMSO-d6, δ): 0. 80 (3H, d,
J = 6.5 Hz), 0.84 (3H, d, J = 6.5)
Hz), 1.22 (1H, m), 1.43 (1H,
m), 1.57 (1H, m), 3.05 (1H, dd,
J = 14.0, 9.1 Hz), 3.16 (1H, dd,
J = 14.0, 5.5 Hz), 3.45 (1H, dd,
J = 9.4, 5.0 Hz), 3.58 (3H, s),
4.70 (1H, ddd, J = 9.1, 7.6, 5.5
Hz), 5.50 (1H, s), 6.00 (1H,
s), 7.17-7.27 (2H, m), 7.66
(1H, ddd, J = 7.7, 7.6, 1.8 Hz),
8.37 (1H, d, J = 7.6Hz), 8.46 (1
H, dd, J = 5.6, 1.8 Hz)

Production Example 2-1) (R) -2- (Di-tert-butoxycarbonyl) methyl-4-methylpentanoic acid (2 g) was produced in Production Example 1-5).
And react with L-p-methoxyphenylalanine methyl ester · hydrochloride in substantially the same manner as in [(R) -4
-Tert-Butoxy-3-tert-butoxycarbonyl-2-isobutylsuccinyl] -L-p-methoxyphenylalanine methyl ester (3.2 g) is obtained as a pale yellow solid. TLC: Rf 0.90 (n-hexane: ethyl acetate =
2: 1) NMR (CD ₃ OD, δ): 0.84 (3H, d, J =
6.0 Hz), 0.94 (3H, d, J = 6.0H
z), 1.10 (1H, ddd, J = 13.5, 1
2.0, 3.0Hz), 1.40 (9H, s), 1.4
6 (9H, s), 1.55 (1H, ddd, J = 1
3.5, 12.0, 3.0 Hz), 1.60 (1H,
m), 2.91-3.03 (3H, m), 3.38 (1
H, d, J = 9.8 Hz), 3.61 (3H, s),
3.75 (3H, s), 4.57 (1H, dd, J =
7.0, 7.1 Hz), 6.83 (2H, d, J = 9.
0Hz), 7.16 (2H, d, J = 9.0Hz)

Production Example 2-2) [(R) -4-hydroxy-3-carboxy-2-iso]
Butylsuccinyl] -L-p-methoxyphenylalani
Methyl ester Production Example 1-6)
Obtained as a white powder. TLC: Rf 0.10 Chloroform: Methanol = 1
0: 1) NMR (CD ₃OD, δ: 0.85 (3
H, d, J = 6.0 Hz), 0.92 (3H, d, J
= 6.0 Hz), 1.20 (1H, ddd, J = 13.
5, 12.0, 3.0 Hz), 1.49-1.62
(3H, m), 3.00 (2H, d, J = 7.0H
z), 3.07 (1H, m), 3.54 (1H,
d, J = 9.8 Hz), 3.60 (3H, s), 3.7
6 (3H, s), 4.60 (1H, dd, J = 7.1,
7.0 Hz), 6.83 (2H, d, J = 9.0H
z), 7.14 (2H, d, J = 9.0Hz)

Production Example 2-3) [(R) -4-hydroxy-2-isobutyl-3-methylenesuccinyl] -L-p-methoxyphenylalanine methyl ester (1.5 g) was prepared in substantially the same manner as in Production Example 1-7). To give a colorless oil. TLC: Rf 0.50 (chloroform: methanol = 1)
0: 1) NMR (CD ₃ OD, δ): 0.86 (3H, d, J =
6.0 Hz), 0.91 (3H, d, J = 6.0H
z), 1.36 (1H, m), 1.50 (1H, m
m), 1.60 (1H, m), 2.87 (1H, dd,
J = 12.0, 7.0 Hz), 3.06 (1H, dd,
J = 12.0, 7.0 Hz), 3.60 (1H, d
d, J = 7.0, 6.0 Hz), 3.68 (3H,
s), 3.75 (3H, s), 4.62 (1H, d
d, J = 7.1, 7.0 Hz), 5.60 (1H,
s), 6.20 (1H, s), 6.80 (2H, d, J
= 9.0 Hz), 7.16 (2H, d, J = 9.0H)
z)

Production Example 2-4) [(2R, 3S) -4-Hydroxy-2-isobutyl-3-methylsuccinyl] -L-p-methoxyphenylalanine methyl ester (1.3 g) was produced in a yield of 86.2%. It is obtained as a colorless oily amorphous substance in substantially the same manner as in (8). TLC: Rf 0.45 (chloroform: methanol =
10: 1) NMR (CD ₃ OD, δ): 0.74 (3H, d,
J = 6.0 Hz), 0.82 (3H, d, J = 6.0H
z), 0.90 (3H, d, J = 6.0 Hz), 1.
04 (1H, m), 1.43 (1H, m), 1.56
(1H, m), 2.34 (1H, ddd, J = 10.
0, 5.3, 3.0 Hz), 2.60 (1H, dd
d, J = 10.0, 5.3, 3.0 Hz), 2.86
(1H, dd, J = 15.0, 12.0Hz), 3.1
6 (1H, dd, J = 15.0, 6.0Hz), 3.6
8 (3H, s), 3.74 (3H, s), 4.73 (1
H, dd, J = 10.0, 5.3 Hz), 6.83
(2H, d, J = 9.0 Hz), 7.16 (2H, d,
J = 9.0Hz)

Production Example 3-1) [(R) -4-Hydroxy-2-isobutyl-3-methylenesuccinyl] -L-2-pyridylalanine-N-methylamide (3.77 g) was obtained in Example 2 in a yield of 75.6%.
It is obtained as a white powder in substantially the same manner as in (1). TLC: Rf 0.70 (chloroform: methanol: acetic acid = 8: 2: 1) NMR (DMSO-d6, δ): 0.80 (3H, d,
J = 6Hz), 0.84 (3H, d, J = 6Hz),
1.31 (2H, m), 1.56 (1H, m), 2.5
7 (3H, d, J = 5Hz), 2.94 (1H, dd,
J = 12, 9 Hz), 3.09 (1H, dd, J = 1)
2,6 Hz), 3.43 (1H, dd, J = 9,6H
z), 4.52 (1H, dd, J = 9, 6Hz), 5.
43 (3H, s), 5.97 (3H, s), 7.16
(1H, d, J = 7.5 Hz), 7.63 (1H, dd
d, J = 7.5, 7.5, 1.5 Hz), 7.73
(1H, q, J = 5Hz), 8.00 (1H, d, J =
7.5 Hz), 8.43 (1H, dd, J = 7.5,
1.5 Hz)

Production Example 3-2) [(R) -4-Hydroxy-2-isobutyl-3-methylenesuccinyl] -L-2-pyridylalanine-N-methylamide (1 g) and 2-mercaptothiophene (1.
A solution of 1 g) in methanol (20 ml) at reflux 1
Stir for 2 hours. After evaporating the solvent under reduced pressure, the residue was triturated with diethyl ether to give [(2R, 3S) -4-hydroxy-2-isobutyl-3- (2-thienylthiomethyl)).
Succinyl] -L-2-pyridylalanine-N-methylamide (0.54 g) is obtained as a white powder. TLC: Rf 0.80 (chloroform: methanol: acetic acid = 8: 2: 1) NMR (CD ₃ OD, δ): 0.81 (3H, d, J =
6.0 Hz), 0.86 (3H, d, J = 6.0H
z), 1.05 (1H, m), 1.34 (1H,
m), 1.57 (1H, m), 2.17 (1H, m),
2.42-2.56 (3H, m), 2.70 (3
H, s), 3.08 (1H, dd, J = 15.0, 1
0.5Hz), 3.20 (1H, dd, J = 10.5,
5.0 Hz), 4.79 (1H, dd, J = 10.
5,5.0Hz), 6.97 (1H, m), 7.07
(1H, m), 7.29 (1H, m), 7.36 (1
H, m), 7.44 (1H, m), 7.75 (1H,
m), 8.48 (1H, m)

Production Example 4- (1) In the same manner as in Production Example 1- (5), the following compound is obtained. [(R) -4-tert-butoxy-3-tert-butoxycarbonyl-2-isobutylsuccinyl] -L-
2-pyridyl-alanine ethyl ester _{NMR (DMSO-d 6, δ} ): 0.78 (d, J = 7
Hz, 3H), 0.88 (d, J = 7Hz, 3H),
0.97 (m, 1H), 1.05 (d, J = 7Hz, 3
H), 1.31 (s, 9H), 1.33 to 1.46
(M, 2H), 1.39 (s, 9H), 1.57 (m,
1H), 2.82 (ddd, J = 9, 9, 4Hz, 1
H), 3.06 (dd, J = 15, 7.5 Hz, 1
H), 3.13 (dd, J = 15, 7.5 Hz, 1
H), 3.25 (d, J = 9 Hz, 1H), 3.97.
(Q, J = 7 Hz, 2H), 4.70 (ddd, J =
7.5, 7.5, 7.5 Hz, 1H), 7.21 (d
d, J = 7.5, 5 Hz, 1H), 7.28 (d, J =
7.5 Hz, 1 H), 7.69 (dd, J = 7.5,
7.5 Hz, 1 H), 8.47 (d, J = 5 Hz, 1
H), 8.51 (d, J = 7.5 Hz, 1H). NMR (CDCl ₃ , δ): 0.87 (d, J = 7H
z, 3H), 0.94 (d, J = 7Hz, 3H), 1.
09 (m, 1H), 1.13 (t, J = 7Hz, 3
H), 1.38 (s, 9H), 1.46 (s, 9H),
1.60-1.82 (m, 2H), 2.87 (ddd,
J = 9, 9, 4 Hz, 1H), 3.23 (dd, J = 1
4,5Hz, 1H), 3.36 (dd, J = 14,7H
z, 1H), 3.52 (d, J = 9Hz, 1H), 4.
08 (q, J = 7 Hz, 2H), 4.91 (ddd, J
= 7.5, 7,5 Hz, 1H), 7.14 (dd, J =
7.5, 5 Hz, 1H), 7.18 (d, J = 7.5H
z, 1H), 7.47 (d, J = 7.5Hz, 1H),
7.60 (dd, J = 7.5, 7.5 Hz, 1H),
8.50 (br-d, J = 5 Hz, 1H). [Α] _D ²⁵ = + 51.1 ° (c1.00, MeO
H) MASS (FB ⁺ ): M + H = 570

Production Example 4- (2) In the same manner as in Production Example 1- (6), the following compound is obtained. [(R) -4-hydroxy-3-carboxy-2-isobutylsuccinyl] -L-2-pyridylalanine ethyl ester trifluoroacetate NMR (DMSO-d ₆ , δ): 0.79 (d, J = 7
Hz, 3H), 0.86 (d, J = 7Hz, 3H),
1.04 (m, 1H), 1.08 (t, J = 7Hz, 3
H), 1.42-1.68 (m, 2H), 2.85 (d
dd, J = 12, 4, 4 Hz, 1H), 3.17 (d
d, J = 14.8 Hz, 1H), 3.31 (d, J = 1)
2Hz, 1H), 3.33 (dd, J = 14.5Hz,
1H), 4.03 (q, J = 7Hz, 2H), 4.80
(M, 1H), 7.48-7.66 (m, 2H), 8.
06 (ddd, J = 8, 8, 2 Hz, 1H), 8.55
-8.71 (m, 2H). [Α] _D ²⁴ = + 15.7 ° (c0.30, MeO
H) Melting point: 138-148 [deg.] C. MASS (FB ^<+> ): M + H = 395 (freeM =
394.42)

Production Example 4- (3) In the same manner as in Production Example 1- (7), the following compound was obtained. [(R) -4-Hydroxy-2-isobutyl-3-methylenesuccinyl] -L-2-pyridylalanine ethyl ester NMR (DMSO-d ₆ , δ): 0.80 (d, J = 7).
Hz, 3H), 0.85 (d, J = 7Hz, 3H),
1.10 (t, J = 7 Hz, 3H), 1.22 (m, 1
H), 1.33-1.70 (m, 2H), 3.05 (d
d, J = 14.9 Hz, 1H), 3.18 (d, J = 1)
4,6 Hz, 1H), 3.46 (dd, J = 10,5H
z, 1H), 4.03 (q, J = 7Hz, 2H), 4.
68 (ddd, J = 9, 7.5, 5 Hz, 1H), 5.
51 (s, 1H), 6.00 (s, 1H), 7.17-
7.31 (m, 2H), 7.70 (ddd, J = 7.
5,7.5,2 Hz, 1H), 8.38 (d, J = 7.
5Hz, 2H), 8.48 (dd, J = 5, 2Hz, 1
H). [Α] _D ²⁴ = + 0.8 ° (c0.33, MeOH) Melting point: 110-113 ° C HPLC: 11.5 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 20: 80, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 363

Production Example 4- (4) The following compounds are obtained in the same manner as in Production Example 1- (8). [(2R, 3S) -4-Hydroxy-2-isobutyl-
3 Mechirusukushiniru] -L-2-pyridyl-alanine ethyl ester _{NMR (DMSO-d 6, δ} ): 0.59 (d, J = 7
Hz, 3H), 0.74 (d, J = 7Hz, 3H),
0.78 (d, J = 7Hz, 3H), 0.88 (m, 1
H), 1.14 (t, J = 7 Hz, 3H), 1.26-
1.55 (m, 2H), 2.15 (dq, J = 10, 7)
Hz, 1H), 2.33 (m, 1H), 3.04 (d
d, J = 14, 10 Hz, 1H), 3.22 (d, J =
14.5Hz, 1H), 4.07 (q, J = 7Hz, 2
H), 4.83 (m, 1H), 7.21 (dd, J =
7.5, 5 Hz, 1H), 7.30 (d, J = 7.5H
z, 1H), 7.70 (ddd, J = 7.5, 7.5,
2 Hz, 1H), 8.38-8.57 (m, 2H). [Α] _D ²⁴ = −28.1 ° (c0.30, MeO
H) Melting point: 124-128 ° C HPLC: 7.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 365

Production Example 5- (1) The following compounds are obtained in the same manner as in Production Example 1- (5). [(2R, 3S) -4-tert-butoxy-2-isobutyl-3-methylsuccinyl] -L-4-pyridylalanine methyl ester NMR (DMSO-d ₆ , δ): 0.84 (d, J = 7).
Hz, 3H), 0.87 (d, J = 7Hz, 3H),
0.91 (d, J = 7Hz, 3H), 1.06 (m, 1
H), 1.36-1.51 (m, 2H), 1.43
(S, 9H), 1.60-1.73 (m, 1H), 2.
37-2.51 (m, 2H), 3.05 (dd, J = 1
4,7Hz, 1H), 3.17 (dd, J = 14,6H
z, 1H), 3.73 (s, 3H), 5.00 (dd
d, J = 8,7,6 Hz, 1H), 6.28 (d, J =
8Hz, 1H), 7.11 (d, J = 7Hz, 2H),
8.51 (d, J = 7 Hz, 2H). [Α] _D ²³ = −14.9 ° (c0.53, MeO
H) Melting point: 97-99 ° C HPLC: 5.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 35: 65, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 407

Production Example 5- (2) In the same manner as in Production Example 1- (6), the following compound is obtained. [(2R, 3S) -4-Hydroxy-2-isobutyl-
3 Mechirusukushiniru] -L-4-pyridyl-alanine methyl ester _{NMR (DMSO-d 6, δ} ): 0.60 (d, J = 7
Hz, 3H), 0.74 (d, J = 7Hz, 3H),
0.79 (d, J = 7Hz, 3H), 0.90 (m, 1
H), 1.32 (m, 1H), 1.43 (m, 1H),
2.15 (dq, J = 10, 7 Hz, 1H), 2.32
(Ddd, J = 10, 10, 3 Hz, 1H), 2.90
(Dd, J = 14, 12 Hz, 1H), 3.14 (d
d, J = 14, 4 Hz, 1H), 3.62 (s, 3
H), 4.67 (ddd, J = 12, 8, 4 Hz, 1
H), 7.28 (d, J = 7 Hz, 2H), 8.44
(D, J = 7 Hz, 2H), 8.50 (d, J = 8H
z, 1H). [Α] _D ²⁵ = -16.8 ° (c0.51, MeO
H) Melting point: 160-170 ° C HPLC: 8.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 351

Production Example 6- (1) In the same manner as in Production Example 1- (5), the following compound is obtained. [(2R, 3S) -4-tert-butoxy-2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine methyl ester NMR (DMSO-d ₆ , δ): 0.59 (d, J = 7).
Hz, 3H), 0.75 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.84 (m, 1
H), 1.23-1.52 (m, 2H), 1.37
(S, 9H), 2.11 (dq, J = 10,7Hz, 1
H), 2.30 (ddd, J = 11, 10, 3 Hz, 1
H), 3.04 (dd, J = 14, 11 Hz, 1H),
3.22 (dd, J = 14.5 Hz, 1H), 3.61
(S, 3H), 4.83 (m, 1H), 7.20 (d
d, J = 7.5, 5 Hz, 1H), 7.28 (d, J =
7 Hz, 1 H), 7.69 (ddd, J = 7.5, 7.
5,1.5Hz, 1H), 8.42-8.51 (m, 2
H). [Α] _D ²⁶ = −23.8 ° (c0.54, MeO
H) Melting point: 63-66 ° C HPLC: 6.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 35: 65, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 407

Production Example 6- (2) In the same manner as in Production Example 1- (6), the following compound is obtained. [(2R, 3S) -4-Hydroxy-2-isobutyl-
3-Methylsuccinyl] -L-2-pyridylalanine methyl ester NMR (DMSO-d ₆ , δ): 0.59 (d, J = 7)
Hz, 3H), 0.74 (d, J = 7Hz, 3H),
0.79 (d, J = 7Hz, 3H), 0.88 (m, 1
H), 1.34 (m, 1H), 1.43 (m, 1H),
2.15 (dq, J = 10, 7 Hz, 1H), 2.33
(Ddd, J = 11, 10, 3 Hz, 1H), 3.04
(Dd, J = 14, 11 Hz, 1H), 3.21 (d
d, J = 14.6 Hz, 1H), 3.61 (s, 3)
H), 4.83 (m, 1H), 7.20 (dd, J =
7.5, 5 Hz, 1H), 7.29 (d, J = 7.5H
z, 1H), 7.69 (dd, J = 7.5, 7.5H
z, 1H), 8.40-8.53 (m, 2H). [Α] _D ²⁶ = −28.9 ° (c0.53, MeO
H) Melting point: 168-172 ° C HPLC: 8.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 351

Example 1 [(2R, 3S) -4-Hydroxy-2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine methyl ester (24.9 g) and HOBT (11.5 g)
In DMF (450 ml) solution of WSCD (13.2
g) is added at room temperature. After stirring the mixture for 10 minutes, O-benzylhydroxylamine hydrochloride (13.6 g) and N, N-diisopropyl-N-ethylamine (11.1 g) were added.
g) is added. The mixture is stirred at room temperature for 15 hours. The mixture was poured into saturated saline (1 l), and ethyl acetate (500 m
Extract with lx2). The combined organic layers are washed with saturated aqueous ammonium chloride solution (1 l), saturated aqueous sodium bicarbonate solution (1 l) and saturated brine (500 ml), and dried over magnesium sulfate. The solvent was distilled off, and the residue was triturated with diethyl ether to give [(2R, 3S) -4- (benzyloxyamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine methyl ester (25.6 g). ) Get. Melting point: 174-176 ° C Mass spectrum (FB ⁺ ): 456.2 (M ⁺ + H) [α] ²⁰ _D = -20.8 ° (C 1.00, methanol) NMR (DMSO-d6, δ): 0 .45 (3H, d,
J = 6.7 Hz), 0.66-0.84 (7H,
m), 1.22-1.44 (2H, m), 1.92 (1
H, dq, J = 10.6, 6.7 Hz), 2.33 (1
H, m), 3.03 (1H, dd, J = 14.0, 1
0.5 Hz), 3.21 (1H, dd, J = 14.0,
4.6 Hz), 3.60 (3 H, s), 4.75 (2
H, s), 4.83 (1H, m), 7.20 (1H,
dd, J = 7.6, 5.0 Hz), 7.29 (1H,
d, J = 7.7 Hz), 7.36 (5H, s), 7.6
9 (1H, ddd, J = 7.7, 7.6, 1.8H
z), 8.43-8.53 (2H, m), 11.01
(1H, s)

Example 2-1) [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine methyl ester (24.2 g) was dissolved in a 40% methanol (150 ml) solution of methylamine,
The mixture is stirred at room temperature for 4 hours and then at 40 ° C. for 1 hour.
The solvent was evaporated from the solution and the residue was triturated with diethyl ether to give [(2R, 3S) -4- (benzyloxyamino) -2-isobutyl-3-methylsuccinyl] -L-
2-pyridylalanine-N-methylamide (21.7
g) is obtained. Mp: 233-235 ° C. Mass spectrometry ^{(FB +): 455.2 (M} + + H) [α] 20 D = + 1.6 ° (C 1.01, methanol) NMR (DMSO-d6, δ ): 0. 38 (3H, d,
J = 6.8 Hz), 0.72 (3H, d, J = 6.5)
Hz), 0.75-0.86 (4H, m), 1.19-
1.38 (2H, m), 1.91 (1H, dq, J = 1
0.5, 6.8 Hz), 2.32 (1 H, m), 2.
56 (3H, d, J = 4.6Hz), 2.96 (1H,
dd, J = 13.9, 10.3 Hz), 3.07 (1
H, dd, J = 13.9, 4.7 Hz), 4.73 (1
H, ddd, J = 10.3, 8.4, 4.7 Hz),
4.74 (2H, s), 7.18 (1H, dd, J =
7.5, 4.8 Hz), 7.29 (1H, d, J = 7.
5 Hz), 7.36 (5 H, s), 7.61-7.71
(2H, m), 8.27 (1H, d, J = 8.4H
z), 8.45 (1H, br d, J = 4.8 Hz),
10.99 (1H, s)

Example 2-2) [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine (15 g) was reacted with 2- (acetamido) ethylamine in substantially the same manner as in Example 2-1) to give [(2R, 3S) -4- (Benzyloxyamino)
-2-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (2-acetamidoethyl) amide (15.5 g) is obtained as a white solid. NMR (CD ₃ OD, δ): 0.60 (3H, d, J =
6.5Hz), 0.80 (3H, d, J = 5.5H
z), 0.87 (3H, d, J = 5.5Hz), 0.
90 (1H, m), 1.30-1.46 (3H, m),
1.92 (3H, s), 2.01 (1H, m), 2.
46 (1H, m), 3.09 (1H, dd, J = 1
5.0, 10.0 Hz), 3.15-3.27 (5H,
m), 4.79 (1H, dd, J = 10.0, 5.0
Hz), 7.25 (1H, dd, J = 9.0, 6.0)
Hz), 7.30-7.42 (6H, m), 7.73
(1H, dd, J = 9.0, 9.0Hz), 8.47
(1H, dd, J = 9.0, 1.5Hz)

Example 2-3) [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (2-hydroxyethyl) amide (0.26 g) is obtained as a white powder in substantially the same manner as in Example 2-2). NMR (CD ₃ OD, δ): 0.55 (3H, d, J =
6 Hz), 0.79 (3H, d, J = 6 Hz), 0.
86 (3H, d, J = 6Hz), 0.89 (1H,
m), 1.33 (1H, m), 1.40 (1H,
m), 1.99 (1H, m), 2.46 (1H, dd
d, J = 10, 10, 3 Hz), 3.09 (1H, d
d, J = 10, 9.5 Hz), 3.24 (1H, dd,
J = 9.5, 6 Hz), 3.29 (2H, t, J = 6.
5Hz), 3.54 (2H, t, J = 6.5Hz),
4.82 (2H, s), 4.87 (1H, m), 7.2
5 (1H, ddd, J = 7.5, 6, 1.5Hz),
7.30-7.42 (6H, m), 7.73 (1H,
ddd, J = 7.5, 6, 1.5 Hz), 8.47
(1H, dd, J = 6, 1.5Hz)

Example 3-1) [(2R, 3S) -4- (benzyloxyamino) -2]
10% Palladium on carbon is added to a solution of -isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (21.5g) in a mixture of cyclohexene (25ml) and ethanol (200ml).
The mixture is stirred at reflux for 1.5 hours. The catalyst was filtered off, the solvent was distilled off from the filtrate, and the residue was triturated with ethyl acetate to give [(2R, 3S) -4- (hydroxylamino).
-2-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (15.6 g) is obtained. Melting point: 219-225 ° C Mass spectrum (FB ⁺ ): 365.2 (M ⁺ + H) [α] ²⁴ _D = -6.3 ° (C 0.50, methanol) NMR (DMSO-d6, δ): 0 .39 (3H, d,
J = 6.8 Hz), 0.73 (3H, d, J = 6.5)
Hz), 0.77-0.92 (4H, m), 1.20-
1.43 (2H, m), 1.94 (1H, dq, J =
10.6, 6.7 Hz), 2.32 (1H, m),
2.57 (3H, d, J = 4.6Hz), 2.96 (1
H, dd, J = 13.8, 10.5 Hz), 3.07
(1H, dd, J = 13.8, 4.8Hz), 4.75
1H, ddd, J = 10.5, 8.4, 4.8H
z), 7.18 (1H, dd, J = 7.7, 4.9H)
z), 7.29 (1H, d, J = 7.7 Hz), 7.6
0-7.75 (2H, m), 8.25 (1H, d, J
= 8.4 Hz), 8.45 (1H, br d, J =
4.9 Hz), 8.72 (1 H, s), 10.38 (1
H, s)

Example 3-2) The following compound is obtained in substantially the same manner as in Example 3-1). [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (2-acetamidoethyl) amide (11.5 g) Melting point: 225-239 ° C ( dec.) [α] ²⁷ _D = + 14.2 ° (C 0.19, methanol) NMR (CD ₃ OD, δ): 0.62 (3H, d, J =
6.5Hz), 0.82 (3H, d, J = 5.5H
z), 0.88 (3H, d, J = 5.5Hz), 0.
97 (1H, m), 1.38 (1H, m), 1.46
(1H, m), 1.93 (3H, s), 2.07 (1
H, m), 2.45 (1H, m), 3.13 (2H,
dd, J = 14.5, 9.5 Hz), 3.24 (4H,
m), 4.80 (1H, t, J = 5.0Hz), 7.2
6 (1H, ddd, J = 9.0, 9.0, 1.5H
z), 7.38 (1H, d, J = 9.0 Hz), 7.7
5 (1H, ddd, J = 9.0, 9.0, 1.5H
z), 8.48 (1H, dd, J = 9.0Hz)

Example 3-3) The following compounds are obtained in substantially the same manner as in Example 3-1). [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (2-hydroxyethyl) amide (0.156g) Melting point: 218-221 ° C α] ²⁷ _D = + 5.7 ° (C 0.105, methanol) NMR (CD ₃ OD, δ): 0.60 (3H, d, J =
6 Hz), 0.82 (3H, d, J = 6 Hz), 0.
88 (3H, d, J = 6Hz), 0.98 (1H,
m), 1.40 (1H, m), 1.47 (1H, m),
2.07 (1H, m), 2.46 (1H, ddd, J
= 10, 10, 3 Hz), 3.13 (1H, dd, J =
10, 9.5 Hz), 3.23 (1H, dd, J = 9.
5,6Hz), 3.28 (2H, t, J = 6.5H
z), 3.54 (2H, t, J = 6.5Hz), 4.8
7 (1H, m), 7.25 (1H, ddd, J = 7.
5, 6, 1.5 Hz), 7.38 (1H, d, J = 7.
5 Hz), 7.74 (1H, ddd, J = 7.5,
6, 1.5 Hz), 8.47 (1H, dd, J = 6
1.5 Hz)

Example 4-1) DMF of [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (10.0 g)
To a (300 ml) solution is added potassium carbonate (3.9 g), chloromethyl pivalate (25.6 g) and tetrabutylammonium iodide (1.0 g). The mixture is stirred at room temperature for 5.5 hours. The mixture was saturated brine (500 m
1) and extract with ethyl acetate (400 ml x 2). The extract is washed with saturated brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (eluent: 0 to 3% in ethyl acetate).
Methanol) and then [(2R, 3S) -4- [N
-Pivaloyloxy-N- (pivaloyloxymethyl)
Amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (9.0
g) is obtained. Melting point: 180-184 ° C Mass spectrum (FB ⁺ ): 563.4 (M ⁺ + H) [α] ²⁰ _D = -8.9 ° (C1.00, chloroform) NMR (CDCl ₃ , δ): 0.76 -1.76 (6
H, m), 0.84 (3H, d, J = 6.4 Hz),
0.90 (3H, d, J = 6.4Hz), 1.20
(9H, s), 1.31 (9H, s), 2.48-2.
80 (2H, m), 2.74 (3H, d, J = 4.7)
Hz), 3.18 (1H, dd, J = 14.9, 5.7)
Hz), 3.29 (1H, dd, J = 14.9, 5.6)
Hz), 4.79 (1H, ddd, J = 7.0, 5.
7, 5.6 Hz), 5.63 (1H, d, J = 1
2.2Hz), 5.68 (1H, d, J = 12.2H
z), 7.03-7.20 (1H, br), 7.16.
(1H, dd, J = 7.6, 5.0 Hz), 7.26
(1H, d, J = 7.7 Hz), 7.62 (1H, d
dd, J = 7.7, 7.6, 1.8 Hz), 7.84
(1H, d, J = 7.0 Hz), 8.48 (1H, d
d, J = 5.0, 1.8 Hz)

Example 4-2 ) The following compounds are obtained in substantially the same manner as in Example 4-1). [(2R, 3S) -4- [N-pivaloyloxy-N-
(Pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (2-acetamidoethyl) amide (0.1 g) Melting point: 123-124 ° C [α] ²⁷ _D = + 11.3 ° (C 0.16, methanol) NMR (CD ₃ OD, δ): 0.58 (3H, m),
0.71 (1H, m), 0.79 (3H, d, J = 6H
z), 0.87 (3H, d, J = 6Hz), 1.30
-1.60 (2H, m), 1.92 (3H, s), 2.
55 (2H, m), 3.11 (2H, m), 3.24
(4H, m), 4.83 (1H, m), 5.65 (2
H, m), 7.25 (1H, ddd, J = 7.5, 6,
1.5 Hz), 7.87 (1H, ddd, J = 7.
5,6,1.5Hz), 8.47 (1H, dd, J =
6,1.5Hz)

Example 5 [(2R, 3S) -4- (benzyloxyamino) -2]
To a solution of -isobutyl-3-methylsuccinyl] -L-2-pyridylalanine methyl ester (1.0g) in methanol (7ml) is added 1N NaOH (7ml). The solution was stirred at room temperature for 0.5 h, then 1N HCl (7
ml). After evaporating the solvent under reduced pressure, the residue is poured into isopropyl alcohol (20 ml) and then filtered off. The combined filtrate is concentrated to give [(2R, 3S) -4- (benzyloxyamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine (0.97 g) as a white solid. NMR (CD ₃ OD, δ): 0.57 (3H, d, J =
6.5Hz), 0.80 (3H, d, J = 6.0H
z), 0.85 (3H, d, J = 6.0 Hz), 0.
89 (1H, m), 1.36-1.53 (2H, m),
2.00 (1H, m), 2.44 (1H, ddd, J
= 11.2, 11.2, 1.5 Hz), 3.14 (1
H, dd, J = 15.0, 10.0 Hz), 3.43
(1H, dd, J = 15.0, 5.0Hz), 4.9
4 (1H, dd, J = 10.0, 5.0 Hz), 7.
26 (1H, ddd, J = 9.0, 6.0, 1.5H
z), 7.32-7.43 (6H, m), 7.74 (1
H, ddd, J = 9.0, 9.0, 1.5 Hz), 8.
44 (1H, dd, J = 9.0, 1.5Hz)

Example 6-1) DMF of [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (0.3 g)
(6 ml) solution, acetic anhydride (0.08 ml) and N, N
-Diisopropyl-N-ethylamine (0.15 ml)
Is added at room temperature. The solution is stirred for 0.5 hours. This solution is poured into ethyl acetate and saturated saline, and the extracted organic layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, the residue was triturated with diethyl ether,
[(2R, 3S) -4- (acetoxyamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (167.7 mg) is obtained as a white powder. Melting point: 191-192 ° C. [α] ²⁰ _D = + 5.0 ° (C 0.12, methanol) NMR (CD ₃ OD, δ): 0.67 (3H, d, J =
6 Hz), 0.81 (3H, d, J = 6 Hz), 0.
87 (3H, d, J = 6Hz), 1.16 (1H, d
dd, J = 12, 9, 1.5 Hz), 1.39 (1H,
m), 1.51 (1H, ddd, J = 12, 9, 1.5
Hz), 2.15 (3H, s), 2.24 (1H, q
d, J = 6, 1.5 Hz), 2.48 (1H, ddd,
J = 9,6,1.5 Hz), 2.70 (3H, s),
3.10 (1H, dd, J = 12, 9Hz), 3.22
(1H, dd, J = 12.6Hz), 4.84 (1
H, dd, J = 9,6 Hz), 7.26 (1H, dd
d, J = 7.5, 6, 1.5 Hz), 7.37 (1
H, dd, J = 7.5, 1.5 Hz), 7.74 (1
H, ddd, J = 7.5, 6, 1.5 Hz), 8.48
(1H, dd, J = 6, 1.5Hz)

Example 6-2 ) [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (60 mg) was used in Example 6
-(2R, 3S) -4- (pivaloyloxyamino) -2-isobutyl-3-methylsuccinyl] -L- by reacting with pivalic anhydride in substantially the same manner as in 1)).
2-pyridylalanine-N-methylamide (56.5m
g) is obtained as a white powder. Melting point: 189-192 ° C. [α] ²⁷ _D = + 3.8 ° (C0.105, methanol) NMR (CD ₃ OD, δ): 0.66 (3H, d, J =
6 Hz), 0.83 (3H, d, J = 6 Hz), 0.
87 (3H, d, J = 6Hz), 1.18 (1H, d
dd, J = 12, 9, 1.5 Hz), 1.28 (3H,
s), 1.38 (1H, m), 1.51 (1H, dd
d, J = 12, 9, 1.5 Hz), 2.23 (1H,
qd, J = 6, 1.5 Hz), 2.47 (1H, dd
d, J = 9, 6, 1.5 Hz), 2.70 (3H,
s), 3.10 (1H, dd, J = 12, 9Hz),
3.21 (1H, dd, J = 12, 6Hz), 4.84
(1H, dd, J = 9, 6Hz), 7.26 (1H,
ddd, J = 7.5, 6, 1.5 Hz), 7.37
(1H, dd, J = 7.5, 1.5Hz), 7.74
(1H, ddd, J = 7.5, 6, 1.5 Hz), 8.
48 (1H, dd, J = 6, 1.5Hz)

Example 6-3 ) [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (0.1 g) was added to Example 6-3.
-(2R, 3S) -4- (benzoyloxyamino) -2-isobutyl-3-methylsuccinyl] -L- by reacting with benzoic anhydride in substantially the same manner as in 1)).
2-pyridylalanine-N-methylamide (18.9m
g) is obtained as a pale yellow powder. Melting point: 173-176 ° C [α] ²⁷ _D = -3.0 ° (C0.10, methanol) NMR (CD ₃ OD, δ): 0.72 (3H, d, J =
6 Hz), 0.85 (3H, d, J = 6 Hz), 0.
90 (3H, d, J = 6Hz), 1.27 (1H, dd
d, J = 12, 9, 1.5 Hz), 1.42 (1H,
m), 1.58 (1H, ddd, J = 12, 9, 1.5
Hz), 2.35 (1H, qd, J = 6, 1.5H
z), 2.53 (1H, ddd, J = 9, 6, 1.5H
z), 2.70 (3H, s), 3.11 (1H, dd,
J = 12.9 Hz, 3.22 (1H, dd, J = 1)
2,6Hz), 4.85 (1H, dd, J = 9, 6H
z), 7.27 (1H, ddd, J = 7.5, 6, 1.
5 Hz), 7.38 (1H, dd, J = 7.5, 1.5
Hz), 7.49-7.56 (2H, m), 7.64
-7.78 (2H, m), 8.04-8. 11 (2H,
m), 8.48 (1H, dd, J = 6, 1.5Hz)

Example 6-4 ) [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (2-acetamidoethyl) amide (0. 1 g) in DMF (8 ml), chloromethyl pivalate (0.033 ml) and triethylamine (0.
032 ml) and tetrabutylammonium iodide (0.
01 g) is added. The reaction mixture is stirred at 50 ° C. for 3 hours. Pour the mixture into ethyl acetate and saturated brine. The extracted organic layer is dried over magnesium sulfate and the solvent is distilled off.
The residue was purified by silica gel chromatography (eluent: chloroform / methanol = 10: 1), triturated with ethyl acetate-diethyl ether, and [(2R, 3S) -4- (N-pivaloyloxyamino)- 2-isobutyl-3-methyl-succinyl] -L-2-pyridylalanine-N- (2-acetamidoethyl) amide (20 m
g) is obtained as a white powder. Melting point: 164-167 ° C. [α] ²⁷ _D = + 7.6 ° (C0.105, methanol) NMR (CD ₃ OD, δ): 0.68 (3H, d, J =
6 Hz), 0.82 (3H, d, J = 6 Hz), 0.
88 (3H, d, J = 6Hz), 1.23 (1H,
m), 1.29 (3H, s), 1.40 (1H, m),
1.54 (1H, m), 1.93 (3H, s), 2.
25 (1H, m), 2.48 (1H, m), 3.10
(2H, m), 3.23 (2H, m), 3.25 (4
H, m), 4.80 (1H, m), 7.26 (1H, d
dd, J = 7.5, 6, 1.5 Hz), 7.38 (1
H, d, J = 7.5 Hz), 7.74 (1H, dd
d, J = 7.55, 6, 1.5 Hz), 8.48 (1
H, dd, J = 6,1.5Hz)

Example 7 [(2R, 3S) -4- [N-pivaloyloxy-N-]
(Pivaloyloxymethyl) -amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (N, N-dimethylcarbamoyloxy) ethyl] amide (24 mg) was used in Example 4- Obtained in substantially the same manner as 1). Melting point: 58-61 ° C NMR (CDCl ₃ , δ): 0.83 (3H, d, J =
6Hz), 0.90 (6H, d, J = 6Hz), 1.
06 (1H, m), 1.19 (9H, s), 1.30
(9H, s), 1.32 (1H, m), 1.38 (1
H, m), 2.52 (2H, m), 2.82 (3H,
s), 2.88 (3H, s), 3.16 (1H,
m), 3.27 (1H, m), 3.45 (2H, m),
4.03 (2H, m), 4.80 (1H, m), 5.
65 (2H, m), 7.16 (1H, m), 7.27
(1H, d, J = 7.5 Hz), 7.52 (1H, b
rs), 7.62 (1H, m), 7.84 (1H, d,
J = 7.5 Hz), 8.47 (1H, m)

Example 8 [(2R, 3S) -4- (N-benzyloxyamino)]
-2-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [1- (ethoxycarbonyl)
Yield 8% piperidin-4-yl] amide (563 mg)
It is obtained as a pale red powder in substantially the same manner as in Example 2-2) at 3.1%. Melting point: 224-228 ° C. [α] ²⁰ _D = + 9.3 ° (C0.52, methanol) NMR (DMSO-d6, δ): 0.40 (3H, d,
J = 6.6 Hz), 0.71 (3H, d, J = 6.5)
Hz), 0.76-0.86 (4H, m), 1.10.
-1.40 (4H, m), 1.17 (3H, t, J =
7.1 Hz), 1.59-1.74 (2H, m),
1.91 (1H, m), 2.32 (1H, m), 2.
82-3.03 (3H, m), 3.08 (1H, dd,
J = 13.6, 4.8 Hz), 3.61-3.90 (3
H, m), 4.02 (2H, q, J = 7.1 Hz),
4.69-4.82 (1H, m), 4.74 (2H,
s), 7.18 (1H, m), 7.28 (1H, d, J
= 7.7 Hz), 7.36 (5H, s), 7.61-
7.71 (2H, m), 8.29 (1H, d, J =
8.4 Hz), 8.45 (1H, d, J = 4.8H
z), 11.00 (1H, s)

Example 9 [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [1- (ethoxycarbonyl) piperidin-4-yl] amide ( 346 mg) yield 77.7
% To give a white powder essentially as in Example 3-1). Melting point: 208-209 ° C. [α] ²⁰ _D = + 18.3 ° (C 0.40, methanol) NMR (DMSO-d6, δ): 0.39 (3H, d,
J = 6.7 Hz), 0.73 (3H, d, J = 6.5)
Hz), 0.77-0.92 (4H, m), 1.10.
-1.43 (7H, m), 1.58-1.74 (2H,
m), 1.95 (1H, dq, J = 10.4, 6.7H
z), 2.33 (1H, m), 2.80-3.03 (3
H, m), 3.09 (1H, dd, J = 13.8, 4.
8 Hz), 3.63-3.89 (3H, m), 4.02
(2H, q, J = 7.0Hz), 4.77 (1H,
m), 7.18 (1H, dd, J = 7.6, 4.9H
z), 7.29 (1H, d, J = 7.7 Hz), 7.6
1-7.73 (2H, m), 8.28 (1H, d, J =
8.7 Hz), 8.45 (1H, d, J = 4.9H
z), 8.73 (1H, brs), 10.39 (1H,
br s)

Example 10 [(2R, 3S) -4- [N-pivaloyloxy-N-
(Pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [1- (ethoxycarbonyl) piperidin-4-yl] amide (346 mg) with a yield of 77.7%. A white powder is obtained in substantially the same manner as in Example 4-1). Melting point: 107-109 ° C. [α] ²⁰ _D = -8.4 ° (C 0.49, chloroform) NMR (CDCl ₃ , δ): 0.84 (3H, d, J =
6.4 Hz), 0.88-0.99 (4H, m), 1.
01-1.88 (9H, m), 1.20 (9H, m
s), 1.25 (3H, t, J = 7.1Hz), 1.3
2 (3H, s), 2.52-2.75 (2H, m),
2.83-3.00 (2H, m), 3.15 (1H,
dd, J = 14.9, 5.4 Hz), 3.30 (1H,
dd, J = 14.9, 5.4 Hz), 3.75-4.
04 (3H, m), 4.11 (2H, q, J = 7.1H
z), 4.77 (1H, ddd, J = 6.0, 5.
4, 5.4 Hz), 5.64 (1H, d, J = 12.0
Hz), 5.68 (1H, d, J = 12.0Hz),
7.10-7.22 (2H, m), 7.25 (1H,
d, J = 7.7 Hz), 7.64 (1H, ddd, J =
7.7, 7.7, 1.8 Hz), 7.93 (1H, br
s), 8.48 (1H, brd, J = 4.8Hz)

Example 11-1 ) The following compound is obtained in substantially the same manner as in Example 2-2). [(2R, 3S) -4- (benzyloxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (3,3-dimethylureido) ethyl] amide (1.2 g) NMR (CD ₃ OD, δ): 0.62 (3H, d, J =
6.5Hz), 0.80 (3H, d, J = 6.0H
z), 0.86 (3H, d, J = 6.0Hz), 0.
90 (1H, m), 1.33 to 1.47 (2H, m),
2.03 (1H, m), 2.46 (1H, m), 2.
87 (6H, s), 3.10 (1H, dd, J = 1
5.0, 10.0 Hz), 3.16-3.27 (5H,
m), 4.82 (1H, dd, J = 10.0, 5.0
Hz), 7.25 (1H, ddd, J = 9.0, 9.
0, 1.5 Hz), 7.32-7.42 (7H,
m), 7.72 (1H, dd, J = 9.0, 9.0H
z), 8.46 (1H, dd, J = 9.0, 1.5H
z)

Example 11-2 ) The following compound is obtained in substantially the same manner as in Example 2-2). [(2R, 3S) -4- (benzyloxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (morpholinocarbonylamino) ethyl] amide (459 mg) Melting point: 201-205 ° C [α] ²⁰ _D = + 7.3 ° (C 0. 52, methanol) NMR (DMSO-d6, δ): 0.41 (3H, d,
J = 6.8 Hz), 0.72 (3H, d, J = 6.5)
Hz), 0.75-0.85 (4H, m), 1.20
−1.38 (2H, m), 1.92 (1H, dq, J =
10.3, 6.8 Hz), 2.33 (1H, m),
2.92-3.17 (6H, m), 3.18-3.2
9 (4H, m), 3.48-3.56 (4H, m),
4.72 (1H, m), 4.74 (2H, s), 6.5
8 (1H, brs), 7.19 (1H, dd, J =
7.6, 4.8 Hz), 7.29 (1H, d, J = 7.
7 Hz), 7.36 (5 H, s), 7.67 (1 H, d
dd, J = 7.7, 7.6, 1.8 Hz), 7.86
(1H, brs), 8.29 (1H, d, J = 8.3H
z), 8.45 (1H, dd, J = 4.8, 1.8H
z)

Example 11-3 ) The following compounds are obtained in substantially the same manner as in Example 2-2). [(2R, 3S) -4- (benzyloxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (N-methyl-N-morpholinocarbonylamino) ethyl] amide (0.5 g) NMR (CDCl ₃ , δ): 0.82 (3H , D, J =
6 Hz), 0.86 (3H, d, J = 6 Hz), 0.
98 (3H, d, J = 6Hz), 1.21 (1H,
m), 1.43 (1H, m), 1.56 (1H, m),
2.34 (1H, m), 2.50 (1H, m), 2.
85 (3H, s), 3.13-3.32 (8H, m),
3.42 (1H, m), 3.60-3.71 (4H,
m), 4.86 (1H, m), 4.91 (2H, s),
7.13 (1H, dd, J = 7.5, 1.5Hz),
7.20 (1H, dd, J = 7.5, 1.5Hz),
7.29-7.44 (5H, m), 7.58 (2H, d
dd, J = 7.5, 7.5, 1.5 Hz), 7.74
(1H, brs), 8.45 (1H, dd, J = 7.
5,1.5Hz), 9.50 (1H, s)

Example 11-4 ) The following compound is obtained in substantially the same manner as in Example 2-2). [(2R, 3S) -4- (benzyloxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (hexamethyleneiminocarbonylamino) ethylamide (0.39 g) NMR (CD ₃ OD-CDCl ₃ (1: 1), δ): 0 ．
61 (3H, d, J = 6Hz), 0.82 (3H, d,
J = 6Hz), 0.87 (3H, d, J = 6Hz),
0.98 (1H, m), 1.38 (1H, m), 1.4
9 (1H, m), 1.52-1.78 (12H,
m), 2.01 (1H, m), 2.41 (1H,
m), 3.13 (1H, m), 3.22 (1H, m),
3.28-3.41 (4H, m), 4.80 (1H,
m), 4.85 (2H, s), 6.15 (1H, br
s), 7.24 (1H, dd, J = 9.5, 6Hz),
7.32-7.44 (7H, m), 7.71 (1H, d
d, J = 9.5, 1.5 Hz), 8.47 (1H, d
d, J = 6,1.5Hz)

Example 11-5 ) The following compounds are obtained in substantially the same manner as in Example 2-2). [(2R, 3S) -4- (benzyloxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- [3- (p-trifluoromethyl) phenylureido] ethyl] amide (0.5 g) TLC: Rf 0.30 (chloroform: methanol =
10: 1) NMR (CD ₃ OD, δ): 0.39 (3H, d, J =
6.5 Hz), 0.70 (3H, d, J = 6.0H
z), 0.78 (3H, d, J = 6.0 Hz), 0.
80 (1H, m), 1.24-1.36 (2H, m),
1.92 (1H, m), 2.33 (1H, m), 2.
91-3.25 (6H, m), 4.76 (1H,
m), 7.16 (1H, ddd, J = 9.0, 9.0)
1.5 Hz), 7.27 (1H, dd, J = 9.0,
1.5 Hz), 7.34 (5 H, s), 7.52-
7.68 (5H, m), 8.43 (1H, dd, J =
9.0, 1.5Hz)

Example 12-1 ) The following compound is obtained in substantially the same manner as in Example 3-1). [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (3,3-dimethylureido)
Ethyl] amide (0.17 g) Melting point: 200-203 ° C NMR (DMSO-d6, δ): 0.42 (3H, d,
J = 6.5 Hz), 0.73 (3H, d, J = 6.5)
Hz), 0.79 (3H, d, J = 6.5Hz), 0.
86 (1H, m), 1.32 (2H, m), 1.96
(1H, m), 2.34 (1H, m), 2.76 (6
H, s), 2.96-3.12 (6H, m), 4.7.
3 (1H, m), 6.30 (1H, m), 7.18
(1H, m), 7.30 (1H, d, J = 7.5H
z), 7.67 (1H, m), 7.83 (1H,
m), 8.26 (1H, m), 8.45 (1H,
m), 8.72 (1H, m)

Example 12-2) The following compound is obtained in substantially the same manner as in Example 3-1). [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (morpholinocarbonylamino) ethyl] amide (250 mg) Melting point: 196-202 C [α] ²⁰ _D = + 11.7 ° (C 0.50, methanol) NMR (DMSO-d6, δ): 0.42 (3H, d,
J = 6.6 Hz), 0.73 (3H, d, J = 6.
5Hz), 0.77-0.93 (4H, m), 1.2
1-1.43 (2H, m), 1.95 (1H, dd, J
= 10.1, 6.6 Hz), 2.34 (1 H, m),
2.90-3.17 (6H, m), 3.18-3.2
9 (4H, m), 3.44-3.64 (4H, m),
4.74 (1H, m), 6.56 (1H, brs),
7.19 (1H, dd, J = 7.2, 4.7 Hz),
7.29 (1H, d, J = 7.7 Hz), 7.67
(1H, dd, J = 7.7, 7.2Hz), 7.83
(1H, brs), 8.26 (1H, d, J = 7.9H
z), 8.45 (1H, brd, J = 4.7Hz),
8.72 (1H, s), 10.34 (1H, s)

Example 12-3 ) The following compound is obtained in substantially the same manner as in Example 3-1). [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (N-methyl-N-morpholinocarbonylamino) ethyl] amide (0. 12 g) Melting point: 195-198 ° C. [α] ²⁷ _D = + 10.0 ° (C0.12, methanol) NMR (DMSO-d6, δ): 0.38 (3H, d,
J = 6.5 Hz), 0.73 (3H, d, J = 6.5)
Hz), 0.79 (3H, d, J = 6.5Hz), 0.
85 (1H, m), 1.32 (2H, m), 1.93
(1H, m), 2.32 (1H, m), 2.75 (3
H, s), 2.97 (2H, m), 3.04 (4H,
m), 3.15 (4H, m), 3.56 (4H,
m), 4.75 (1H, m), 7.18 (1H, dd,
J = 5.0, 8.5 Hz), 7.30 (1H, d, J =
8.5 Hz), 7.68 (1H, ddd, J = 8.
5,8.5,1.5Hz), 7.88 (1H, m),
8.24 (1H, d, J = 8.5Hz), 8.45 (1
H, m), 8.71 (1H, s)

Example 12-4) The following compounds are obtained in substantially the same manner as in Example 3-1). [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (hexamethyleneiminocarbonylamino) ethyl] amide (0.13 g) Melting point _{^{: 209-212 ℃ [α] 27 D}} = + 13.3 ° (C0.21, _{methanol) NMR (CD 3 OD-CDCl} 3 (1: 1), δ): 0.
67 (3H, d, J = 6Hz), 0.82 (3H, d,
J = 6Hz), 0.88 (3H, d, J = 6Hz),
1.03 (1H, m), 1.36 (1H, m), 1.4
9 (1H, m), 1.53-1.72 (12H,
m), 2.10 (1H, m), 2.45 (1H,
m), 3.13 (1H, m), 3.25 (1H, m),
3.28-3.45 (4H, m), 4.82 (1H,
m), 6.22 (1H, brs), 7.14 (1H, d
d, J = 9.5, 6 Hz), 7.35 (1H, d, J =
9.5 Hz), 7.66 (1 H, s), 7.71 (1
H, dd, J = 9.5, 1.5 Hz), 8.47 (1
H, dd, J = 6,1.5Hz)

Example 12-5 ) The following compounds are obtained in substantially the same manner as in Example 3-1). [(2R, 3S) -4- (Benzyloxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- [3- (p-trifluoromethyl) phenylureido] ethyl] Amide (0.25
g) Melting point: 224-226 ° C NMR (DMSO-d6, δ): 0.41 (3H, d,
J = 6.5 Hz), 0.73 (3H, d, J = 6.5)
Hz), 0.80 (3H, d, J = 6.5Hz), 0.
85 (1H, m), 1.33 (2H, m), 1.96
(1H, m), 2.34 (1H, m), 3.01 (2
H, m), 3.08-3.20 (4H, m), 4.7
8 (1H, m), 6.33 (1H, brs), 7.18
(1H, dd, J = 5, 7.5 Hz), 7.28 (1
H, d, J = 7.5 Hz), 7.52-7.71 (5
H, m), 7.90 (1H, brs), 8.25 (1
H, d, J = 7.5 Hz), 8.46 (1 H, m),
8.73 (1H, s), 9.01 (1H, s)

Example 13-1 ) The following compound is obtained in substantially the same manner as in Example 4-1). [(2R, 3S) -4- [N-pivaloyloxy-N-
(Pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (3,3-dimethylureido) ethyl] amide (106.8 mg) Melting point: 100- 103 ° C. [α] ²⁷ _D = + 9.4 ° (C0.16, methanol) NMR (CD ₃ OD, δ): 0.60 (1H, m),
0.74 (1H, m), 0.80 (3H, d, J = 6H
z), 0.88 (3H, d, J = 6Hz), 1.12.
(3H, d, J = 6Hz), 1.17 (9H, s),
1.28 (9H, s), 1.41 (1H, m), 2.
57 (1H, m), 2.88 (6H, s), 3.11
(1H, m), 3.17-3.33 (6H, m),
4.84 (1H, m), 5.68 (2H, m), 7.2
6 (1H, m), 7.36 (1H, d, J = 7.5H
z), 7.75 (1H, m), 8.47 (1H, m)

Example 13-2) The following compound is obtained in substantially the same manner as in Example 4-1). [(2R, 3S) -4- [N-pivaloyloxy-N-
(Pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (morpholinocarbonylamino) ethyl]
Amide (148 mg) Melting point: 92-94 ° C. [α] ²⁰ _D = -9.1 ° (C 0.50, chloroform) NMR (CDCl ₃ , δ): 0.84 (3H, d, J =
6.6 Hz), 0.89 (3H, d, J = 6.5H
z), 0.95 (1H, m), 1.01-1.65 (5
H, m), 1.20 (9H, s), 1.31 (9H,
s), 2.52-2.73 (2H, m), 3.14-
3.41 (10H, m), 3.59-3.70 (4H,
m), 4.74 (1H, m), 5.57-5.73 (3
H, m), 7.19 (1H, dd, J = 7.6, 5.
0Hz), 7.23 (1H, d, J = 7.7Hz),
7.26 (1H, brs), 7.64 (1H, ddd,
J = 7.7, 7.6, 1.7 Hz), 7.81 (1H,
brd, J = 4.9 Hz), 8.48 (1H, br
d, J = 5.0Hz)

Example 14 [(2R, 3S) -4- (N-hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (3,3-dimethylureido)] Ethyl] amide (100 g) was reacted with chloromethyl propionate substantially as in Example 4-1) to give [(2R, 3S) -4- [N-propionyloxy-N- (propionyloxymethyl)]. Amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (3,3-dimethylureido) ethyl] amide (20.7 mg) is obtained. Melting point: 45-48 ° C NMR (CD ₃ OD, δ): 0.82 (3H, d, J =
6 Hz), 0.85 (3H, d, J = 6 Hz), 0.
89 (3H, d, J = 6Hz), 0.94 (1H,
m), 1.13 (3H, t, J = 6Hz), 1.23
(3H, t, J = 6Hz), 1.37 (1H, m),
1.45 (1H, m), 2.35 (2H, q, J = 6
Hz), 2.50 (2H, q, J = 6Hz), 2.60
(1H, m), 2.84 (6H, s), 3.12-
3.39 (7H, m), 4.76 (1H, m), 5.
15 (2H, m), 7.18 (1H, m), 7.24
(1H, d, J = 7.5 Hz), 7.43 (1H, br
s), 7.53 (1H, m), 7.74 (1H,
m), 8.48 (1H, m)

Example 15 [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (trans-4-hydroxycyclohexyl) amide (505 mg) was obtained in a yield of 84.9% in substantially the same light red color as in Example 2-2). Obtained as a powder. Melting point: 220-224 ° C [α] ²⁰ _D = -2.5 ° (C0.53, methanol) NMR (DMSO-d6, δ): 0.37 (3H, d,
J = 6.6 Hz), 0.65-0.85 (7H,
m), 1.00-1.37 (6H, m), 1.60-
1.83 (4H, m), 1.90 (1H, dq, J = 1
0.3, 6.6 Hz), 2.31 (1H, m), 2.9
3 (1H, dd, J = 13.7, 10.6Hz),
3.07 (1H, dd, J = 13.7, 4.6Hz),
3.24-3.52 (2H, m), 4.53 (1H,
d, J = 4.3 Hz), 4.66-4.80 (1H,
m), 4.74 (2H, s), 7.17 (1H, d
d, J = 7.7, 4.8 Hz), 7.28 (1H, d,
J = 7.7 Hz), 7.36 (5H, s), 7.41
(1H, d, J = 7.7 Hz), 7.66 (1H, d
dd, J = 7.7, 7.7, 1.7 Hz), 8.29
(1H, d, J = 8.5 Hz), 8.44 (1H, b
rd, J = 4.8 Hz), 11.00 (1H, s)

Example 16 [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (trans-4-hydroxycyclohexyl) amide (292 mg) was collected. A white powder is obtained in substantially the same manner as in Example 3-1) at a rate of 73.6%. Melting point: 220-223 ° C. [α] ²⁴ _D = -16.0 ° (C0.25, DMSO) NMR (DMSO-d6, δ): 0.38 (3H, d,
J = 6.6 Hz), 0.74 (3H, d, J = 6.2)
Hz), 0.77-0.93 (4H, m), 0.98
-1.45 (6H, m), 1.58-1.86 (4H,
m), 1.94 (1H, dq, J = 10.4, 6.6H
z), 2.32 (1H, m), 2.94 (1H, dd,
J = 13.87, 10.5 Hz), 3.08 (1H, d
d, J = 13.8, 4.6 Hz), 3.18-3.53.
(2H, m), 4.54 (1H, d, J = 4.3H
z), 4.74 (1H, ddd, J = 10.5, 8.
4, 4.6 Hz), 7.18 (1H, dd, J = 7.
6,4.9 Hz), 7.28 (1H, d, J = 7.8)
Hz), 7.40 (1H, d, J = 7.7 Hz), 7.
66 (1H, ddd, J = 7.7, 7.6, 1.7H
z), 8.27 (1H, d, J = 8.4 Hz), 8.4
5 (1H, brd, J = 4.9 Hz), 8.73 (1
H, s), 10.39 (1H, s)

Example 17 [(2R, 3S) -4- [N-pivaloyloxy-N-
(Pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (trans-4-hydroxycyclohexyl) amide (139 mg) in Example 4 with a yield of 56.7%. 1)
In substantially the same manner as to obtain a white powder. Melting point: 124-125 ° C. [α] ²⁰ _D = -13.5 ° (C 0.53, chloroform) NMR (CDCl ₃ , δ): 0.85 (3H, d, J =
6.4 Hz), 0.87-1.47 (13H, m),
1.20 (9H, s), 1.31 (9H, s), 1.7
2-1.98 (2H, m), 2.51-2.76 (2
H, m), 3.14 (1H, dd, J = 14.8, 6.
0 Hz), 3.29 (1H, dd, J = 14.8, 5.
8 Hz), 3.50-3.72 (2H, m), 4.77
(1H, m), 5.57-5.72 (2H, m),
6.84 (1H, br s), 7.16 (1H, dd,
J = 7.6, 3.9 Hz), 7.24 (1H, d, J
= 7.7 Hz), 7.63 (1H, ddd, J = 7.
7, 7.6, 1.7 Hz), 7.92 (1 H, m),
8.47 (1H, brd, J = 3.9Hz)

Example 18 [(2R, 3S) -4- (N-benzyloxyamino)]
-2-Isobutyl-3-methylsuccinyl] -L-p-methoxyphenylalanine methyl ester (0.4g)
Is obtained as a white powder in substantially the same manner as in Example 1 with a yield of 24.1%. NMR (CD ₃ OD, δ): 0.58 (3H, d, J =
6.5Hz), 0.82 (3H, d, J = 6.0H
z), 0.88 (3H, d, J = 6.0 Hz), 0.
91 (1H, m), 1.35-1.48 (2H, m),
1.97 (1H, m), 2.45 (1H, m), 2.
85 (1H, dd, J = 15.0, 10.0Hz),
3.16 (1H, dd, J = 15.0, 5.0Hz),
3.68 (3H, s), 3.74 (3H, s), 4.
72 (1H, dd, J = 10.0, 5.0Hz), 6.
82 (2H, d, J = 9.0 Hz), 7.16 (2
H, d, J = 9.0 Hz), 7.31-7.44
(5H, m)

Example 19 [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L-p-methoxyphenylalanine methyl ester (0.5 g) in methanol (10 ml) was added with 1N NaOH (10 m).
1) is added and the solution is stirred at room temperature for 2 hours. Pour this solution into 1N HCl (10 ml). After distilling off the methanol in a vacuum, ethyl acetate is added to the residue. The extracted organic layer is washed with saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give [(2R,
3S) -4- (Benzyloxyamino) -2-isobutyl-3-methylsuccinyl] -L-p-methoxyphenylalanine (0.5 g) is obtained as a white powder. TLC: Rf 0.10 (chloroform: methanol = 10: 1) NMR (CD ₃ OD, δ): 0.55 (3H, d,
J = 6.5 Hz), 0.80 (3H, d, J =
6.0 Hz), 0.87 (3H, d, J = 6.
0Hz), 0.89 (1H, m), 1.35-
1.52 (2H, m), 1.97 (1H,
m), 2.44 (1H, m), 2.83 (1
H, dd, J = 15.0, 10.0 Hz),
3.20 (1H, dd, J = 15.0, 5.0H
z), 3.72 (3H, s), 4.69 (1
H, dd, J = 10.0, 5.0 Hz), 6.8
0 (2H, d, J = 9.0 Hz), 7.17
(2H, d, J = 9.0 Hz), 7.32-7.
44 (5H, m)

Example 20 [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L-p-methoxyphenylalanine (0.5g) in DMF (10m
l) In solution, 2- (3,3-dimethylureido) ethylamine hydrochloride (0.17 g), diphenylphosphoryl azide (0.23 ml) and triethylamine (0.35 g).
ml) is added. The mixture is stirred at room temperature for 15 hours and then poured sequentially into ethyl acetate and saturated aqueous sodium bicarbonate solution. The extracted organic layer is washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2R, 3S) -4- (benzyloxyamino) -2-isobutyl-3-methylsuccinyl] -Lp-methoxyphenylalanine-N- [2- (3,3-dimethyl). Ureido) Ethyl]
The amide (256 mg) is obtained as a white solid. TLC: Rf 0.30 (chloroform: methanol = 10: 1) NMR (CD ₃ OD, δ):
0.54 (3H, d, J = 6.5Hz), 0.8
0 (3H, d, J = 6.0Hz), 0.87
(3H, d, J = 6.0 Hz), 0.90 (1
H, m), 1.28-1.46 (2H, m),
2.02 (1H, m), 2.47 (1H, m
m), 2.82 (1H, dd, J = 15.0,
10.0 Hz), 3.00 (1H, dd, J =
15.0, 7.0 Hz), 3.15-3.25
(4H, m), 3.74 (6H, s), 4.5
6 (1H, dd, J = 10.0, 7.0H
z), 6.80 (2H, d, J = 9.0 Hz),
7.17 (2H, d, J = 9.0Hz),
7.32-7.44 (5H, m)

Example 21 [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -Lp-methoxyphenylalanine-N- [2- (3,3-dimethylureido) ethyl] The amide (0.18g) is obtained as a white powder. Melting point: 260-265 ° C. (dec.) [Α] ²⁷ _D = + 26.7 ° (C 0.12
Methanol) NMR (CD ₃ OD, δ): 0.68 (3H, d,
J = 6Hz), 0.82 (3H, d, J = 6H
z), 0.88 (3H, d, J = 6Hz),
1.01 (1H, m), 1.39 (1H, m
m), 1.50 (1H, m), 2.10 (1
H, m), 2.48 (1H, m), 2.84
(1H, dd, J = 10, 9.5 Hz), 2.
86 (6H, s), 3.01 (1H, dd, J
= 9.5, 6 Hz), 3.14-3.27 (4
H, m), 3.74 (3H, s), 4.57
(1H, dd, J = 10, 6Hz), 6.8
2 (2H, d, J = 9Hz), 7.18 (2
H, d, J = 9 Hz) Example 22 [(2R, 3S) -4- [N-pivaloyloxy-N-
(Pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -Lp-methoxyphenylalanine-N- [2- (3,3-dimethylureido) ethyl] amide (44.7 mg) in a yield of 26 It is obtained as a white powder in substantially the same manner as in Example 4-1) with 0.6%. Melting point: 107-109 ° C. [α] ²⁷ _D = + 19.0 ° (C 0.20,
Methanol) NMR (CD ₃ OD, δ): 0.62 (1H,
m), 0.76 (1H, m), 0.79 (3
H, d, J = 6 Hz), 0.88 (3H, d,
J = 6 Hz), 1.10 (3H, d, J = 6H
z), 1.18 (9H, s), 1.28 (9
H, s), 1.38 (1H, m), 2.60.
(1H, m), 2.82 (1H, m), 2.
87 (6H, s), 3.00 (1H, m),
3.15-3.25 (5H, m), 3.73
(3H, s), 4.58 (1H, m), 5.
67 (2H, m), 6.81 (2H, d,
J = 9 Hz), 7.18 (2H, d, J = 9H
z)

Example 23 [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L-p-methoxyphenylalanine-N-methylamide (0.4g)
Is quantitatively obtained as a white powder in substantially the same manner as in Example 2-1). NMR (CD ₃ OD, δ): 0.53 (3H, d,
J = 6.5 Hz), 0.80 (3H, d, J =
6.0 Hz), 0.87 (3H, d, J = 6.
0Hz), 0.90 (1H, m), 1.30-
1.46 (2H, m), 2.01 (1H,
m), 2.46 (1H, m), 2.67 (3H,
s), 2.82 (1H, dd, J = 15.
0, 10.0 Hz), 3.00 (1H, dd,
J = 15.0, 7.0 Hz), 3.74 (3
H, s), 4.57
(1H, dd, J = 10.0, 7.0Hz),
6.82 (2H, d, J = 9.0Hz), 7.1
7 (2H, d, J = 9.0 Hz), 7.32-
7.44 (5H, m)

Example 24 [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -Lp-methoxyphenylalanine-N-methylamide (0.254
g) is obtained as a white powder with a yield of 78% in substantially the same manner as in Example 3-1). [Α] ²⁷ _D = + 18.0 ° (C 0.10,
Methanol) NMR (DMSO-d6, δ): 0.47
(3H, d, J = 6.5Hz), 0.73 (3
H, d, J = 6.5 Hz), 0.81 (3H,
d, J = 6.5 Hz), 0.85 (3H,
s), 1.30 (2H, m), 1.96 (1
H, m), 2.37 (1H, m), 2.57
(3H, d, J = 5Hz), 2.71 (1H,
dd, J = 10, 15 Hz), 2.87 (1
H, dd, J = 5, 15 Hz), 3.68
(3H, s), 4.46 (1H, m), 6.
80 (2H, d, J = 9 Hz), 7.18 (2
H, d, J = 9 Hz), 7.74 (1H,
m), 8.18 (1H, d, J = 9 Hz) NMR (CD ₃ OD, δ): 0.66 (3H, d,
J = 6Hz), 0.81 (3H, d, J = 6H
z), 0.88 (3H, d, J = 6Hz),
0.98 (1H, m), 1.37 (1H,
m), 1.48 (1H, m), 2.08 (1
H, m), 2.48 (1H, ddd, J = 10,
10, 2.5 Hz), 2.68 (3H,
s), 2.82 (1H, dd, J = 12.5, 1
0 Hz), 3.00 (1H, dd, J = 10,
5Hz), 3.73 (3H, s), 4.59
(1H, dd, J = 10, 5Hz), 6.82
(2H, d, J = 9Hz), 7.18 (2H,
d, J = 9Hz)

Example 25 [(2R, 3S) -4- [N-pivaloyloxy-N-
Yield 32. (pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -Lp-methoxyphenylalanine-N-methylamide (38 mg).
A white powder is obtained in substantially the same manner as in Example 4-1) at 8%. Melting point: 186-188 ° C [α] ²⁷ _D = + 13.8 ° (C 0.16
Methanol) NMR (CDCl ₃ , δ): 0.83 (9
H, m), 0.88-1.12 (3H, m),
1.18 (9H, s), 1.31 (9H, s)
s), 2.46 (1H, m), 2.62 (1
H, m), 2.71 (3H, d, J = 6H
z), 2.96 (1H, m), 3.00 (2)
H, m), 3.77 (3H, s), 4.52
(1H, m), 5.63 (2H, m), 5.
70 (1H, br s), 6.32 (1H, b)
rs), 6.82 (2H, d, J = 9H
z), 7.14 (2H, d, J = 9Hz)

Example 26 [(2R, 3S) -4-Hydroxy-2-isobutyl-3- (2-thienylthiomethyl) succinyl] -L-2
-Pyridylalanine-N-methylamide (0.24g)
HOBT (0.084) in a DMF (5 ml) solution of
g), WSCD (0.1 g), hydroxylamine hydrochloride (0.056 g) and N, N-diisopropyl-N-
Add ethylamine (0.14 ml). The solution is stirred at 0 ° C. for 1 hour and poured into saturated saline solution and ethyl acetate. The extracted organic layer is dried over magnesium sulfate and the solvent is distilled off. The residue was recrystallized from ethanol / water, [(2R,
3S) -4- (hydroxylamino) -2-isobutyl-3- (2-thienylthiomethyl) succinyl] -L-
2-Pyridylalanine-N-methylamide (67 mg)
Is obtained as colorless crystals. Melting point: 215-217 ° C. [α] ²⁷ _D = −96.0 ° (C 0.050,
Methanol) NMR (DMSO-d6, δ): 0.73
(3H, d, J = 6.5Hz), 0.79 (3
H, d, J = 6.5 Hz), 0.86 (1H,
m), 1.27 (1H, m), 1.37 (1
H, m), 1.99 (1H, m), 2.17
(1H, m), 2.39 (2H, m), 2.
54 (3H, d, J = 4.5Hz), 3.00
(2H, m), 4.70 (1H, m), 7.
02 (2H, m), 7.14 (1H, dd,
J = 5.0, 8.5 Hz), 7.28 (1H,
d, J = 8.5 Hz), 7.60 (2H,
m), 7.78 (2H, m), 8.32 (1H,
d, J = 8.5 Hz), 8.38 (1H,
m), 8.94 (1H, s)

Example 27 [(2R, 3S) -4- [N-pivaloyloxy-N-]
(Pivaloyloxymethyl) amino] -2-isobutyl-3- (2-thienylthiomethyl) succinyl] -L-
2-Pyridylalanine-N-methylamide (21 mg)
Is obtained as an oily amorphous substance in substantially the same manner as in Example 4-1) with a yield of 45%. NMR (CDCl ₃ , δ): 0.84 (1
H, d, J = 6 Hz), 1.00 (1H,
m), 1.17-1.30 (9H, m), 1.3
1-1.40 (2H, m), 2.53 (1H,
m), 2.77 (3H, d, J = 6Hz),
2.83 (1H, m), 2.97-3.10 (2
H, m), 3.20-3.36 (2H, m),
4.76 (1H, m), 5.66 (2H,
m), 6.91-7.36 (5H, m), 7.6
0-7.70 (2H, m), 7.78 (1H,
m), 8.50 (1H, m)

Example 28 [(2R, 3S) -4- [N-pivaloyloxy-N-
(Pivaloyloxymethyl) amino] -2-isobutyl-3- (2-thienylthiomethyl) succinyl] -L-phenylalanine-N-methylamide (60.1 mg)
Is obtained as a white powder in substantially the same manner as in Example 4-1) with a yield of 42.5%. Melting point: 170-173 ° C. [α] ²⁷ _D = -42.0 ° (C 0.10,
Methanol) NMR (CDCl ₃ , δ): 0.79 (3
H, d, J = 6 Hz), 0.81 (3H,
d, J = 6 Hz), 1.19 (9H, s),
1.25 (9H, s), 1.39 (1H,
m), 1.61 (1H, m), 2.37 (1
H, m), 2.51 (1H, m), 2.70
(3H, d, J = 6Hz), 2.78-3.14
(4H, m), 4.50 (1H, m), 5.6
8 (1H, m), 6.30 (1H, m),
6.94 (1H, m), 7.06 (1H,
m), 7.16-7.35 (5H, m)

Example 29-1 ) [(2R, 3S) -4- (benzyloxyamino) -2]
-Isobutyl-3-methylsuccinyl] -L- (1-oxy-pyridin-2-yl) alanine-N-methylamide (0.165 g) is obtained as a white powder in substantially the same manner as in Example 30 with a yield of 79.7%. NMR (DMSO-d ₆ , δ): 0.51
(3H, d, J = 6.0 Hz), 0.82 (3
H, d, J = 6.0 Hz), 0.89 (3H,
d, J = 6.0 Hz), 0.92 (1H, m),
1.22-1.38 (2H, m), 1.96
(1H, m), 2.30 (1H, m), 2.
56 (3H, d, J = 1.5Hz), 3.09
-3.15 (2H, m), 4.73 (1H,
m), 7.27-7.40 (6H, m), 7.4
3 (1H, m), 7.60-7.71 (2H,
m), 7.88 (1H, br s), 8.27
(1H, m), 8.48 (1H, d, J = 9.0
Hz)

Example 29-2 ) [(2R, 3S) -4- (hydroxylamino) -2-isobutyl-3-methylsuccinyl] -L- (1-oxy-pyridin-2-yl) alanine-N-methylamide (30.5 mg) Is obtained as a white powder in substantially the same manner as in Example 30 with a yield of 26.9%. Melting point: 238-240 ° C. (dec.) [Α] ²⁷ _D = −22.6 ° (C 0.115,
Methanol) NMR (CD ₃ OD, δ): 0.74 (3H, d,
J = 6Hz), 0.82 (3H, d, J = 6H
z), 0.88 (3H, d, J = 6Hz),
1.02 (1H, m), 1.39 (1H, m
m), 1.48 (1H, m), 2.11 (1
H, m), 2.47 (1H, m), 2.71
(3H, s), 3.32 (2H, m), 4.
95 (1H, m), 7.40-7.57 (3H,
m), 8.34 (1H, dd, J = 6, 1.5
Hz)

Example 30 [(2R, 3S) -4- [N-pivaloyloxy-N-]
(Pivaloyloxymethyl) amino] -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (0.1 g) in chloroform (2 m
l) To the solution, add mCPBA (0.04g). The solution was stirred at room temperature for 0.5 hours and the solution was sequentially saturated with N 2
Wash with a2SO3 aqueous solution and saturated sodium bicarbonate aqueous solution and dry over magnesium sulfate. After removing the solvent in vacuo, the residue was triturated with a mixture of diethyl ether / diisopropyl ether (1: 1) to give [(2R, 3S) -4- [N-pivaloyloxy-N- (pivaloyloxy). Methyl) amino] -2-isobutyl-3-methylsuccinyl] -L- (1-oxy-pyridin-2-yl) alanine-N-methylamide (51.3 mg) was obtained in 49.
Obtained as a white powder at 9%. Melting point: 85-88 ° C [α] ²⁷ _D = -12.6 ° (C 0.135,
Methanol) NMR (CD ₃ OD3, δ): 0.71 (1
H, br s), 0.81 (3H, d, J =
6Hz), 0.89 (3H, d, J = 6H
z), 1.03 (1H, m), 1.12 (3
H, d, J = 6 Hz), 1.17 (9H,
s), 1.28 (9H, s), 1.41 (1
H, m), 2.57 (1H, m), 2.70
(3H, s), 3.34 (1H, m), 4.
92 (1H, m), 5.77 (2H, m),
7.39-7.57 (3H, m), 8.36
(1H, d, J = 6Hz)

Example 31- (1) In the same manner as in Example 1, the following compound is obtained. [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine ethyl ester NMR (DMSO-d ₆ , δ): 0.46 (d, J = 7)
Hz, 3H), 0.65-0.88 (m, 1H), 0.
74 (d, J = 7Hz, 3H), 0.80W (d, J =
7Hz, 3H), 1.14 (t, J = 7Hz, 3H),
1.22-1.51 (m, 2H), 1.93 (dq, J
= 10, 7 Hz, 1H), 2.33 (m, 1H), 3.
03 (dd, J = 14, 10 Hz, 1H), 3.21
(Dd, J = 14.5 Hz, 1H), 4.06 (q, J
= 7 Hz, 2H), 4.75 (s, 2H), 4.81
(M, 1H), 7.20 (dd, J = 7.5, 5 Hz,
1H), 7.30 (d, J = 7.5 Hz, 1H), 7.
37 (s, 5H), 7.70 (ddd, J = 7.5,
7.5, 5 Hz, 1H), 8.40-8.55 (m, 2
H), 11.00 (s, 1H) NMR (CDCl ₃ , δ): 0.82 (d, J = 7H
z, 3H), 0.88 (d, J = 7Hz, 3H), 0.
95 (d, J = 7 Hz, 3H), 1.10 (m, 1
H), 1.15 (t, J = 7 Hz, 3H), 1.43-
1.66 (m, 2H), 2.44 (m, 1H), 2.4
8 (m, 1H), 3.25 (dd, J = 15.5Hz,
1H), 3.32 (dd, J = 15, 5Hz, 1H),
4.11 (q, J = 7Hz, 2H), 4.90 (m, 1
H), 4.91 (s, 2H), 7.06-7.21.
(M, 2H), 7.29-7.45 (m, 5H), 7.
47-7.67 (m, 2H), 8.47 (dd, J =
5,2 Hz, 1H), 9.21 (s, 1H). [Α] _D ²⁴ = -19.1 ° (c0.32, MeO
H) Melting point: 183-186 ° C HPLC: 7.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 470

Example 31- (2) In the same manner as in Example 1, the following compound is obtained. [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine methyl ester NMR (DMSO-d ₆ , δ): 0.45 (d, J = 7)
Hz, 3H), 0.68-0.84 (m, 1H), 0.
72 (d, J = 7 Hz, 3H), 0.77 (d, J = 7
Hz, 3H), 1.22-1.40 (m, 2H), 1.
91 (dq, J = 10, 7 Hz, 1H), 2.32 (d
dd, J = 11, 10, 3 Hz, 1H), 2.88 (d
d, J = 14, 11 Hz, 1H), 3.13 (dd, J
= 14,4 Hz, 1H), 3.61 (s, 3H), 4.
66 (ddd, J = 11,8,4Hz, 1H), 4.7
4 (s, 2H), 7.28 (d, J = 7Hz, 2H),
7.35 (s, 5H), 8.42 (d, J = 7Hz, 2
H), 8.50 (d, J = 8 Hz, 1H), 11.00
(S, 1H). [Α] _D ²⁵ = -10.6 ° (c0.35, MeO
H) Melting point: 199-202 ° C (decomposition) HPLC: 5.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 456

Example 32 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- (3-hydroxy-3-methylbutyl) amide NMR (DMSO-d ₆ , δ): 0.37 (d, J =
6.6 Hz, 3 H), 0.67-0.86 (m, 1
H), 0.73 (d, J = 6.5 Hz, 3H), 0.8
0 (d, J = 6.5 Hz, 3H), 1.07 (s, 6
H), 1.22-1.39 (m, 2H), 1.44
(M, 2H), 1.91 (dq, J = 10.2, 6.6)
Hz, 1H), 2.32 (m, 1H), 2.94 (d
d, J = 13.9, 10.1 Hz, 1H), 3.03-
3.18 (m, 3H), 4.28 (s, 1H), 4.7
4 (m, 1H), 4.74 (s, 2H), 7.18 (d
d, J = 7.6, 5.0 Hz, 1H), 7.29 (d,
J = 7.8 Hz, 1H), 7.36 (s, 5H), 7.
52 (t, J = 5.1 Hz, 1 H), 7.67 (dd
d, J = 7.8, 7.6, 1.7 Hz, 1H), 8.3
0 (d, J = 8.1 Hz, 1H), 8.45 (dd, J
= 5.0, 1.7 Hz, 1H), 11.00 (s, 1
H). [Α] _D ²⁰ = −4.5 ° (c1.00, MeOH) Melting point: 170-172 ° C. HPLC: 4.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 527

Example 33 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- (2-anilinocarbonyloxyethyl) amide NMR (DMSO-d ₆ , δ): 0.38 (d, J =
6.7 Hz, 3 H), 0.66-0.85 (m, 1
H), 0.70 (d, J = 6.5 Hz, 3H), 0.7
9 (d, J = 6.5 Hz, 3H), 1.20-1.37
(M, 2H), 1.91 (dq, J = 10.4, 6.7)
Hz, 1H), 2.33 (m, 1H), 2.98 (d
d, J = 13.8, 10.5 Hz, 1H), 3.11
(Dd, J = 13.8, 4.4 Hz, 1H), 3.34
(M, 2H), 4.04 (m, 2H), 4.74 (s,
2H), 4.79 (m, 5H), 7.35 (s, 5)
H), 7.66 (br-dd, J = 7.7, 7.3, H
z, 1H), 7.96 (t, J = 5.3Hz, 1H),
8.31 (d, J = 8.4 Hz, 1H), 8.45 (b
rd, J = 4.4 Hz, 1H), 9.66 (s, 1)
H), 11.00 (s, 1H). [Α] _D ²⁰ = + 6.0 ° (c0.48, MeOH) Melting point: 210-213 ° C HPLC: 7.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 35: 65, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 604

Example 34 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- [1- (2S-hydroxymethyl) pyrrolidinyl] carbonyloxyethyl] amide NMR (DMSO-d ₆ , δ): 0.37 (d, J = 7)
Hz, 3H), 0.70 (d, J = 7Hz, 3H),
0.75-0.90 (m, 1H), 0.78 (d, J =
7 Hz, 3H), 1.17-1.40 (m, 2H),
1.65-2.01 (m, 5H), 2.33 (m, 1
H), 2.89-3.71 (m, 7H), 3.09 (d
d, J = 14.4 Hz, 1H), 3.71 (m, 1)
H), 3.92 (m, 2H), 4.61-4.86.
(M, 1H), 4.73 (s, 2H), 7.18 (d
d, J = 8, 5 Hz, 1H), 7.29 (d, J = 8H
z, 1H), 7.36 (s, 5H), 7.66 (dd
d, J = 8, 8, 2 Hz, 1H), 7.86 (m, 1
H), 8.32 (br-d, J = 7 Hz, 1H), 8.
45 (br-d, J = 5 Hz, 1H), 11.00
(S, 1H). [Α] _D ²⁷ = -17.4 ° (c0.25, MeO
H) Melting point: 167-172 ° C HPLC: 10.3 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 35: 65, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 612

Example 35 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-[(1-hydroxycyclohexyl) methyl] amide NMR (DMSO-d ₆ , δ): 0.35 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.91 (m, 1H), 0.77 (d, J =
7Hz, 3H), 1.06-1.64 (m, 12H),
1.90 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.96 (dd, J = 14, 10 Hz,
1H), 3.03 (d, J = 6Hz, 2H), 3.14
(Dd, J = 14.5 Hz, 1H), 4.21 (s, 1
H), 4.73 (s, 2H), 4.84 (ddd, J =
10, 8, 5 Hz, 1H), 7.17 (dd, J = 8,
5Hz, 1H), 7.30 (d, J = 8Hz, 1H),
7.34 (s, 5H), 7.41 (t, J = 6Hz, 1
H), 7.66 (ddd, J = 8, 8, 2 Hz, 1
H), 8.36 (d, J = 8Hz, 1H), 8.45
(Br-d, J = 5 Hz, 1H), 11.00 (s, 1
H). [Α] _D ²⁷ = + 3.4 ° (c0.25, MeOH) Melting point: 205-207 ° C HPLC: 9.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 553

Example 36 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (isobutoxycarbonyl) aminoethyl] amide NMR (DMSO-d ₆ , δ): 0.40 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.84 (m, 1H), 0.78 (d, J =
7Hz, 3H), 0.87 (d, J = 7Hz, 6H),
1.21-1.38 (m, 2H), 1.70-1.99
(M, 2H), 2.33 (m, 1H), 2.92-3.
20 (m, 6H), 3.72 (d, J = 7Hz, 2
H), 4.73 (m, 1H), 4.75 (s, 2H),
7.07 (m, 1H), 7.18 (dd, J = 7.5,
5Hz, 1H), 7.30 (d, J = 7.5Hz, 1
H), 7.36 (s, 5H), 7.67 (ddd, J =
7.5, 7.5, 2Hz, 1H), 7.85 (m, 1
H), 8.30 (d, J = 7.5 Hz, 1H), 8.4
5 (br-d, J = 5 Hz, 1 H), 11.00 (s,
1H). [Α] _D ²⁷ = + 5.4 ° (c0.25, MeOH) Melting point: 197-204 ° C HPLC: 12.5 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 30: 70, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 584

Example 37 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- methoxyamide _{NMR (DMSO-d 6, δ} ): 0.44 (d, J = 7
Hz, 3H), 0.70 (d, J = 7Hz, 3H),
0.75-0.88 (m, 1H), 0.78 (d, J =
7 Hz, 3H), 1.18-1.40 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.34
(M, 1H), 3.00 (d, J = 8Hz, 2H),
3.47 (s, 3H), 4.62 (dt, J = 8, 8H
z, 1H), 4.73 (s, 2H), 7.18 (dd,
J = 8, 5 Hz, 1H), 7.26 (d, J = 8 Hz,
1H), 7.35 (s, 5H), 7.66 (dd, J =
8,8Hz, 1H), 8.37 (d, J = 8Hz, 1
H), 8.45 (d, J = 5 Hz, 1H), 10.98
(S, 1H), 11.20 (s, 1H). [Α] _D ²³ = -11.3 ° (c0.50, MeO
H) Melting point: 220-225 ° C (decomposition) HPLC: 6.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 210 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 471

Example 38 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (N, N ′, N′-triethylureido) ethyl] amide NMR (DMSO-d ₆ , δ): 0.38 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.95 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.02 (t, J = 7Hz, 9H),
1.18-1.41 (m, 2H), 1.91 (dq, J
= 10, 7 Hz, 1H), 2.33 (m, 1H), 2.
86-3.23 (m, 12H), 4.73 (s, 2)
H), 4.74 (m, 1H), 7.18 (dd, J =
8.5Hz, 1H), 7.29 (d, J = 8Hz, 1
H), 7.36 (s, 5H), 7.66 (ddd, J =
8,8,2Hz, 1H), 7.81 (t, J = 5Hz,
1H), 8.30 (d, J = 8Hz, 1H), 8.46
(Br-d, J = 5 Hz, 1H), 11.00 (s, 1
H) [α] _D ²³ = + 0.8 ° (c0.15, MeO
H) Melting point: 154-157 ° C HPLC: 12.8 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 30: 70, 210 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 611

Example 39 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- (2-morpholinocarbonylo
Xyethyl) amide NMR (DMSO-d₆, Δ): 0.38 (d, J = 7
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.74-0.90 (m, 1H), 0.80 (d, J =
7 Hz, 3H), 1.15-1.42 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.96 (dd, J = 14, 10 Hz,
1H), 3.09 (dd, J = 14.5Hz, 1H),
3.17-3.45 (m, 6H), 3.48-3.64
(M, 4H), 3.95 (t, J = 5Hz, 2H),
4.75 (s, 2H), 4.79 (ddd, J = 10,
8.5Hz, 1H), 7.18 (dd, J = 8.5H)
z, 1H), 7.30 (d, J = 8Hz, 1H), 7.
35 (s, 5H), 7.67 (ddd, J = 8, 8, 2)
Hz, 1H), 7.92 (t, J = 5Hz, 1H),
8.33 (d, J = 8 Hz, 1H), 8.45 (br-
d, J = 5 Hz, 1H). 11.00 (s, 1H)
[Α] _D ²²= + 0.6 ° (c0.50, MeOH) Melting point: 174-177 ° C HPLC: 5.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 210 nm, flow rate
 1.0 ml / min. , At R .; T. ) MASS (FB⁺): M + H = 598

Example 40 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-2- (N, N-diethylaminocarbonyloxyethyl) amide NMR (DMSO-d ₆ , δ): 0.38 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.74-0.85 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.03 (t, J = 7Hz, 6H),
1.18-1.42 (m, 2H), 1.90 (dq, J
= 10, 7 Hz, 1H), 2.32 (m, 1H), 2.
96 (dd, J = 14, 10 Hz, 1H), 3.08
(Dd, J = 14, 4 Hz, 1H), 3.11-3.6.
0 (m, 2H), 3.20 (q, J = 7Hz, 4H),
3.93 (m, 2H), 4.75 (s, 2H), 4.8
0 (ddd, J = 10, 8, 4 Hz, 1H), 7.18
(Dd, J = 8.5 Hz, 1H), 7.30 (d, J =
8 Hz, 1 H), 7.36 (s, 5 H), 7.66 (d
dd, J = 8, 8, 2 Hz, 1H), 7.88 (t, J
= 6 Hz, 1 H), 8.30 (d, J = 8 Hz, 1
H), 8.45 (dd, J = 5, 2 Hz, 1H), 1
1.00 (s, 1H) [α] _D ²⁴ = -7.3 ° (c
0.11, MeOH) Melting point: 196-201 ° C HPLC: 23.9 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 25: 75, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 584

Example 41 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-(2-piperidinocarbonyl oxyethyl) amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.75-0.93 (m, 1H), 0.79 (d, J =
7 Hz, 3H), 1.15 to 1.66 (m, 8H),
1.91 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.95 (dd, J = 14, 10 Hz,
1H), 3.08 (dd, J = 14.4Hz, 1H),
3.15-3.50 (m, 6H), 3.91 (m, 2)
H), 4.74 (s, 2H), 4.80 (ddd, J =
10,8,5Hz, 1H), 7.18 (dd, J = 8,
5Hz, 1H), 7.30 (d, J = 8Hz, 1H),
7.35 (s, 5H), 7.67 (ddd, J = 8,
8,2Hz, 1H), 7.88 (t, J = 8Hz, 1
H), 8.30 (d, J = 8 Hz, 1H), 8.44
(Dd, J = 5, 2 Hz, 1H). 11.00 (s, 1
H) [α] _D ²² = + 0.8 ° (c0.50, MeO
H) Melting point: 190-193 ° C HPLC: 33.3 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 25: 75, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 596

Example 42 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- [2- [N- (2- hydroxyethyl) -N- methylamino] carbonyl oxy ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.62-0.90 (m, 1H), 0.
71 (d, J = 7 Hz, 3H), 0.78 (d, J = 7
Hz, 3H), 1.19-1.39 (m, 2H), 1.
91 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.85 (s, 3H), 2.94 (d
d, J = 14, 10 Hz, 1H), 3.08 (dd, J
= 14,4 Hz, 1H), 3.15-3.42 (m, 4
H), 3.48 (m, 2H), 3.91 (m, 2H),
4.60-4.90 (m, 2H), 4.73 (s, 2)
H), 7.18 (dd, J = 7.5 Hz, 1H), 7.
30 (d, J = 7.5 Hz, 1 H), 7.36 (s, 5
H), 7.67 (dd, J = 7.5, 7 Hz, 1H),
7.88 (br, 1H), 8.31 (d, J = 7.5H
z, 1H), 8.45 (d, J = 5Hz, 1H), 1
1.00 (s, 1H) [α] _D ²⁴ = + 0.7 ° (c
0.03, MeOH) Melting point: 172-176 ° C HPLC: 5.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 586

Example 43 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- (1-aminopiperidyl) amide NMR (DMSO-d ₆ , δ): 0.41 (d, J = 7)
Hz, 3Hx3 / 5), 0.55 (d, J = 7Hz, 3
Hx2 / 5), 0.65-0.84 (m, 1H), 0.
70 (d, J = 7Hz, 3Hx2 / 5), 0.72
(D, J = 7 Hz, 3Hx3 / 5), 0.79 (d, J
= 7 Hz, 3H), 1.20-1.66 (m, 8H),
1.92 (m, 1H), 2.33 (m, 1H), 2.4
7-2.63 (m, 3H), 2.85-3.10 (m,
3H), 4.68 (m, 1Hx3 / 5), 4.75
(S, 2Hx3 / 5), 4.76 (s, 2Hx2 /
5), 5.43 (m, 1Hx2 / 5), 7.18 (d
d, J = 7.5, 5 Hz, 1H), 7.28 (d, J =
7.5 Hz, 1 Hx3 / 5, 7.29 (d, J = 7.
5 Hz, 1Hx2 / 5), 7.36 (s, 5H), 7.
67 (m, 1H), 8.16 (d, J = 7.5 Hz, 1
Hx2 / 5), 8.31 (d, J = 7.5Hz, 1Hx
3/5), 8.42 (s, 1Hx2 / 5), 8.44
(Br-d, J = 5 Hz, 1Hx3 / 5), 8.46
(Br-d, J = 5 Hz, 1Hx2 / 5), 8.63
(S, 1Hx3 / 5), 11.00 (s, 1H) [α] _D ²⁴ = + 5.0 ° (c0.08, MeOH) Melting point: 222-230 ° C HPLC: 6.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ). ． ． 1
2.5 min. (MeCN: 0.05% TFAaq = 2
5:75) MASS (FB ⁺ ): M + H = 524

Example 44 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- methoxy -N- methylamide _{NMR (DMSO-d 6, δ} ): 0.43 (d, J = 7
Hz, 3H), 0.62-0.90 (m, 1H), 0.
72 (d, J = 7Hz, 3H), 0.80 (d, J = 7
Hz, 3H), 1.20-1.42 (m, 2H), 1.
92 (dq, J = 10, 7 Hz, 1H), 2.37
(M, 1H), 2.93 (dd, J = 14, 10 Hz,
1H), 3.07 (dd, J = 14, 4Hz, 1H),
3.13 (s, 3H), 3.77 (s, 3H), 4.7
5 (s, 2H), 5.28 (br, 1H), 7.21
(Dd, J = 7.5 Hz, 1H), 7.32 (d, J =
7 Hz, 1 H), 7.37 (s, 5 H), 7.69 (d
dd, J = 7, 7, 2 Hz, 1H), 8.36 (br-
d, J = 8 Hz, 1H), 8.49 (dd, J = 5, 2
Hz, 1H), 11.00 (s, 1H) [α] _D ²³
= + 8.6 ° (c0.30, MeOH) Melting point: 170-180 ° C HPLC: 5.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 485

Example 45 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-[(4-ethoxycarbonyl)
Piperidino] amide NMR (DMSO-d ₆ , δ): 0.53 (m, 3
H), 0.65-0.92 (m, 1H), 0.72
(D, J = 7Hz, 3H), 0.79 (d, J = 7H
z, 3H), 1.05-1.61 (m, 4H), 1.1
8 (t, J = 7 Hz, 3H), 1.70-2.07
(M, 2H), 1.96 (dq, J = 10, 7 Hz, 1
H), 2.28-3.25 (m, 6H), 3.96-
4.32 (m, 2H), 4.07 (q, J = 7Hz, 2
H), 4.76 (s, 2H), 5.32 (m, 1H),
7.18 (dd, J = 7.5, 5 Hz, 1H), 7.2
7 (d, J = 7.5 Hz, 1H), 7.35 (s, 5
H), 7.67 (dd, J = 7.5, 7.5 Hz, 1
H), 8.40-8.56 (m, 2H). 1H 1
1.00 (s, 1H) [α] _D ²³ = + 11.3 °
(C0.30, MeOH) Melting point: 166-170 ° C HPLC: 9.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 581

Example 46 In the same manner as in Example 2- (2), the following compound is obtained. [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-[(4-methylcarbamoyl)
Piperidino] amide NMR (DMSO-d ₆ , δ): 0.37-0.63
(M, 3H), 0.72 (d, J = 7Hz, 3H),
0.75-0.95 (m, 1H), 0.80 (d, J =
7Hz, 3H), 1.13-1.81 (m, 6H),
1.95 (dq, J = 10, 7 Hz, 1H), 2.20
-2.72 (m, 3H), 2.57 (d, J = 5Hz,
3H), 2.82-3.18 (m, 3H), 4.03-
4.43 (m, 2H), 4.75 (s, 2H), 5.3
0 (m, 1H), 7.19 (dd, J = 8, 5 Hz, 1
H), 7.27 (d, J = 8Hz, 1H), 7.36
(S, 5H), 7.67 (ddd, J = 8, 8, 2H
z, 1H), 7.75 (br, 1H), 8.33-8.
60 (m, 2H). 1H. [Α] _D ²³ = + 17.2 ° (c0.31, MeO
H) Melting point: 208-214 ° C HPLC: 5.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 566, M + Na = 5
88

Example 47 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [1- (4-acetyl) piperazinyl] amide NMR (DMSO-d ₆ , δ): 0.50 (d, J = 7)
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.76-0.90 (m, 1H), 0.80 (d, J =
7 Hz, 3H), 1.17-1.43 (m, 2H),
1.95 (dq, J = 10,7 Hz, 1H), 2.02
(S, 3H), 2.38 (m, 1H), 2.98 (d
d, J = 14, 10 Hz, 1H), 3.10 (dd, J
= 14,5 Hz, 1 H), 3.22-3.80 (m, 8
H), 4.75 (s, 2H), 5.30 (m, 1H),
7.20 (dd, J = 7.5, 5 Hz, 1H), 7.3
0 (d, J = 7.5 Hz, 1H), 7.36 (s, 5
H), 7.68 (ddd, J = 7.5, 7.5, 2H
z, 1H), 8.42-8.57 (m, 2H). 1
H. [Α] _D ²⁵ = + 26.0 ° (c0.15, MeO
H) Melting point: 189-192 ° C HPLC: 7.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 552

Example 48 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [1- (4-ethoxycarbonyl) piperazinyl] amide NMR (DMSO-d ₆ , δ): 0.50 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.88 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.12-1.40 (m, 2H),
1.19 (t, J = 7 Hz, 3H), 1.95 (dq,
J = 10,7 Hz, 1H), 2.37 (m, 1H),
2.97 (dd, J = 14,9 Hz, 1H), 3.10
(Dd, J = 14.5 Hz, 1H), 3.19-3.7.
3 (m, 8H), 4.05 (q, J = 7Hz, 2H),
4.75 (s, 2H), 5.27 (m, 1H), 7.1
9 (dd, J = 7.5, 5 Hz, 1H), 7.30
(D, J = 7.5 Hz, 1H), 7.36 (s, 5
H), 7.67 (ddd, J = 7.5, 7.5, 2H
z, 1H), 8.42-8.56 (m, 2H). 1
H. [Α] _D ²⁵ = + 21.4 ° (c0.36, MeO
H) Melting point: 168-172 ° C HPLC: 8.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 582

Example 49 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (phenoxycarbonyl) aminoethyl] amide NMR (DMSO-d ₆ , δ): 0.40 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.85 (m, 1H), 0.79 (d, J =
7 Hz, 3H), 1.23 to 1.39 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.92-3.40 (m, 5H), 2.
98 (dd, J = 14, 10 Hz, 1H), 4.75
(S, 2H), 4.77 (m, 1H), 7.10 (d,
J = 7.5 Hz, 2H), 7.15−7.24 (m, 2
H), 7.30 (d, J = 7.5 Hz, 1H), 7.3
6 (s, 5H), 7.37 (dd, J = 7.5, 7.5)
Hz, 2H), 7.63-7.75 (m, 2H), 7.
93 (m, 1H), 8.29 (d, J = 8Hz, 1
H), 8.47 (br-d, J = 5 Hz, 1H). 1
H. [Α] _D ²⁵ = + 7.7 ° (c0.40, MeOH) Melting point: 205-209 ° C HPLC: 11.3 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 30: 70, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 604

Example 50 The following compound was obtained in the same manner as in Example 1. [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (N, N ′, N′-trimethylureido) ethyl] amide NMR (DMSO-d ₆ , δ): 0.30-0.94
(M, 10H), 1.05-1.40 (m, 2H),
1.81-2.12 (m, 1H), 2.33 (m, 1
H), 2.68 (s, 6H), 2.73 (s, 3Hx4
/ 7), 2.74 (s, 3Hx3 / 7), 2.80-
3.38 (m, 6H), 4.64-4.84 (m, 3)
H), 7.11-7.42 (m, 3H), 7.36.
(S, 5H), 7.67 (ddd, J = 7, 7, 1H
z, 1H), 7.86 (m, 1Hx4 / 7), 8.00
(M, 1Hx3 / 7), 8.29 (ddd, J = 7,
7,1Hz, 1H), 8.45 (dd, J = 5,1H
z, 1H). 1H 11.00 (s, 1H). There is a rotamer peak. [Α] _D ²³ = + 16.5 ° (c0.15, MeO
H) Melting point: 104-107 ° C HPLC: 5.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 569

Example 51 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (dimethylcarbamoyl) oxyethyl] amide NMR (DMSO-d ₆ , δ): 0.40 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.91 (m, 1H), 0.78 (d, J =
7 Hz, 3H), 1.16-1.41 (m, 2H),
1.91 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.81 (s, 6H), 2.96 (d
d, J = 14, 10 Hz, 1H), 3.09 (dd, J
= 14,5 Hz, 1 H), 3.20-3.50 (m, 2
H), 3.90 (t, J = 5 Hz, 2H), 4.74
(S, 2H), 4.80 (ddd, J = 10, 8, 5H
z, 1H), 7.18 (dd, J = 7.5, 5 Hz, 1
H), 7.30 (d, J = 7.5 Hz, 1H), 7.3
5 (s, 5H), 7.66 (ddd, J = 7.5, 7.
5,2Hz, 1H), 7.87 (t, J = 5Hz, 1
H), 8.32 (d, J = 8Hz, 1H), 8.45
(Dd, J = 5, 2 Hz, 1H). 1H. [Α] _D ²³ = -1.5 ° (c0.31, MeOH) Melting point: 194-200 ° C HPLC: 12.1 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 25: 75, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 556

Example 52 The following compound was obtained in the same manner as in Example 1. [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (N-methyl-N ',
N′-diethylureido) ethyl] amide NMR (DMSO-d ₆ , δ): 0.37 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.74-0.84 (m, 1H), 0.78 (d, J =
7Hz, 3H), 1.02 (t, J = 7Hz, 6H),
1.20-1.37 (m, 2H), 1.90 (m, 1
H), 2.32 (m, 1H), 2.72 (s, 3H),
2.87-3.33 (m, 10H), 4.73 (m, 1
H), 4.74 (s, 2H), 7.17 (dd, J =
7.5, 5 Hz, 1H), 7.29 (d, J = 7.5H
z, 1H), 7.35 (s, 5H), 7.66 (dd
d, J = 7.5, 7.5, 1 Hz, 1H), 7.86
(T, J = 5 Hz, 1 H), 8.27 (d, J = 7.5)
Hz, 1H), 8.44 (dd, J = 5, 1Hz, 1
H). 1H 11.00 (s, 1H). [Α] _D ²³ = −2.9 ° (c0.09, MeOH) Melting point: 163-165 ° C. HPLC: 8.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 597

Example 53 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (N-ethyl-N ',
N′-Dimethylureido) ethyl] amide NMR (DMSO-d ₆ , δ): 0.39 (d, J = 7)
Hz, 3H), 0.65-0.89 (m, 1H), 0.
71 (d, J = 7 Hz, 3H), 0.80 (d, J = 7
Hz, 3H), 1.02 (t, J = 7Hz, 3H),
1.17-1.42 (m, 2H), 1.92 (dq, J
= 10, 7 Hz, 1H), 2.33 (m, 1H), 2.
70 (s, 6H), 2.85-3.25 (m, 8H),
4.66-4.83 (m, 3H), 7.18 (dd, J
= 7,5 Hz, 1 H), 7.30 (d, J = 7 Hz, 1
H), 7.36 (s, 5H), 7.67 (ddd, J =
7,7,1 Hz, 1H), 7.82 (br-t, J = 5)
Hz, 1H), 8.30 (d, J = 8Hz, 1H),
8.45 (dd, J = 5, 1 Hz, 1H). 11.0
0 (s, 1H) [α] _D ²³ = -1.0 ° (c0.31, MeOH) Melting point: 168-170 ° C HPLC: 13.3 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 25: 75, 260 nm, flowrate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 583

Example 54 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- (2-phenethyl) amide NMR (DMSO-d ₆ , δ): 0.38 (d, J =
6.8 Hz, 3 H), 0.71 (d, J = 6.4 Hz,
3H), 0.75-0.87 (m, 1H), 0.79
(D, J = 6.5 Hz, 3H), 1.21-1.38
(M, 2H), 1.91 (dq, J = 10.3, 6.8)
Hz, 1H), 2.32 (m, 1H), 2.66 (t,
J = 7.1 Hz, 2H), 2.93 (dd, J = 13.
7, 10.1 Hz, 1 H), 3.04 (dd, J = 1
3.7, 4.9 Hz, 1H), 3.16-3.40.
(M, 2H), 4.74 (s, 2H), 4.75 (m,
1H), 7.14-7.42 (m, 7H), 7.36
(S, 5H), 7.66 (ddd, J = 7.7, 7.
6, 1.7 Hz, 1H), 7.82 (t, J = 5.5H
z, 1H), 8.28 (d, J = 8.4Hz, 1H),
8.44 (br-d, J = 3.8 Hz, 1H), 10.
99 (s, 1H). [Α] _D ²⁷ = + 0.6 ° (c0.38, MeOH) Melting point: 217-221 ° C. HPLC: 9.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 35: 65, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 545

Example 55 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-(2-morpholinoethyl) amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J =
6.6 Hz, 3 H), 0.68-0.86 (m, 1
H), 0.72 (d, J = 6.1 Hz, 3H), 0.7
9 (d, J = 6.1 Hz, 3H), 1.20-1.39
(M, 2H), 1.92 (dq, J = 10.3, 6.6)
Hz, 1H), 2.21-2.40 (m, 7H), 2.
96 (dd, J = 13.9, 10.2 Hz, 1 H),
3.05-3.24 (m, 3H), 3.49-3.61
(M, 4H), 4.74 (s, 2H), 4.77 (m,
1H), 7.18 (dd, J = 7.2, 5.0 Hz, 1
H), 7.30 (d, J = 7.7 Hz, 1H), 7.3
6 (s, 5H), 7.61 (t, J = 5.5Hz, 1
H), 7.67 (dd, J = 7.7, 7.2 Hz, 1
H), 8.33 (d, J = 7.3 Hz, 1H), 8.4
5 (br-d, J = 5.0 Hz, 1H), 11.00
(S, 1H). [Α] _D ²⁷ = −0.4 ° (c0.3
4, MeOH) Melting point: 205-210 ° C. HPLC: 8.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 554

Example 56 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- (2,2,2- trifluoroethyl) amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J = 7
Hz, 3H), 0.70 (d, J = 7Hz, 3H),
0.74-0.82 (m, 1H), 0.78 (d, J =
7Hz, 3H), 1.21-1.36 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.99 (dd, J = 14, 10 Hz,
1H), 3.09 (dd, J = 14, 4Hz, 1H),
3.90 (m, 2H), 4.74 (s, 2H), 4.8
8 (ddd, J = 10, 8, 4 Hz, 1H), 7.18
(Dd, J = 7.5, 5 Hz, 1H), 7.30 (d,
J = 7.5 Hz, 1H), 7.35 (s, 5H), 7.
66 (ddd, J = 7.5, 7.5, 1.5 Hz, 1
H), 8.36 (d, J = 8Hz, 1H), 8.43-
8.51 (m, 2H), 11.00 (s, 1H). [Α] _D ²⁸ = −4.1 ° (c0.30, MeOH) Melting point: 214-220 ° C. HPLC: 4.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 35: 65, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 523

Example 57 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- (4-hydroxypiperidino)
Amide NMR (DMSO-d ₆ , δ): 0.50 (m, 3)
H), 0.72 (m, 3H), 0.76-0.90
(M, 4H), 1.12-1.40 (m, 3H), 1.
56-1.80 (m, 2H), 1.95 (dq, J = 1
0,7 Hz, 1H), 2.36 (m, 1H), 2.88
-3.12 (m, 4H), 3.26 (m, 1H), 3.
67 (m, 1H), 3.75-3.93 (m, 2H),
4.74 (m, 1H), 4.75 (s, 2H), 5.3
0 (m, 1H), 7.18 (dd, J = 8.5Hz, 1
H), 7.27 (d, J = 8 Hz, 1H), 7.35
(S, 5H), 7.65 (dd, J = 8, 8Hz, 1
H), 8.41 (d, J = 8Hz, 1H), 8.47
(Br-d, J = 5 Hz, 1H), 11.01 (s, 1
H). [Α] _D ²⁸ = + 12.4 ° (c0.33, MeO
H) Melting point: 116-120 ° C HPLC: 6.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 525

Example 58 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N - [(2R) -2- hydroxypropyl] amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.76-0.85 (m, 1H), 0.80 (d, J =
7Hz, 3H), 0.99 (d, J = 7Hz, 3H),
1.23-1.40 (m, 2H), 1.92 (dq, J
= 10, 7 Hz, 1H), 2.33 (m, 1H), 2.
91-3.05 (m, 3H), 3.14 (dd, J = 1
4,5 Hz, 1H), 3.61 (m, 1H), 4.68
(D, J = 4 Hz, 1H), 4.75 (s, 2H),
4.80 (m, 1H), 7.19 (dd, J = 7, 4H
z, 1H), 7.30 (d, J = 8Hz, 1H), 7.
37 (s, 5H), 7.59 (dd, J = 6, 6Hz,
1H), 7.68 (ddd, J = 8, 7, 2Hz, 1
H), 8.34 (d, J = 8Hz, 1H), 8.46
(Br-d, J = 4 Hz, 1H), 11.00 (s, 1
H). [Α] _D ²⁴ = −4.8 ° (c0.29, MeOH) Melting point: 201-209 ° C. HPLC: 6.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 499

Example 59 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N - [(2S) -2- hydroxypropyl] amide _{NMR (DMSO-d 6, δ} ): 0.37 (d, J = 7
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.74-0.83 (m, 1H), 0.79 (d, J =
7Hz, 3H), 0.96 (d, J = 7Hz, 3H),
1.23-1.37 (m, 2H), 1.91 (dq, J
= 10, 7 Hz, 1H), 2.33 (m, 1H), 2.
88-3.08 (m, 3H), 3.12 (dd, J = 1
4,5Hz, 1H), 3.58 (m, 1H), 4.64
(D, J = 6 Hz, 1H), 4.73 (s, 2H),
4.79 (m, 1H), 7.18 (dd, J = 7.5H)
z, 1H), 7.29 (d, J = 8Hz, 1H), 7.
35 (s, 5H), 7.56 (dd, J = 5, 5Hz,
1H), 7.67 (ddd, J = 8, 7, 2 Hz, 1
H), 8.31 (d, J = 8Hz, 1H), 8.44
(Dd, J = 5, 2 Hz, 1H), 10.98 (s, 1
H). [Α] _D ²⁴ = + 7.3 ° (c0.34, MeOH) Melting point: 211-217 ° C HPLC: 6.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 499

Example 60 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- (4-phenoxypiperidino)
Amide NMR (DMSO-d ₆ , δ): 0.52 (m, 3)
H), 0.73 (d, J = 7 Hz, 3H), 0.76-
0.85 (m, 1H), 0.80 (d, J = 7Hz, 3
H), 1.22-1.64 (m, 4H), 1.75-
2.03 (m, 3H), 2.38 (m, 1H), 2.9
7 (dd, J = 14, 8 Hz, 1H), 3.04-3.
54 (m, 3H), 3.71-4.00 (m, 2H),
4.60 (m, 1H), 4.75 (s, 2H), 5.3
3 (m, 1H), 6.88-7.01 (m, 3H),
7.19 (m, 1H), 7.27-7.32 (m, 3
H), 7.36 (s, 5H), 7.67 (dd, J =
7.5, 7.5 Hz, 1H), 8.42-8.51
(M, 2H), 11.01 (s, 1H). [Α] _D ²⁵ = + 21.4 ° (c0.28, MeO
H) Melting point: 130-134 ° C HPLC: 6.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 40: 60, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 601

Example 61 The following compound was obtained as in Example 2- (1). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine -N- methylamide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J = 7
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.85 (m, 1H), 0.80 (d, J =
7Hz, 3H), 1.20-1.36 (m, 2H),
1.91 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.58 (d, J = 5Hz, 3H),
2.80 (dd, J = 14, 11 Hz, 1H), 2.9
3 (dd, J = 14.5 Hz, 1H), 4.57 (dd
d, J = 11, 8, 5 Hz, 1H), 4.74 (s, 2
H), 7.28 (d, J = 7 Hz, 2H), 7.36
(S, 5H), 7.81 (q, J = 5Hz, 1H),
8.29 (d, J = 8 Hz, 1H), 8.42 (d, J
= 7 Hz, 2H), 10.98 (s, 1H). [Α] _D ²⁵ = + 2.9 ° (c0.28, MeOH) Melting point: 248-252 ° C HPLC: 4.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ), 8.7m
in. (MeCN: 0.05% TFAaq = 30: 7
0). MASS (FB ⁺ ): M + H = 455

Example 62 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N-(2-Asetamidoechiru) amide _{NMR (DMSO-d 6, δ} ): 0.42 (d, J = 7
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.86 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.20-1.37 (m, 2H),
1.79 (s, 3H), 1.92 (dq, J = 10, 7)
Hz, 1H), 2.34 (m, 1H), 2.80 (d
d, J = 14, 11 Hz, 1H), 2.93-3.20.
(M, 5H), 4.57 (m, 1H), 4.74 (s,
2H), 7.19 (d, J = 7Hz, 2H), 7.36
(S, 5H), 7.85 (br, 1H), 8.02 (b
r, 1H), 8.31 (d, J = 8Hz, 1H), 8.
43 (d, J = 7 Hz, 2H), 11.00 (s, 1
H). [Α] _D ²² = + 12.1 ° (c0.34, MeO
H) Melting point: 214-219 [deg.] C. HPLC: 4.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 526

Example 63 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N-(2-hydroxyethyl) amide _{NMR (DMSO-d 6, δ} ): 0.37 (d, J = 7
Hz, 3H), 0.67-0.86 (m, 1H), 0.
71 (d, J = 7 Hz, 3H), 0.80 (d, J = 7
Hz, 3H), 1.20-1.38 (m, 2H), 1.
91 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.79 (dd, J = 14, 12Hz,
1H), 2.98 (dd, J = 14,5Hz, 1H),
3.12 (dt, J = 7.5 Hz, 2H), 3.36
(Dt, J = 7.5 Hz, 2H), 4.63 (ddd,
J = 12, 8.5 Hz, 1H), 4.68 (t, J = 5)
Hz, 1H), 4.74 (s, 2H), 7.30 (d,
J = 6 Hz, 2H), 7.36 (s, 5H), 7.82
(T, J = 5 Hz, 1H), 8.29 (d, J = 8H
z, 1H), 8.41 (d, J = 6Hz, 2H), 1
0.98 (s, 1H). [Α] _D ²² = + 6.1 ° (c0.29, MeOH) Melting point: 235-239 ° C HPLC: 4.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 485

Example 64 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-[(1R) -1-benzyloxymethyl-2-hydroxyethyl] amide NMR (DMSO-d ₆ , δ): 0.35 (d, J = 7)
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.73-0.82 (m, 1H), 0.76 (d, J =
7Hz, 3H), 1.21-1.38 (m, 2H),
1.90 (dq, J = 10, 7 Hz, 1H), 2.31
(M, 1H), 2.96 (dd, J = 14, 10 Hz,
1H), 3.14 (dd, J = 14, 5 Hz, 1H),
3.20-3.48 (m, 4H), 3.88 (m, 1
H), 4.48 (s, 2H), 4.74 (s, 2H),
4.77 (m, 1H), 4.81 (ddd, J = 10,
8,5 Hz, 1 H), 7.18 (dd, J = 7.5, 5)
Hz, 1H), 7.24-7.45 (m, 10H),
7.30 (d, J = 7.5 Hz, 1H), 7.41
(D, J = 7.5 Hz, 1H), 7.66 (ddd, J
= 7.5, 7.5, 1.5 Hz, 1H), 8.37
(D, J = 8 Hz, 1H), 8.44 (dd, J = 5
1.5 Hz, 1H), 11.01 (s, 1H). [Α] _D ²⁵ = + 4.1 ° (c0.22, MeOH) Melting point: 204-206 ° C HPLC: 6.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 35: 65, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + Na = 627

Example 65 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N-[(1R) -1-benzyloxymethyl-2-hydroxyethyl] amide NMR (DMSO-d ₆ , δ): 0.33 (d, J = 7)
Hz, 3H), 0.66 (d, J = 7Hz, 3H),
0.70-0.83 (m, 1H), 0.77 (d, J =
7Hz, 3H), 1.20-1.35 (m, 2H),
1.90 (dq, J = 10, 7 Hz, 1H), 2.31
(M, 1H), 2.78 (dd, J = 14, 11 Hz,
1H), 3.00 (dd, J = 14.4Hz, 1H),
3.34-3.46 (m, 4H), 3.89 (m, 1)
H), 4.47 (s, 2H), 4.70 (ddd, J =
11,8,4Hz, 1H), 4.73 (s, 2H),
4.75 (t, J = 5 Hz, 1H), 7.23-7.4
0 (m, 10H), 7.30 (d, J = 7Hz, 2
H), 7.63 (d, J = 8Hz, 1H), 8.31
(D, J = 8Hz, 1H), 8.41 (d, J = 7H
z, 2H), 10.98 (s, 1H). [Α] _D ²⁵ = + 11.8 ° (c0.30, MeO
H) Melting point: 233-235 [deg.] C. HPLC: 6.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 35: 65, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 605

Example 66 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N'-acetylhydrazide NMR
(DMSO-d ₆ , δ): 0.35 (d, J = 7 Hz,
3Hx9 / 10), 0.43 (d, J = 7Hz, 3Hx
1/10), 0.65-0.83 (m, 1H), 0.7
0 (d, J = 7Hz, 3H), 0.79 (d, J = 7H
z, 3H), 1.21-1.40 (m, 2H), 1.8.
5 (s, 3H), 1.90 (dq, J = 10, 7 Hz,
1H), 2.32 (m, 1H), 3.00 (dd, J =
14, 12Hz, 1H), 3.15 (dd, J = 14,
4 Hz, 1 H), 4.73 (s, 2 H), 4.88 (d
dd, J = 12, 8, 4 Hz, 1H), 7.19 (d
d, J = 7.5, 5 Hz, 1H), 7.30-7.40
(M, 6H), 7.68 (ddd, J = 7.5, 7.
5,1.5Hz, 1H), 8.28 (d, J = 8Hz,
1Hx9 / 10), 8.28 (d, J = 8Hz, 1Hx
1/10), 8.46 (dd, J = 5, 1.5 Hz, 1
H), 9.86 (d, J = 9 Hz, 2H), 10.98
(S, 1H). [Α] _D ²⁵ = −32.3 ° (c0.34, MeO
H) Melting point: 227-228 ° C HPLC: 6.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 498

Example 67 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- (cyclopropylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.08-0.16
(M, 2H), 0.32-0.42 (m, 5H), 0.
72 (d, J = 7 Hz, 3H), 0.75-0.89
(M, 2H), 0.80 (s, 3H), 1.22-1.
39 (m, 2H), 1.91 (dq, J = 10, 7H
z, 1H), 2.33 (m, 1H), 2.89-3.0.
2 (m, 3H), 3.10 (dd, J = 14, 4 Hz,
1H), 4.74 (s, 2H), 4.78 (m, 1
H), 7.18 (dd, J = 7.5, 5 Hz, 1H),
7.30 (d, J = 7.5 Hz, 1H), 7.35
(S, 5H), 7.58-7.70 (m, 2H), 8.
32 (d, J = 8 Hz, 1 H), 8.45 (br-d,
J = 5 Hz, 1H), 10.99 (s, 1H). [Α] _D ²⁵ = -3.6 ° (c0.27, MeOH) Melting point: 218-220 ° C HPLC: 8.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 495

Example 68 In the same manner as in Example 5 and Example 2- (2), the following compound is obtained. [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine -N- (cyclopropylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.08-0.18
(M, 2H), 0.32-0.44 (m, 5H), 0.
62 (d, J = 7 Hz, 3H), 0.65-0.90
(M, 2H), 0.70 (s, 3H), 1.21-1.
37 (m, 2H), 1.91 (dq, J = 10, 7H
z, 1H), 2.34 (m, 1H), 2.80 (dd,
J = 14, 12 Hz, 1H), 2.89-3.03.
(M, 3H), 4.63 (m, 1H), 4.74 (s,
2H), 7.30 (dd, J = 7Hz, 1H), 7.3
5 (s, 5H), 7.83 (t, J = 5Hz, 1H),
8.31 (d, J = 8Hz, 1H), 8.42 (d, J
= 7 Hz, 2H), 10.98 (s, 1H). [Α] _D ²⁵ = + 3.8 ° (c0.28, MeOH) Melting point: 235-240 ° C. (decomposition) HPLC: 6.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 495

Example 69 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- (cyclobutyl) amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.75-0.86 (m, 2H), 0.80 (d, J =
7Hz, 3H), 1.21-1.38 (m, 2H),
1.52-1.68 (m, 2H), 1.70-1.98
(M, 3H), 2.04-2.21 (m, 2H), 2.
32 (m, 1H), 2.93 (dd, J = 14, 12H
z, 1H), 3.07 (dd, J = 14,5Hz, 1
H), 4.15 (m, 1H), 4.71 (m, 1H),
4.74 (s, 2H), 7.18 (dd, J = 7.5,
5Hz, 1H), 7.27 (d, J = 7.5Hz, 1
H), 7.35 (s, 5H), 7.66 (ddd, J =
7.5, 7.5, 1.5 Hz, 1H), 7.80 (d,
J = 8Hz, 1H), 8.27 (d, J = 8Hz, 1
H), 8.45 (dd, J = 5, 1.5 Hz, 1H),
11.00 (s, 1H). [Α] _D ²⁵ = + 0.7 ° (c0.30, MeOH) Melting point: 240-244 ° C HPLC: 8.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 495

Example 70 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- (cyclopropyl) amide _{NMR (DMSO-d 6, δ} ): 0.23-0.36
(M, 2H), 0.39 (d, J = 7Hz, 3H),
0.53-0.66 (m, 2H), 0.72 (d, J =
7Hz, 3H), 0.75-0.85 (m, 1H),
0.79 (d, J = 7 Hz, 3H), 1.19-1.3
7 (m, 2H), 1.91 (dq, J = 10, 7 Hz,
1H), 2.32 (m, 1H), 2.58 (m, 1
H), 2.94 (dd, J = 14, 11 Hz, 1H),
3.05 (dd, J = 14.6 Hz, 1H), 4.69
(Ddd, J = 11,8,6 Hz, 1H), 4.73
(S, 2H), 7.18 (dd, J = 7.5, 5 Hz,
1H), 7.27 (d, J = 7.5Hz, 1H), 7.
35 (s, 5H), 7.66 (ddd, J = 7.5,
7.5, 1.5 Hz, 2H), 7.76 (d, J = 4H
z, 1H), 8.25 (d, J = 8Hz, 1H), 8.
44 (dd, J = 5, 1.5 Hz, 1H), 10.99
(S, 1H). [Α] _D ²³ = −2.2 ° (c0.33, MeOH) Melting point: 241-243 ° C. HPLC: 5.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 481

Example 71 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine -N- [2- (4- hydroxyphenyl) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J = 7
Hz, 3H), 0.67-0.86 (m, 1H), 0.
71 (d, J = 7 Hz, 3H), 0.80 (d, J = 7
Hz, 3H), 1.21-1.38 (m, 2H), 1.
92 (dq, J = 10, 7 Hz, 1H), 2.34
(M, 1H), 2.55 (m, 2H), 2.75 (d
d, J = 14, 11 Hz, 1H), 2.89 (dd, J
= 14,4 Hz, 1H), 3.21 (m, 2H), 4.
60 (ddd, J = 11,8,4Hz, 1H), 4.7
4 (s, 2H), 6.65 (d, J = 8Hz, 2H),
6.97 (d, J = 8 Hz, 2H), 7.27 (d, J
= 6 Hz, 2H), 7.36 (s, 5H), 7.90
(T, J = 5 Hz, 1H), 8.27 (d, J = 8H
z, 1H), 8.41 (d, J = 6Hz, 2H), 9.
16 (s, 1H), 10.98 (s, 1H). [Α] _D ²⁵ = + 5.6 ° (c0.21, DMSO) Melting point: 243-248 ° C. HPLC: 6.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 561

Example 72 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (4-hydroxyphenyl) ethyl] amide NMR (DMSO-d ₆ , δ): 0.38 (d, J = 7)
Hz, 3H), 0.70 (d, J = 7Hz, 3H),
0.74-0.85 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.21-1.38 (m, 2H),
1.91 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.53 (m, 2H), 2.92 (d
d, J = 14, 11 Hz, 1H), 3.04 (dd, J
= 14,6 Hz, 1H), 3.19 (m, 2H), 4.
74 (s, 2H), 4.75 (ddd, J = 11, 8,
6Hz, 1H), 6.65 (d, J = 8Hz, 2H),
6.96 (d, J = 8 Hz, 2H), 7.18 (dd,
J = 7.5, 5 Hz, 1H), 7.28 (d, J = 7.
5 Hz, 1 H), 7.35 (s, 5 H), 7.66 (d
d, J = 7.5, 7.5 Hz, 1H), 7.72 (t,
J = 5 Hz, 1 H), 8.27 (d, J = 8 Hz, 1
H), 8.44 (br-d, J = 5 Hz, 1H), 9.
14 (s, 1H), 10.99 (s, 1H). [Α] _D ²⁵ = -18.1 ° (c0.24, DMS
O) Melting point: 221-225 ° C (decomposition) HPLC: 7.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 561

Example 73 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N- [2- (3,4-dihydroxyphenyl) ethyl] amide NMR (DMSO-d ₆ , δ): 0.40 (d, J = 7).
Hz, 3H), 0.67-0.86 (m, 1H), 0.
71 (d, J = 7 Hz, 3H), 0.80 (d, J = 7
Hz, 3H), 1.22-1.37 (m, 2H), 1.
92 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.48 (m, 2H), 2.77 (d
d, J = 14, 12 Hz, 1H), 2.91 (dd, J
= 14,5 Hz, 1H), 3.18 (m, 2H), 4.
59 (ddd, J = 12, 8, 5 Hz, 1H), 4.7
4 (s, 2H), 6.57 (d, J = 1Hz, 1H),
6.62 (d, J = 8Hz, 1H), 7.27 (d, J
= 7 Hz, 2H), 7.36 (s, 5H), 7.90
(T, J = 4 Hz, 1H), 8.27 (d, J = 8H
z, 1H), 8.41 (d, J = 7Hz, 2H), 8.
66 (br, 1H), 8.72 (br, 1H), 10.
99 (s, 1H). [Α] _D ²⁵ = + 0.8 ° (c0.21, DMSO) Melting point: 242-249 ° C. (decomposition) HPLC: 5.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 577

Example 74 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- [2- (3,4- dihydroxyphenyl) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.65-0.86 (m, 1H), 0.
71 (d, J = 7 Hz, 3H), 0.79 (d, J = 7
Hz, 3H), 1.20-1.39 (m, 2H), 1.
91 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.45 (m, 2H), 2.94 (d
d, J = 14, 12 Hz, 1H), 3.06 (dd, J
= 14,5 Hz, 1H), 3.17 (m, 2H), 4.
73 (ddd, J = 12, 8, 5 Hz, 1H), 4.7
3 (s, 2H), 6.41 (dd, J = 8, 1Hz, 1
H), 6.55 (d, J = 1 Hz, 1H), 6.61
(D, J = 8 Hz, 1H), 7.18 (dd, J = 7.
5,5 Hz, 1 H), 7.28 (d, J = 7.5 Hz,
1H), 7.35 (s, 5H), 7.66 (dd, J =
7.5, 7.5 Hz, 1H), 7.72 (t, J = 4H
z, 1H), 8.28 (d, J = 8Hz, 1H), 8.
45 (d, J = 5 Hz, 1H), 8.56-8.79.
(Br, 2H), 10.99 (s, 1H). [Α] _D ²⁵ = −29.6 ° (c0.21, DMS
O) Melting point: 197-199 ° C. (decomposition) HPLC: 5.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 577

Example 75 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N-[(2S) -2,3-dihydroxypropyl] amide NMR (DMSO-d ₆ , δ): 0.35 (d, J = 7)
Hz, 3H), 0.66-0.85 (m, 1H), 0.
71 (d, J = 7 Hz, 3H), 0.80 (d, J = 7
Hz, 3H), 1.20-1.37 (m, 2H), 1.
90 (dq, J = 10, 7 Hz, 1H), 2.32 (d
dd, J = 10, 10, 3 Hz, 1H), 2.79 (d
d, J = 14, 12 Hz, 1H), 2.89-3.05
(M, 2H), 3.17-3.40 (m, 3H), 3.
45 (m, 1H), 4.50 (t, J = 4Hz, 1
H), 4.67 (m, 1H), 4.74 (s, 2H),
4.77 (d, J = 4 Hz, 1H), 7.30 (d, J
= 6 Hz, 2H), 7.36 (s, 5H), 7.81
(T, J = 5 Hz, 1H), 8.29 (d, J = 8H
z, 1H), 8.49 (d, J = 6Hz, 2H), 1
0.98 (s, 1H). [Α] _D ²⁶ = + 2.7 ° (c0.25, MeOH) Melting point: 242-249 ° C. (decomposition) HPLC: 6.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 515

Example 76 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-(2-pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.41 (d, J = 7
Hz, 3H), 0.67 (d, J = 7Hz, 3H),
0.71-0.85 (m, 1H), 0.85 (d, J =
7 Hz, 3H), 1.18-1.40 (m, 2H),
1.93 (dq, J = 10, 7 Hz, 1H), 2.35
(M, 1H), 3.02 (dd, J = 14, 11 Hz,
1H), 3.18 (dd, J = 14,5Hz, 1H),
4.35 (d, J = 6 Hz, 2H), 4.74 (s, 2
H), 4.89 (ddd, J = 11, 8, 5 Hz, 1
H), 7.16-7.22 (m, 2H), 7.25 (d
d, J = 7.5, 5 Hz, 1H), 7.32 (d, J =
7.5 Hz, 1H), 7.35 (s, 5H), 7.63
-7.73 (m, 2H), 8.33 (t, J = 6Hz,
1H), 8.39 (d, J = 8Hz, 1H), 8.44
-8.51 (m, 2H), 11.00 (s, 1H). [Α] _D ²³ = + 1.8 ° (c0.35, MeOH) Melting point: 217-219 ° C. HPLC: 8.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 532, MH = 530

Example 77 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N- [2- (2-pyridyl) ethyl] amide NMR (DMSO-d ₆ , δ): 0.38 (d, J = 7)
Hz, 3H), 0.70 (d, J = 7Hz, 3H),
0.74-0.84 (m, 1H), 0.78 (d, J =
7Hz, 3H), 1.20-1.37 (m, 2H),
1.91 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.82 (t, J = 7Hz, 2H),
2.93 (dd, J = 14, 10 Hz, 1H), 3.0
4 (dd, J = 14.5 Hz, 1H), 3.41 (m,
2H), 4.74 (s, 2H), 4.75 (ddd, J
= 10, 8, 5 Hz, 1H), 7.13-7.24
(M, 3H), 7.27 (d, J = 7.5 Hz, 1
H), 7.35 (s, 5H), 7.61-7.73.
(M, 2H), 7.83 (t, J = 5Hz, 1H),
8.28 (d, J = 8 Hz, 1H), 8.44 (dd,
J = 5,2 Hz, 1H), 8.48 (dd, J = 5,2
Hz, 1H), 10.99 (s, 1H). [Α] _D ²³ = + 3.0 ° (c0.33, MeOH) Melting point: 220-223 ° C. HPLC: 8.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 546, MH = 544

Example 78 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-(3- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.42 (d, J = 7
Hz, 3H), 0.66 (d, J = 7Hz, 3H),
0.72 (d, J = 7Hz, 3H), 0.75 (m, 1
H), 1.12 to 1.37 (m, 2H), 1.92 (d
q, J = 10,7 Hz, 1H), 2.33 (m, 1
H), 3.00 (dd, J = 14, 10 Hz, 1H),
3.12 (dd, J = 14, 6 Hz, 1H), 4.25
(Dd, J = 15,7 Hz, 1H), 4.31 (dd,
J = 15,7Hz, 1H), 4.74 (s, 2H),
4.84 (m, 1H), 7.19 (dd, J = 7.5,
5Hz, 1H), 7.26-7.34 (m, 2H),
7.35 (s, 5H), 7.57 (br-d, J = 7.
5 Hz, 1 H), 7.67 (dd, J = 7.5, 7.5)
Hz, 1H), 8.29-8.40 (m, 2H), 8.
41-8.51 (m, 3H), 11.00 (s, 1
H). [Α] _D ²³ = + 1.9 ° (c0.32, MeOH) Melting point: 213-215 ° C. HPLC: 6.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 532, MH = 530

Example 79 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- (4- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.45 (d, J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.72-0.85 (m, 1H), 0.75 (d, J =
7 Hz, 3H), 1.15-1.40 (m, 2H),
1.95 (dq, J = 10,7 Hz, 1H), 2.36
(M, 1H), 3.03 (dd, J = 14, 11 Hz,
1H), 3.14 (dd, J = 14, 6 Hz, 1H),
4.25 (dd, J = 15, 7.5 Hz, 1H), 4.
31 (dd, J = 15, 7.5 Hz, 1H), 4.74
(S, 2H), 4.88 (m, 1H), 7.12-7.
24 (m, 3H), 7.30 (d, J = 7.5 Hz, 1
H), 7.35 (s, 5H), 7.68 (dd, J =
7.5, 7.5 Hz, 1H), 8.35-8.55
(M, 5H), 11.00 (s, 1H). [Α] _D
²³ = + 3.6 ° (c0.36, MeOH) Melting point: 230-232 ° C (decomposition) HPLC: 5.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 532

Example 80 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N-(2-pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.41 (d, J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.73-0.85 (m, 1H), 0.78 (d, J =
7Hz, 3H), 1.20-1.39 (m, 2H),
1.93 (dq, J = 10, 7 Hz, 1H), 2.37
(M, 1H), 2.86 (dd, J = 14, 12Hz,
1H), 3.06 (dd, J = 14, 4Hz, 1H),
4.35 (dd, J = 16,5 Hz, 1H), 4.40
(Dd, J = 16.5 Hz, 1H), 4.74 (dd
d, J = 12, 8, 4 Hz, 1H), 4.75 (s, 2
H), 7.21 (d, J = 7.5 Hz, 1H), 7.2
8 (dd, J = 7.5, 5 Hz, 1H), 7.33
(D, J = 6 Hz, 2H), 7.37 (s, 5H),
7.72 (dd, J = 7.5, 7.5 Hz, 1H),
8.40 (d, J = 8Hz, 1H), 8.45 (d, J
= 6 Hz, 2H), 8.48-8.56 (m, 2H),
11.00 (s, 1H). [Α] _D ²⁵ = -7.3 ° (c0.45, 1N-HC
l) Melting point: 234-237 ° C HPLC: 4.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 532

Example 81 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N-(3- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.67 (d, J = 7Hz, 3H),
0.71-0.83 (m, 1H), 0.75 (d, J =
7Hz, 3H), 1.13-1.35 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.34
(M, 1H), 2.83 (dd, J = 14, 12Hz,
1H), 2.98 (dd, J = 14,5Hz, 1H),
4.25 (dd, J = 15, 6 Hz, 1H), 4.34
(Dd, J = 15.6 Hz, 1H), 4.69 (m, 1
H), 4.74 (s, 2H), 7.29 (d, J = 6H
z, 2H), 7.31 (m, 1H), 7.35 (s, 5
H), 7.57 (br-d, J = 7.5 Hz, 1H),
8.33-8.53 (m, 6H), 10.99 (s, 1
H). [Α] _D ²⁵ = -3.1 ° (c0.36, 1N-HC
l) Melting point: 224-226 ° C. HPLC: 5.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 532

Example 82 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine -N- [2- (2- pyridyl) amino ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.67 (d, J = 7Hz, 3H),
0.71-0.84 (m, 1H), 0.77 (d, J =
7Hz, 3H), 1.20-1.37 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.32
(Ddd, J = 10, 10, 3 Hz, 1H), 2.95
(Dd, J = 14, 11 Hz, 1H), 3.09 (d
d, J = 14, 6 Hz, 1H), 3.14-3.41.
(M, 4H), 4.74 (s, 2H), 4.77 (dd
d, J = 11,8,6 Hz, 1H), 7.15 (dd,
J = 7.5, 5 Hz, 1H), 7.27 (d, J = 7.
5Hz, 1H), 7.35 (s, 5H), 7.57-
7.68 (m, 2H), 7.92-8.07 (m, 3
H), 8.27 (d, J = 7.5 Hz, 1H), 8.4
3 (br-d, J = 5 Hz, 1H), 8.64 (br-
d, J = 5Hz, 1H), 8.86 (t, J = 5Hz,
1H), 11.00 (s, 1H). [Α] _D ²³ = -5.8 ° (c0.34, 1N-HC
l) Melting point: 203-206 ° C HPLC: 5.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 589

Example 83 The following compound was obtained in the same manner as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-(2-nicotinoyl-aminoethyl) amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.71-0.84 (m, 1H), 0.77 (d, J =
7Hz, 3H), 1.20-1.36 (m, 2H),
1.93 (dq, J = 10, 7 Hz, 1H), 2.33
(Ddd, J = 10, 10, 3 Hz, 1H), 3.00
(Dd, J = 14, 11 Hz, 1H), 3.07-3.
38 (m, 5H), 4.74 (s, 2H), 4.75
(M, 1H), 7.16 (dd, J = 7.5, 5 Hz,
1H), 7.30 (d, J = 7.5 Hz, 1H), 7.
35 (s, 5H), 7.50 (dd, J = 7.5, 5H
z, 1H), 7.65 (ddd, J = 7.5, 7.5,
1.5Hz, 1H), 8.07 (t, J = 5Hz, 1
H), 8.23 (dd, J = 7.5, 1.5 Hz, 1
H), 8.36 (d, J = 8Hz, 1H), 8.44
(Dd, J = 5, 1.5 Hz, 1 H), 8.70 (d,
J = 5Hz, 1H), 8.81 (t, J = 4Hz, 1
H), 9.03 (d, J = 1.5 Hz, 1H), 11.
06 (s, 1H). [Α] _D ²³ = -4.2 ° (c0.33, 1N-HC
l) Melting point: 219-222 ° C HPLC: 5.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 589

Example 84 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N-(2-nicotinoyl-aminoethyl) amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.72-0.85 (m, 1H), 0.78 (d, J =
7Hz, 3H), 1.20-1.37 (m, 2H),
1.91 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.79 (dd, J = 14, 11 Hz,
1H), 3.00 (dd, J = 14.5Hz, 1H),
3.12-3.42 (m, 4H), 4.60 (ddd,
J = 1,8,5Hz, 1H), 4.74 (s, 2)
H), 7.28 (d, J = 7 Hz, 2H), 7.36
(S, 5H), 7.51 (dd, J = 7.5, 5Hz,
1H), 8.11 (t, J = 4Hz, 1H), 8.17
(Ddd, J = 7.5, 1.5, 1.5Hz, 1H),
8.31 (d, J = 8Hz, 1H), 8.42 (d, J
= 7 Hz, 2H), 8.64-8.74 (m, 2H),
9.00 (d, J = 1.5 Hz, 1H), 10.98
(S, 1H). [Α] _D ²³ = -1.1 ° (c0.27, 1N-HC
l) Melting point: 236-238 ° C HPLC: 4.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 589

Example 85 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine-N- [2- (2-pyridylcarbonyl) aminoethyl] amide NMR (DMSO-d < ₆ >, [delta]): 0.41 (d, J = 7).
Hz, 3H), 0.69 (d, J = 7Hz, 3H),
0.72-0.86 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.20-1.38 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.34
(Ddd, J = 10, 10, 3 Hz, 1H), 2.80
(Dd, J = 14, 12 Hz, 1H), 2.99 (d
d, J = 14, 4 Hz, 1H), 3.21 (m, 1
H), 3.28-3.44 (m, 3H), 4.62 (d
dd, J = 12, 8, 4 Hz, 1H), 4.75 (s,
2H), 7.28 (d, J = 6Hz, 2H), 7.37
(S, 5H), 7.61 (dd, J = 7.5, 5Hz,
1H), 7.95-8.15 (m, 3H), 8.30
(D, J = 8 Hz, 1H), 8.42 (d, J = 6H
z, 2H), 8.65 (d, J = 5Hz, 1H), 8.
87 (t, J = 5 Hz, 1H), 11.00 (s, 1
H). [Α] _D ²³ = -1.3 ° (c0.40, 1N-HC
l) Melting point: 242-245 ° C. HPLC: 5.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 589

Example 86 The following compound was obtained in the same manner as in Example 5 and Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine -N- (4- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.43 (d, J = 7
Hz, 3H), 0.67 (d, J = 7Hz, 3H),
0.72-0.85 (m, 1H), 0.76 (d, J =
7 Hz, 3H), 1.17-1.38 (m, 2H),
1.94 (dq, J = 10, 7 Hz, 1H), 2.36
(M, 1H), 2.86 (dd, J = 14, 12Hz,
1H), 3.02 (dd, J = 14,5Hz, 1H),
4.26 (dd, J = 16, 6 Hz, 1H), 4.33
(Dd, J = 16,6 Hz, 1H), 4.71 (m, 1
H), 4.75 (s, 2H), 7.17 (d, J = 7H)
z, 2H), 7.30 (d, J = 6Hz, 2H), 7.
35 (s, 5H), 8.36-8.49 (m, 5H),
8.58 (dd, J = 6, 6 Hz, 1H), 11.00
(S, 1H). [Α] _D ²⁵ = + 2.2 ° (c0.35, 1N-HC
l) Melting point: 241-243 ° C HPLC: 5.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 532

Example 87 The following compound was obtained as in Example 2- (2). [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
Pyridylalanine-N-[(2S) -2,3-dihydroxypropyl] amide NMR (DMSO-d ₆ , δ): 0.36 (d, J = 7)
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.75-0.84 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.20-1.38 (m, 2H),
1.91 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.88-3.03 (m, 2H), 3.
13 (dd, J = 14.5 Hz, 1H), 3.19-
3.35 (m, 3H), 3.44 (m, 1H), 4.5
1 (t, J = 6 Hz, 1H), 4.68-4.85
(M, 4H), 7.18 (dd, J = 7.5, 5 Hz,
1H), 7.30 (d, J = 7.5 Hz, 1H), 7.
35 (s, 5H), 7.58 (t, J = 5Hz, 1
H), 7.67 (ddd, J = 7.5, 7.5, 1.5)
Hz, 1H), 8.33 (d, J = 8Hz, 1H),
8.45 (dd, J = 5, 1.5 Hz, 1H), 11.
01 (s, 1H). [Α] _D ²⁵ = -4.1 ° (c0.22, MeOH) Melting point: 207-213 ° C HPLC: 7.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 515

Example 88 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(3- hydroxy-3-methylbutyl) amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J =
6.6 Hz, 3 H), 0.74 (d, J = 6.1 Hz,
3H), 0.79 (d, J = 6.1 Hz, 3H), 0.
82 (m, 1H), 1.07 (s, 6H), 1.20-
1.51 (m, 4H), 1.94 (m, 1H), 2.3
3 (m, 1H), 2.95 (dd, J = 13.7, 1
0.7Hz, 1H), 3.01-3.16 (m, 3
H), 4.28 (s, 1H), 4.74 (m, 1H),
7.17 (dd, J = 7.2, 4.9 Hz, 1H),
7.29 (d, J = 7.6 Hz, 1H), 7.52 (d
d, J = 5.4, 5.1 Hz, 1H), 7.64 (dd
d, J = 7.6, 7.2, 1.1 Hz, 1H), 8.2
7 (d, J = 8.6 Hz, 1 H), 8.45 (br-
d, J = 4, 9 Hz, 1H), 8.72 (br, 1
H), 10.38 (br, 1H). [Α] _D ²⁰ = + 3.7 ° (c0.49, MeOH) Melting point: 180-182 ° C HPLC: 4.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 437

Example 89 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(2-anilinocarbonyl oxyethyl) amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J =
6.7 Hz, 3 H), 0.72 (d, J = 6.5 Hz,
3H), 0.75-0.90 (m, 1H), 0.79
(D, J = 6.4 Hz, 3H), 1.23-1.42
(M, 2H), 1.94 (dq, J = 10.3, 6.7)
Hz, 1H), 2.33 (m, 1H), 2.98 (d
d, J = 14.2, 10.6 Hz, 1H), 3.11
(Dd, J = 14.2, 4.7 Hz, 1H), 3.35
(M, 2H), 4.04 (m, 2H), 4.80 (dd
d, J = 10.6, 8.5, 4.7 Hz, 1H), 6.
98 (dd, J = 7.4, 7.3 Hz, 1H), 7.1
7 (dd, J = 7.6, 5.0 Hz, 1H), 7.22
-7.33 (m, 3H), 7.46 (d, J = 7.8H
z, 2H), 7.66 (ddd, J = 7.7, 7.6,
1.8 Hz, 1 H), 7.96 (t, J = 5.6 Hz,
1H), 8.29 (d, J = 8.5Hz, 1H), 8.
45 (br-d, J = 5.0 Hz, 1H), 8.71
(Br, 1H), 9.67 (s, 1H), 10.38
(Br, 1H). [Α] _D ²⁰ = + 15.2 ° (c0.46, MeO
H) Melting point: 185-186 ° C HPLC: 5.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 514

Example 90 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-Hydroxy-N-methylamino) succinyl]-
L-2-pyridylalanine-N-methylamide NMR
(DMSO-d ₆ , δ): 0.40 (d, J = 7.0H
z, 3H), 0.71 (d, J = 6.5Hz, 3H),
0.75-0.90 (m, 1H), 0.79 (d, J =
6.5Hz, 3H), 1.25 (m, 1H), 1.36
(M, 1H), 2.39 (ddd, J = 11.0, 1
0.7, 2.8 Hz, 1H), 2.57 (d, J = 4.
6Hz, 3H), 2.86-3.14 (m, 3H),
3.05 (s, 1H), 4.74 (m, 1H), 7.1
7 (dd, J = 7.2, 5.2 Hz, 1H), 7.29
(D, J = 7.7 Hz, 1H), 7.61−7.72
(M, 2H), 8.22 (d, J = 8.3 Hz, 1
H), 8.45 (dd, J = 5.2, 1.5 Hz, 1
H), 9.77 (s, 1H). [Α] _D ¹⁹ = + 4.2 ° (c0.40, MeOH) Melting point: 198-204 ° C HPLC: 5.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At 30 ° C), 3.1 mi
n. (MeCN: 0.05% TFAaq = 20: 80) MASS (FB ⁺ ): M + H = 379

Example 91 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2-[[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] carbonyloxy] ethyl] amide NMR (DMSO-d ₆ , δ: 0.39 (d, J =
6.6 Hz, 3 H), 0.72 (d, J = 6.5 Hz,
3H), 0.76-0.90 (m, 1H), 0.79
(D, J = 6.3 Hz, 3H), 1.20-1.42
(M, 2H), 1.65-2.02 (m, 5H), 2.
33 (m, 1H), 2.90-3.39 (m, 6H),
3.09 (dd, J = 13.7, 4.4 Hz, 1H),
3.46 (m, 1H), 3.70 (m, 1H), 3.9
0 (m, 2H) 4.63-4.86 (m, 1H), 7.
18 (dd, J = 7.2, 5.4 Hz, 1H), 7.3
0 (d, J = 7.4 Hz, 1H), 7.66 (ddd,
J = 7.4, 7.2, 1.6 Hz, 1H), 7.85
(Br, 1H), 8.30 (d, J = 7.6 Hz, 1
H), 8.45 (br-d, J = 5.4 Hz, 1H),
8.72 (br, 1H), 10.38 (br, 1H). [Α] _D ²¹ = −14.0 ° (c0.51, MeO
H) Melting point: 169-173 [deg.] C. HPLC: 5.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 522

Example 92 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(1-hydroxycyclohexyl) methyl] amide _{NMR (DMSO-d 6, δ} ): 0.36 (d, J =
6.8 Hz, 3 H), 0.73 (d, J = 6.3 Hz,
3H), 0.77-0.91 (m, 1H), 0.79
(D, J = 6.3 Hz, 3H), 1.09-1.63
(M, 12H), 1.94 (dq, J = 10.4, 6.
8 Hz, 1H), 2.33 (m, 1H), 2.96 (d
d, J = 13.8, 10.5 Hz, 1H), 3.04
(D, J = 5.6 Hz, 2H), 3.14 (dd, J =
13.8, 4.6 Hz, 1H), 4.21 (s, 1
H), 4.85 (ddd, J = 10.5, 8.2, 4.
6 Hz, 1 H), 7.18 (dd, J = 7.6, 5.0
Hz, 1H), 7.31 (d, J = 7.7Hz, 1
H), 7.41 (t, J = 5.6 Hz, 1H), 7.6
6 (ddd, J = 7.7, 7.6, 1.8 Hz, 1
H), 8.34 (d, J = 8.2 Hz, 1H), 8.4
5 (dd, J = 5.0, 1.8 Hz, 1H), 8.71
(S, 1H), 10.38 (s, 1H). [Α] _D ²⁰ = + 11.5 ° (c0.52, MeO
H) Melting point: 193-197 ° C HPLC: 5.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 463

Example 93 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl-alanine-N-[2-(iso-butoxycarbonylamino) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.46 (d, J =
6.6 Hz, 3H), 0.69-0.99 (m, 1
H), 0.74 (d, J = 6.3 Hz, 3H), 0.7
9 (d, J = 6.2 Hz, 3 H), 0.86 (d, J =
6.7 Hz, 6 H), 1.20-1.43 (m, 2
H), 1.81 (tqq, J = 6.7, 6.7, 6.7).
Hz, 1H), 1.98 (dq, J = 10.0, 6.6)
Hz, 1H), 2.37 (m, 1H), 2.90-3.
31 (m, 5H), 3.40 (m, 1H), 3.72
(D, J = 6.7 Hz, 2H), 4.78 (m, 1
H), 7.10 (m, 1H), 7.70-7.90.
(M, 2H), 8.02 (m, 1H), 8.35 (m,
1H), 8.42 (d, J = 8.3Hz, 1H), 8.
79 (br-d, J = 5.5 Hz, 1H), 10.45
(S, 1H). [Α] _D ²¹ = + 6.6 ° (c0.30, MeOH) Melting point: 192-196 ° C. (decomposition) HPLC: 8.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 494 (free M)
= 493.60)

Example 94 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridylalanine -N- methoxyamide _{NMR (DMSO-d 6, δ} ): 0.46 (d, J = 7
Hz, 3H), 0.74 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.85 (m, 1
H), 1.17-1.42 (m, 2H), 1.97 (d
q, J = 10,7 Hz, 1H), 2.36 (m, 1
H), 3.02 (d, J = 7 Hz, 2H), 3.49
(S, 3H), 4.65 (dt, J = 7, 7 Hz, 1
H), 7.20 (dd, J = 7.5 Hz, 1H), 7.
29 (d, J = 7 Hz, 1 H), 7.67 (dd, J =
7,7 Hz, 1 H), 8.37 (d, J = 7 Hz, 1
H), 8.46 (d, J = 5 Hz, 1H), 8.74
(S, 1H), 10.40 (br, 1H), 11.24
(Br, 1H). [Α] _D ²² = −2.2 ° (c0.10, MeOH) Melting point: 183-193 ° C. (decomposition) HPLC: 4.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 381

Example 95 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- [2- (N, N ' , N'- triethyl ureido) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.40 ( d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.84 (m, 1
H), 1.03 (t, J = 7 Hz, 9H), 1.21-
1.44 (m, 2H), 1.96 (dq, J = 10, 7)
Hz, 1H), 2.34 (m, 1H), 2.92-3.
23 (m, 12H), 4.76 (m, 1H), 7.18
(Dd, J = 7.5, 5 Hz, 1H), 7.30 (d,
J = 7.5 Hz, 1H), 7.67 (dd, J = 7.
5,7.5Hz, 1H), 7.81 (t, J = 5Hz,
1H), 8.28 (d, J = 8Hz, 1H), 8.46
(D, J = 5 Hz, 1H), 8.72 (s, 1H), 1
0.39 (s, 1H). [Α] _D ²¹ = + 4.6 ° (c0.31, MeOH) Melting point: 162-167 ° C HPLC: 9.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 521

Example 96 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(2-morpholinoethyl carbonyloxy ethyl) amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.76-0.95 (m, 1H), 0.80 (d, J =
7Hz, 3H), 1.17-1.46 (m, 2H),
1.94 (dq, J = 10, 7 Hz, 1H), 2.34
(M, 1H), 2.96 (dd, J = 14, 10 Hz,
1H), 3.09 (dd, J = 14.5Hz, 1H),
3.17-3.45 (m, 6H), 3.49-3.63
(M, 4H), 3.95 (m, 2H), 4.79 (dd
d, J = 10, 8, 5 Hz, 1H), 7.18 (dd,
J = 8, 5 Hz, 1 H), 7.30 (d, J = 8 Hz,
1H), 7.67 (ddd, J = 8, 8, 2 Hz, 1
H), 7.90 (t, J = 6 Hz, 1H), 8.30
(D, J = 8 Hz, 1H), 8.45 (dd, J = 5
2 Hz, 1H), 8.73 (s, 1H). 10.40
(S, 1H). [Α] _D ²² = + 13.3 ° (c0.03, MeO
H) Melting point: 189-198 ° C HPLC: 5.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 508

Example 97 [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
A solution of pyridylalanine-N-2- (N, N-diethylaminocarbonyloxyethyl) amide (363 mg) in methanol (7 ml) is hydrogen-reduced with 10% palladium-carbon (35 mg) under 3 atm of hydrogen. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give [(2R, 3S) -4- (N-hydroxyamino) -2-isobutyl-3-methylsuccinyl] -L.
-2-Pyridylalanine-N-2- (N, N-diethylaminocarbonyloxyethyl) amide (185 mg)
To get NMR (DMSO-d ₆ , δ): 0.38 (d, J =
6.8 Hz, 3 H), 0.73 (d, J = 6.5 Hz,
3H), 0.75-0.91 (m, 1H), 0.79
(D, J = 6.5 Hz, 3 H), 1.04 (t, J =
7.1 Hz, 6 H), 1.20-1.43 (m, 2
H), 1.94 (dq, J = 10.6, 6.8 Hz, 1
H), 2.33 (m, 1H), 2.89-3.43.
(M, 2H), 2.96 (dd, J = 13.8, 10.
1 Hz, 1 H), 3.08 (dd, J = 13.8, 4.
5Hz, 1H), 3.20 (q, J = 7.1Hz, 4
H), 3.92 (m, 2H), 4.80 (ddd, J =
10.1, 8.2, 4.5Hz, 1H), 7.18 (d
d, J = 7.2, 4.8 Hz, 1H), 7.30 (d,
J = 7.8 Hz, 1H), 7.66 (ddd, J = 7.
8, 7.2, 1.8 Hz, 1H), 7.87 (br-
t, J = 5.7 Hz, 1H), 8.28 (d, J = 8.
2Hz, 1H), 8.45 (dd, J = 4.8, 1.8)
Hz, 1H), 8.72 (s, 1H), 10.38
(S, 1H). [Α] _D ²¹ = + 5.5 ° (c0.30, MeOH) Melting point: 198-205 ° C HPLC: 6.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 494

Example 98 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(2-piperidinocarbonyl oxyethyl) amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J = 7
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.75-0.94 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.18-1.65 (m, 8H),
1.95 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.96 (dd, J = 14, 10 Hz,
1H), 3.09 (dd, J = 14, 4Hz, 1H),
3.15-3.52 (m, 6H), 3.92 (m, 2)
H), 4.79 (ddd, J = 10, 8, 4 Hz, 1
H), 7.18 (dd, J = 8, 5 Hz, 1H), 7.
30 (d, J = 8Hz, 1H), 7.67 (ddd, J
= 8,8,2 Hz, 1H), 7.89 (t, J = 8H
z, 1H), 8.37 (d, J = 8Hz, 1H), 8.
45 (dd, J = 5, 2 Hz, 1H), 8.73 (s,
1H), 10.39 (s, 1H) [α] _D ²¹ = +
7.4 ° (c0.28, MeOH) Melting point: 196-203 ° C HPLC: 7.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 506

Example 99 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- [2- [N- (2- hydroxyethyl) -N- methylamino] carbonyl oxy ethyl] amide _{NMR (DMSO-d 6, δ} ) : 0.39 (d, J =
6.6 Hz, 3 H), 0.73 (d, J = 6.2 Hz,
3H), 0.78-0.93 (m, 1H), 0.80
(D, J = 6.2 Hz, 3H), 1.22-1.45
(M, 2H), 1.94 (dq, J = 10.0, 6.6
Hz, 1H), 2.33 (m, 1H), 2.86 (d,
J = 5.1 Hz, 3H), 2.97 (dd, J = 13.
8, 10.4 Hz, 1 H), 3.12 (dd, J = 1
3.8, 4.5 Hz, 1H), 3.18-3.59
(M, 6H), 3.91 (m, 2H), 4.62-4.
88 (m, 2H), 7.18 (dd, J = 7.4, 4.
8Hz, 1H), 7.30 (d, J = 7.7Hz, 1
H), 7.67 (br-dd, J = 7.7, 7.4H)
z, 1H), 7.88 (br-t, J = 5.1 Hz, 1
H), 8.30 (d, J = 8.4 Hz, 1H), 8.4
5 (br-d, J = 4.8 Hz, 1H), 8.73
(S, 1H), 10.39 (s, 1H). [Α] _D ²⁴ = + 7.7 ° (c0.25, MeOH) Melting point: 187-191 ° C. HPLC: 13.1 min. (Nucleosil 5
C18, 4 mmφ x 15 cm, MeCN: 0.05% T
FAaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 496

Example 100 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(1-amino-piperidyl) amide _{NMR (DMSO-d 6, δ} ): 0.43 (d, J =
6.8 Hz, 3Hx2 / 3), 0.56 (d, J = 6.
7Hz, 3Hx1 / 3), 0.67-0.92 (m, 7
H), 1.21-1.69 (m, 8H), 1.96.
(M, 1H), 2.20-2.67 (m, 5H), 2.
84-3.11 (m, 2H), 4.68 (m, 1Hx2
/ 3), 5.44 (m, 1Hx1 / 3), 7.18 (d
d, J = 7.1, 5.2 Hz, 1H), 7.28 (d,
J = 7.7 Hz, 1H × 2/3), 7.29 (d, J =
7.7 Hz, 1Hx1 / 3), 7.66 (m, 1H),
8.12 (d, J = 8.6Hz, 1Hx1 / 3), 8.
29 (d, J = 8.4 Hz, 1Hx2 / 3), 8.40
(S, 1Hx1 / 3), 8.45 (m, 1H), 8.6
2 (s, 1H2 / 3), 8.71 (br, 1H), 1
0.38 (br, 1H). rotamer's peak
Is coming out. [Α] _D ²⁰ = + 14.9 ° (c0.52, MeO
H) Melting point: 202-206 ° C (decomposition) HPLC: 5.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 434

Example 101 The following compound was obtained in the same manner as in Example 97. [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridylalanine -N- methoxy -N- methylamide _{NMR (DMSO-d 6, δ} ): 0.45 (d, J = 7
Hz, 3H), 0.63-0.95 (m, 1H), 0.
73 (d, J = 7 Hz, 3 H), 0.81 (d, J = 7
Hz, 3H), 1.19-1.47 (m, 2H), 1.
96 (dq, J = 10, 7 Hz, 1H), 2.37
(M, 1H), 2.93 (dd, J = 14, 10 Hz,
1H), 3.07 (dd, J = 14, 4Hz, 1H),
3.13 (s, 3H), 3.76 (s, 3H), 5.2
8 (br, 1H), 7.19 (dd, J = 7.5, 5H
z, 1H), 7.31 (d, J = 7.5Hz, 1H),
7.68 (dd, J = 7.5, 7.5 Hz, 1H),
8.32 (br-d, J = 7.5 Hz, 1H), 8.4
8 (br-d, J = 5 Hz, 1H), 8.75 (br,
1H). 10.39 (s, 1H). [Α] _D ²² = + 17.1 ° (c0.20, MeO
H) Melting point: 168-176 ° C (decomposition) HPLC: 4.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 395

Example 102 The following compound was obtained as in Example 97. [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(4-ethoxycarbonyl) piperidino] amide _{NMR (DMSO-d 6, δ} ): 0.47 (m, 3
H), 0.65-0.82 (m, 4H), 0.79
(D, J = 6.4 Hz, 3H), 1.08-1.57
(M, 7H), 1.69-1.90 (m, 2H), 1.
99 (dq, J = 10.4, 6.6 Hz, 1H), 2.
37 (m, 1H), 2.52-2.78 (m, 2H),
2.95 (m, 1H), 3.01-3.20 (m, 2
H), 3.98-4.28 (m, 4H), 5.31.
(M, 1H), 7.18 (br-dd, J = 7.3,
3.5 Hz, 1 H), 7.27 (d, J = 7.7 Hz,
1H), 7.66 (br-dd, J = 7.7, 7.3H)
z, 1H), 8.35-8.50 (m, 2H), 8.7.
2 (s, 1H), 10.40 (s, 1H). [Α] _D ²¹ = + 14.6 ° (c0.51, MeO
H) Melting point: 181-188 ° C. HPLC: 6.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 491

Example 103 The following compound was obtained as in Example 97. [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(4-methylcarbamoyl) piperidino] amide _{NMR (DMSO-d 6, δ} ): 0.50 (m, 3
H), 0.73 (d, J = 6.2 Hz, 3H), 0.7
6-0.92 (m, 4H), 0.79 (d, J = 6.2)
Hz, 3H), 1.17-1.78 (m, 6H), 1.
97 (m, 1H), 2.23-2.44 (m, 2H),
2.55 (d, J = 4.4 Hz, 3H), 2.85-
3.13 (m, 4H), 4.15 (m, 1H), 4.2
9 (m, 1H), 5.30 (m, 1H), 7.18
(M, 1H), 7.28 (d, J = 7.9Hz, 1
H), 7.66 (m, 1H), 7.73 (m, 1H),
8.38 (br-d, J = 6.1 Hz, 1H), 8.4
7 (m, 1H), 8.72 (s, 1H), 10.40
(S, 1H). [Α] _D ²¹ = + 19.4 ° (c0.53, MeO
H) Melting point: 154-160 ° C HPLC: 7.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 476, M + Na = 4
98

Example 104 The following compound was obtained in the same manner as in Example 97. [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- [1- (4- acetyl) -piperazinyl] amide _{NMR (DMSO-d 6, δ} ): 0.51 (d, J =
6.6 Hz, 3 H), 0.73 (d, J = 6.2 Hz,
3H), 0.77-0.93 (m, 1H), 0.80
(D, J = 6.5 Hz, 3H), 1.22-1.43
(M, 2H), 1.99 (m, 1H), 2.02 (s,
3H), 2.38 (m, 1H), 2.99 (dd, J =
14.3, 8.4 Hz, 1H), 3.09 (dd, J =
14.3, 5.7 Hz, 1H), 3.20-3.79.
(M, 8H), 5.30 (m, 1H), 7.20 (br
-Dd, J = 7.6, 5.4 Hz, 1H), 7.30
(D, J = 7.7 Hz, 1H), 7.67 (br-d
d, J = 7.7, 7.6 Hz, 1H), 8.41-8.
53 (m, 2H), 8.73 (s, 1H), 10.41
(S, 1H). [Α] _D ²¹ = + 33.6 ° (c0.50, MeO
H) Melting point: 137-141 ° C HPLC: 7.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 462, M + Na = 4
84

Example 105 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [1- (4-ethoxycarbonyl)
Piperazinyl] amide NMR (DMSO-d ₆ , δ): 0.51 (d, J =
6.7 Hz, 3 H), 0.73 (d, J = 6.4 Hz,
3H), 0.75-0.92 (m, 1H), 0.79
(D, J = 6.5 Hz, 3H), 1.11-1.42
(M, 2H), 1.19 (t, J = 7.1 Hz, 3
H), 1.99 (dq, J = 10.6, 6.7 Hz, 1
H), 2.37 (m, 1H), 2.98 (dd, J = 1)
4.0, 8.5 Hz, 1H), 3.09 (dd, J = 1)
4.0, 5.3 Hz, 1H), 3.15-3.74
(M, 8H), 4.05 (q, J = 7.1Hz, 2
H), 5.29 (m, 1H), 7.19 (dd, J =
7.2, 5.4 Hz, 1H), 7.29 (d, J = 7.
6 Hz, 1 H), 7.67 (ddd, J = 7.6, 7.
2,1.6 Hz, 1H), 8.37-8.54 (m, 2
H), 8.72 (s, 1H), 10.40 (s, 1)
H). [Α] _D ²¹ = + 31.6 ° (c0.51, MeO
H) Melting point: 180-186 ° C HPLC: 4.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 492

Example 106 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl-alanine-N-[2-(phenoxycarbonyl) amino ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.42 (d, J = 7
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.77-0.95 (m, 1H), 0.80 (d, J =
7 Hz, 3H), 1.19-1.50 (m, 2H),
1.96 (dq, J = 10, 7 Hz, 1H), 2.35
(M, 1H), 2.88-3.54 (m, 6H), 4.
77 (m, 1H), 7.02-7.45 (m, 7H),
7.58-7.79 (m, 2H), 7.93 (m, 1
H), 8.28 (d, J = 8Hz, 1H), 8.46
(Br-d, J = 5 Hz, 1H), 8.73 (s, 1
H). 10.40 (s, 1H). [Α] _D ²¹ = + 12.0 ° (c0.10, MeO
H) Melting point: 240-250 ° C (decomposition) HPLC: 8.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 514

Example 107 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- [2- (N, N ' , N'- trimethyl ureido) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.30- 1.01
(M, 10H), 1.20-1.45 (m, 2H),
1.85-2.15 (m, 1H), 2.34 (m, 1
H), 2.68 (s, 6H), 2.73 (s, 3Hx4
/ 7), 2.74 (s, 3Hx3 / 7), 2.88-
3.29 (m, 6H), 4.75 (m, 1H), 7.1
2-7.35 (m, 2H), 7.66 (ddd, J =
7,7,1Hz, 1H), 7.87 (m, 1Hx4 /
7), 8.01 (m, 1Hx3 / 7), 8.28 (dd
d, J = 7, 7, 1 Hz, 1H), 8.46 (br-
d, J = 4 Hz, 1H), 8.74 (br, 1H). 1
The peak of 0.40 (br, 1H) rotormer appears. HPLC: 5.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 479

Example 108 In the same manner as in Example 97, the following compound was obtained. [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl-alanine-N-[2-(dimethylcarbamoyl) oxyethyl] amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.75-0.94 (m, 1H), 0.79 (d, J =
7 Hz, 3H), 1.18-1.49 (m, 2H),
1.95 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.81 (s, 6H), 2.96 (d
d, J = 14, 10 Hz, 1H), 3.10 (dd, J
= 14,5 Hz, 1 H), 3.15-3.47 (m, 2
H), 3.90 (t, J = 5 Hz, 2H), 4.79.
(Ddd, J = 10, 8, 5 Hz, 1H), 7.18
(D, J = 7.5, 5 Hz, 1H), 7.30 (d, J
= 7.5 Hz, 1H), 7.67 (ddd, J = 7.
5,7.5,2Hz, 1H), 7.87 (t, J = 5H
z, 1H), 8.30 (d, J = 8Hz, 1H), 8.
45 (dd, J = 5, 2 Hz, 1H), 8.73 (s,
1H). 10.40 (s, 1H). [Α] _D ²³ = + 48.1 ° (c0.20, DMS
O) Melting point: 194-202 ° C (decomposition) HPLC: 4.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 466

Example 109 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (N-methyl-N ', N'-
Diethylureido) ethyl] amide NMR (DMSO-d ₆ , δ): 0.39 (d, J = 7)
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.77-0.91 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.02 (t, J = 7Hz, 6H),
1.21-1.42 (m, 2H), 1.95 (m, 1
H), 2.32 (m, 1H), 2.73 (s, 3H),
2.89-3.31 (m, 10H), 4.75 (M, 1
H), 7.18 (dd, J = 7.5, 5 Hz, 1H),
7.29 (d, J = 7.5 Hz, 1H), 7.66 (d
dd, J = 7.5, 7.5, 1 Hz, 1H), 7.78
(T, J = 5 Hz, 1 H), 8.26 (d, J = 7.5)
Hz, 1H), 8.45 (dd, J = 5, 1Hz, 1
H), 8.74 (br, 1H). 1H. HPLC: 6.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 507, M + Na = 5
29

Example 110 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (N-ethyl-N ', N'-
Dimethylureido) ethyl] amide NMR (DMSO-d ₆ , δ): 0.40 (d, J = 7)
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.79 (d, J = 7 Hz, 3H), 0.95-1.1
0 (m, 4H), 1.20-1.46 (m, 2H),
1.94 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.70 (s, 6H), 2.87-3.
23 (m, 8H), 4.75 (m, 1H), 7.19
(D, J = 7.5 Hz, 1H), 7.30 (d, J = 7
Hz, 1H), 7.67 (ddd, J = 7, 7, 1H
z, 1H), 7.82 (br-t, J = 5Hz, 1
H), 8.28 (d, J = 8Hz, 1H), 8.45
(Dd, J = 5, 1 Hz, 1H), 8.73 (br, 1
H). 10.40 (s, 1H). [Α] _D ²¹ = + 5.8 ° (c0.32, MeOH) Melting point: 166-171 ° C HPLC: 7.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 493, M + Na = 5
15

Example 111 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(2-phenethyl) amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J =
6.8Hz, 3H), 0.63-0.95 (m, 1
H), 0.73 (d, J = 6.5 Hz, 3H), 0.7
9 (d, J = 6.2 Hz, 3H), 1.20-1.45
(M, 2H), 1.95 (dq, J = 10.1, 6.8)
Hz, 1H), 2.33 (m, 1H), 2.66 (t,
J = 7.6 Hz, 2H), 2.93 (dd, J = 13.
9,10.5Hz, 1H), 3.04 (dd, J = 1)
3.9, 4.6 Hz, 1H), 3.14-3.45.
(M, 2H), 4.76 (ddd, J = 10.5, 8.
1, 4.6 Hz, 1 H), 7.08-7.37 (m, 7
H), 7.66 (ddd, J = 7.6, 7.6, 1.7)
Hz, 1H), 7.82 (t, J = 5.6Hz, 1
H), 8.26 (d, J = 8.1 Hz, 1H), 8.4
5 (br-d, J = 3.7 Hz, 1H), 8.71
(S, 1H), 10.38 (s, 1H). [Α] _D ²⁰ = + 8.9 ° (c0.35, MeOH) Melting point: 212-215 ° C (decomposition) HPLC: 6.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 455

Example 112 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(2-morpholinoethyl) amide _{NMR (DMSO-d 6, δ} ): 0.46 (d, J =
6.5 Hz, 3 H), 0.72 (d, J = 6.6 Hz,
3H), 0.77 (d, J = 6.5Hz, 3H), 0.
87 (m, 1H), 1.24 (m, 1H), 1.34
(M, 1H), 1.96 (m, 1H), 2.22-2.
40 (m, 7H), 2.97 (dd, J = 13.8, 1
0.5 Hz, 1 H), 3.06-3.24 (m, 3
H), 3.55 (t, J = 4.6 Hz, 4H), 4.7
3 (m, 1H), 7.17 (dd, J = 7.7, 4.9)
Hz, 1H), 7.29 (d, J = 7.7Hz, 1
H), 7.66 (ddd, J = 7.7, 7.7, 1.9)
Hz, 1H), 7.76 (m, 1H), 8.45 (br
-D, J = 4.9 Hz, 1H), 8.50 (m, 1
H). [Α] _D ²⁷ = + 0.7 ° (c0.37, MeOH) Melting point: 191-197 ° C. (decomposition) HPLC: 4.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 464, M + Na = 4
86

Example 113 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- (2,2,2- trifluoroethyl) amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.78 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.23-1.41 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.33 (m, 1
H), 3.00 (dq, J = 14, 10 Hz, 1H),
3.09 (dd, J = 14, 4 Hz, 1H), 3.90
(M, 2H), 4.88 (ddd, J = 10, 8, 4H
z, 1H), 7.18 (dd, J = 7.5, 5 Hz, 1
H), 7.30 (d, J = 7.5 Hz, 1H), 7.6
7 (ddd, J = 7.5, 7.5, 1.5 Hz, 1
H), 8.35 (d, J = 7.5 Hz, 1H), 8.4
4-8.52 (m, 2H), 8.72 (br, 1H),
10.37 (br, 1H). [Α] _D ²⁸ = + 2.4 ° (c0.31, MeOH) Melting point: 200-205 ° C. (decomposition) HPLC: 6.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 433

Example 114 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- (4- hydroxypiperidino) amide _{NMR (DMSO-d 6, δ} ): 0.51 (m, 3
H), 0.73 (m, 3H), 0.76-0.90
(M, 4H), 1.12-1.42 (m, 3H), 1.
56-1.81 (m, 2H), 1.98 (dq, J = 1
0,7 Hz, 1H), 2.36 (m, 1H), 2.87
-3.12 (m, 4H), 3.25 (m, 1H), 3.
67 (m, 1H), 3.75-3.94 (m, 2H),
4.74 (m, 1H), 5.30 (m, 1H), 7.1
8 (dd, J = 8, 5 Hz, 1H), 7.27 (d, J
= 8 Hz, 1 H), 7.66 (dd, J = 8,8 Hz,
1H), 8.38 (d, J = 8Hz, 1H), 8.46
(Br-d, J = 5 Hz, 1H), 8.71 (s, 1
H), 10.40 (s, 1H). [Α] _D ²³ = + 21.3 ° (c0.30, MeO
H) Melting point: 190-193 ° C HPLC: 6.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 435

Example 115 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(2R) -2- hydroxypropyl] amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 0.98 (d, J = 7 Hz, 3H), 1.23-
1.43 (m, 2H), 1.95 (dq, J = 10, 7)
Hz, 1H), 2.33 (m, 1H), 2.91-3.
06 (m, 3H), 3.13 (dd, J = 14, 4H
z, 1H), 3.60 (m, 1H), 4.67 (d, J
= 5 Hz, 1H), 4.80 (m, 1H), 7.18
(D, J = 7.5 Hz, 1H), 7.30 (d, J = 8
Hz, 1H), 7.57 (dd, J = 5, 5 Hz, 1
H), 7.67 (ddd, J = 8, 7, 2 Hz, 1
H), 8.30 (d, J = 8 Hz, 1H), 8.45
(Dd, J = 5, 2 Hz, 1H), 8.72 (s, 1
H), 10.38 (s, 1H). [Α] _D ²³ = + 21.3 ° (c0.30, MeO
H) Melting point: 190-193 ° C HPLC: 6.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 409

Example 116 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(2S) -2- hydroxypropyl] amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 0.97 (d, J = 7 Hz, 3H), 1.24-
1.42 (m, 2H), 1.95 (dq, J = 10, 7)
Hz, 1H), 2.34 (m, 1H), 2.91-3.
09 (m, 3H), 3.12 (dd, J = 14,5H)
z, 1H), 3.59 (m, 1H), 4.64 (d, J
= 5 Hz, 1H), 4.80 (m, 1H), 7.18
(Dd, J = 7.5 Hz, 1H), 7.30 (d, J =
8Hz, 1H), 7.55 (dd, J = 5, 5Hz, 1
H), 7.66 (ddd, J = 8, 7, 2 Hz, 1
H), 8.30 (d, J = 8 Hz, 1H), 8.45
(Dd, J = 5, 2 Hz, 1H), 8.71 (s, 1
H), 10.37 (s, 1H). [Α] _D ²³ = + 17.9 ° (c0.29, MeO
H) Melting point: 202-206 ° C HPLC: 6.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 409

Example 117 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (4-phenoxypiperidino) amide NMR (DMSO-d < ₆ >, [delta]): 0.53 (m, 3).
H), 0.75 (d, J = 7 Hz, 3H), 0.80
(D, J = 7 Hz, 3H), 0.85 (m, 1H),
1.22-1.68 (m, 4H), 1.76-2.08
(M, 3H), 2.40 (m, 1H), 2.97 (d
d, J = 14.8 Hz, 1H), 3.04-3.57
(M, 3H), 3.74-4.05 (m, 2H), 4.
61 (m, 1H), 5.34 (m, 1H), 6.87-
7.03 (m, 3H), 7.20 (m, 1H), 7.2
4-7.34 (m, 3H), 7.66 (dd, J = 7.
5,7.5 Hz, 1H), 8.44 (m, 1H), 8.
48 (d, J = 5 Hz, 1 H), 8.72 (s, 1
H), 10.40 (s, 1H). [Α] _D ²⁵ = + 34.5 ° (c0.17, MeO
H) Melting point: 180-184 ° C HPLC: 5.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 511

Example 118 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridylalanine -N- methylamide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.84 (m, 1
H), 1.21-1.41 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.35 (m, 1
H), 2.59 (d, J = 5 Hz, 3H), 2.81
(Dd, J = 14, 11 Hz, 1H), 2.95 (d
d, J = 14.5 Hz, 1H), 4.58 (ddd, J
= 11, 8, 5 Hz, 1H), 7.29 (d, J = 7H
z, 2H), 7.82 (q, J = 5Hz, 1H), 8.
25 (d, J = 8Hz, 1H), 8.42 (d, J = 7)
Hz, 2H), 8.71 (s, 1H), 10.37
(S, 1H). [Α] _D ²⁵ = + 13.6 ° (c0.32, MeO
H) Melting point: 253-261 ° C (decomposition) HPLC: 5.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 365

Example 119 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridyl-alanine-N-(2-Asetamidoechiru) amide _{NMR (DMSO-d 6, δ} ): 0.41 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.81 (d, J = 7Hz, 3H), 0.84 (m, 1
H), 1.20-1.42 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.35 (m, 1
H), 2.81 (dd, J = 14, 11 Hz, 1H),
2.92-3.21 (m, 5H), 4.58 (m, 1
H), 7.30 (d, J = 7 Hz, 2H), 7.82
(Br-t, J = 4 Hz, 1H), 7.98 (br-
t, J = 4 Hz, 1 H), 8.26 (d, J = 8 Hz,
1H), 8.42 (d, J = 7Hz, 2H), 8.72
(S, 1H), 10.38 (s, 1H). [Α] _D
²² = + 10.2 ° (c0.33, MeOH) Melting point: 247-252 ° C. (decomposition) HPLC: 4.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 436

Example 120 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridyl-alanine-N-(2-hydroxyethyl) amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.21-1.42 (m, 2H), 1.94 (d
q, J = 10,7 Hz, 1H), 2.33 (m, 1
H), 2.80 (dd, J = 14, 12 Hz, 1H),
2.99 (dd, J = 14.5 Hz, 1H), 3.13
(Dt, J = 7.5 Hz, 2H), 3.36 (dt, J
= 7, 5 Hz, 2H), 4.64 (ddd, J = 12,
8.5Hz, 1H), 4.68 (t, J = 5Hz, 1
H), 7.30 (d, J = 6 Hz, 2H), 7.82
(T, J = 5 Hz, 1H), 8.26 (d, J = 8H
z, 1H), 8.42 (d, J = 6Hz, 2H), 8.
72 (s, 1H), 10.38 (s, 1H). [Α] _D ²² = + 17.4 ° (c0.25, 1N-H
Cl) Melting point: 229-234 ° C (decomposition) HPLC: 3.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 395

Example 121 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(1R) -1- benzyloxymethyl-2-hydroxyethyl] amide _{NMR (DMSO-d 6, δ} ): 0.35 (d , J = 7
Hz, 3H), 0.69 (d, J = 7Hz, 3H),
0.77 (d, J = 7Hz, 3H), 0.81 (m, 1
H), 1.21-1.43 (m, 2H), 1.94 (d
q, J = 10,7 Hz, 1H), 2.32 (m, 1
H), 2.97 (dd, J = 14, 10 Hz, 1H),
3.13 (dd, J = 14.5 Hz, 1H), 3.30
-3.48 (m, 4H), 3.88 (m, 1H), 4.
48 (s, 2H), 4.77 (t, J = 5Hz, 1
H), 4.83 (ddd, J = 10, 8, 5 Hz, 1
H), 7.17 (dd, J = 7.5, 5 Hz, 1H),
7.23-7.45 (m, 5H), 7.30 (d, J =
7.5 Hz, 1 H), 7.40 (d, J = 7.5 Hz,
1H), 7.66 (ddd, J = 7.5, 7.5, 1.
5Hz, 1H), 8.35 (d, J = 8Hz, 1H),
8.44 (dd, J = 5, 1.5 Hz, 1H), 8.7
1 (s, 1H), 10.39 (s, 1H). [Α] _D ²⁵ = + 12.5 ° (c0.22, MeO
H) Melting point: 201-205 ° C HPLC: 5.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + Na = 537, M + H = 5
15

Example 122 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridylalanine -N - [(1R) -1- benzyloxymethyl-2-hydroxyethyl] amide _{NMR (DMSO-d 6, δ} ): 0.34 (d , J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.77 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.20-1.40 (m, 2H), 1.93 (d
q, J = 10,7 Hz, 1H), 2.32 (m, 1
H), 2.79 (dd, J = 14, 11 Hz, 1H),
3.00 (dd, J = 14, 4 Hz, 1H), 3.34
-3.48 (m, 4H), 3.90 (m, 1H), 4.
48 (s, 2H), 4.70 (ddd, J = 11, 8,
4Hz, 1H), 4.75 (t, J = 5Hz, 1H),
7.23-7.40 (m, 5H), 7.30 (d, J =
7Hz, 1H), 7.63 (d, J = 8Hz, 1H),
8.29 (d, J = 8 Hz, 1H), 8.41 (d, J
= 7 Hz, 2H), 8.71 (s, 1H), 10.38
(S, 1H). [Α] _D ²⁵ = + 18.1 ° (c0.20, MeO
H) Melting point: 227-231 ° C HPLC: 5.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 515

Example 123 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N'- acetyl hydrazide _{NMR (DMSO-d 6, δ} ): 0.35 (d, J = 7
Hz, 3Hx9 / 10), 0.44 (d, J = 7Hz,
3Hx1 / 10), 0.71 (d, J = 7Hz, 3
H), 0.74-0.90 (m, 1H), 0.78
(D, J = 7 Hz, 3 H), 1.22-1.42 (m,
2H), 1.85 (s, 3H), 1.93 (m, 1
H), 2.31 (m, 1H), 3.00 (dd, J = 1
4,12Hz, 1H), 3.15 (dd, J = 14, 4)
Hz, 1H), 4.87 (ddd, J = 12, 8, 4H
z, 1H), 7.19 (dd, J = 7.5, 5 Hz, 1
H), 7.32 (d, J = 5 Hz, 1Hx1 / 10),
7.35 (d, J = 5 Hz, 1Hx9 / 10), 7.6
6 (ddd, J = 7.5, 7.5, 1.5 Hz, 1
H), 8.25 (d, J = 8Hz, 1Hx9 / 10),
8.38 (d, J = 8 Hz, 1Hx1 / 10), 8.4
6 (br, 1Hx9 / 10), 8.97 (br, 1Hx
1/10), 9.86 (br, 1H), 10.32 (b
r, 1H). [Α] _D ²⁵ = -16.3 ° (c0.32, 1N-H
Cl) Melting point: 203-213 [deg.] C. HPLC: 3.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 408

Example 124 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- (cyclopropylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.08-0.16
(M, 2H), 0.30-0.43 (m, 5H), 0.
74 (d, J = 7 Hz, 3H), 0.77-0.90
(M, 2H), 0.80 (d, J = 7Hz, 3H),
1.23-1.44 (m, 2H), 1.94 (dq, J
= 10, 7 Hz, 1H), 2.34 (m, 1H), 2.
88-3.02 (m, 3H), 3.10 (dd, J = 1)
4,4 Hz, 1H), 4.79 (m, 1H), 7.17
(Dd, J = 7.5, 5 Hz, 1H), 7.29 (d,
J = 7.5 Hz, 1H), 7.56-7.71 (m, 2
H), 8.30 (d, J = 8 Hz, 1H), 8.45
(Br-d, J = 5 Hz, 1H), 8.72 (s, 1
H), 10.38 (s, 1H). [Α] _D ²⁵ = + 3.5 ° (c0.20, MeOH) Melting point: 208-212 ° C. HPLC: 7.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 405

Example 125 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridylalanine -N- (cyclopropylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.09-0.18
(M, 2H), 0.31-0.47 (m, 5H), 0.
73 (d, J = 7 Hz, 3H), 0.76-0.93
(M, 2H), 0.80 (d, J = 7Hz, 3H),
1.21-1.42 (m, 2H), 1.95 (dq, J
= 10, 7 Hz, 1H), 2.34 (m, 1H), 2.
80 (dd, J = 14, 12 Hz, 1H), 2.90-
3.03 (m, 3H), 4.64 (m, 1H), 7.2
0 (d, J = 7 Hz, 1H), 7.83 (t, J = 5H
z, 1H), 8.28 (d, J = 8Hz, 1H), 8.
43 (d, J = 7 Hz, 2H), 8.72 (s, 1
H), 10.38 (s, 1H). [Α] _D ²⁵ = + 13.0 ° (c0.22, MeO
H) Melting point: 244-247 ° C (decomposition) HPLC: 6.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 405

Example 126 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- (cyclobutyl) amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J = 7
Hz, 3H), 0.74 (d, J = 7Hz, 3H),
0.81 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 1.21-1.45 (m, 2H), 1.51-
1.67 (m, 2H), 1.70-1.87 (m, 2
H), 1.94 (dq, J = 10, 7 Hz, 1H),
2.03-2.21 (m, 2H), 2.33 (m, 1
H), 2.94 (dd, J = 14, 11 Hz, 1H),
3.08 (dd, J = 14.5 Hz, 1H), 4.15
(M, 1H), 4.72 (ddd, J = 11,8,5H
z, 1H), 7.17 (dd, J = 7.5, 5 Hz, 1
H), 7.28 (d, J = 7.5 Hz, 1H), 7.6
6 (ddd, J = 7.5, 7.5, 1.5 Hz, 1
H), 7.80 (d, J = 8Hz, 1H), 8.24
(D, J = 8 Hz, 1H), 8.44 (dd, J = 5
1.5Hz, 1H), 8.71 (s, 1H), 10.3
8 (s, 1H). [Α] _D ²⁵ = + 10.5 ° (c0.22, MeO
H) Melting point: 217-220 ° C (decomposition) HPLC: 4.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 405

Example 127 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (cyclopropyl) amide NMR
(DMSO-d ₆ , δ): 0.22-0.36 (m, 2
H), 0.40 (d, J = 7 Hz, 3H), 0.53-
0.68 (m, 2H), 0.75 (d, J = 7Hz, 3
H), 0.80 (d, J = 7 Hz, 3H), 0.82
(M, 1H), 1.19-1.41 (m, 2H), 1.
94 (dq, J = 10, 7 Hz, 1H), 2.32 (d
dd, J = 11, 10, 3 Hz, 1H), 2.59
(M, 1H), 2.94 (dd, J = 14, 11 Hz,
1H), 3.06 (dd, J = 14, 4Hz, 1H),
4.69 (ddd, J = 11,8,4Hz, 1H),
7.18 (dd, J = 7.5, 5 Hz, 1H), 7.2
7 (d, J = 7.5 Hz, 1H), 7.66 (dd, J
= 7.5, 7.5 Hz, 1H), 7.74 (d, J = 4)
Hz, 1H), 8.22 (d, J = 8Hz, 1H),
8.45 (br-d, J = 5 Hz, 1H), 8.71
(S, 1H), 10.40 (s, 1H). [Α] _D ²⁵ = + 7.7 ° (c0.21, MeOH) Melting point: 230-237 ° C. (decomposition) HPLC: 4.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 391

Example 128 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-4-pyridylalanine-N- [2- (4-hydroxyphenyl)
Ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 1.23-1.41 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.35 (m, 1
H), 2.56 (m, 2H), 2.76 (dd, J = 1)
4,11Hz, 1H), 2.89 (dd, J = 14, 4)
Hz, 1H), 3.22 (m, 2H), 4.61 (dd
d, J = 1, 8, 4 Hz, 1H), 6.67 (d, J
= 8 Hz, 2 H), 6.98 (d, J = 8 Hz, 2
H), 7.27 (d, J = 6 Hz, 2H), 7.91
(T, J = 5 Hz, 1H), 8.24 (d, J = 8H
z, 1H), 8.42 (d, J = 6Hz, 1H), 8.
71 (s, 1H), 9.16 (s, 1H), 10.37
(S, 1H). [Α] _D ²⁵ = + 15.3 ° (c0.46, 1N-H
Cl) Melting point: 233-246 ° C (decomposition) HPLC: 4.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 471

Example 129 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (4-hydroxyphenyl)
Ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.79 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 1.21-1.42 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.33 (m, 1
H), 2.53 (m, 2H), 2.94 (dd, J = 1)
4,11Hz, 1H), 3.05 (dd, J = 14,5)
Hz, 1H), 3.20 (m, 2H), 4.75 (dd
d, J = 1, 8, 5 Hz, 1H), 6.66 (d, J
= 8 Hz, 2 H), 6.97 (d, J = 8 Hz, 2
H), 7.17 (dd, J = 7.5, 5 Hz, 1H),
7.28 (d, J = 7.5 Hz, 1H), 7.66 (d
dd, J = 7.5, 7.5, 1.5 Hz, 1H), 7.
73 (t, J = 5 Hz, 1H), 8.26 (d, J = 8)
Hz, 1H), 8.45 (dd, J = 5, 1.5 Hz,
1H), 8.71 (br, 1H), 9.16 (br, 1
H), 10.37 (br, 1H). [Α] _D ²⁵ = +
13.2 ° (c0.31, 1N-HCl) Melting point: 220-223 ° C HPLC: 5.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 471

Example 130 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridylalanine -N- [2- (3,4- dihydroxyphenyl) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.40 (d, J = 7
Hz, 3H), 0.74 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 1.22-1.42 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.33 (m, 1
H), 2.48 (m, 2H), 2.77 (dd, J = 1)
4,12Hz, 1H), 2.91 (dd, J = 14, 8)
Hz, 1H), 3.19 (m, 2H), 4.59 (dd
d, J = 12, 8, 4 Hz, 1H), 6.42 (dd,
J = 7.5, 1 Hz, 1H), 6.57 (d, J = 1H
z, 1H), 6.62 (d, J = 7.5Hz, 1H),
7.28 (d, J = 7 Hz, 2H), 7.90 (t, J
= 4 Hz, 1 H), 8.26 (d, J = 8 Hz, 1
H), 8.41 (d, J = 7 Hz, 2H), 8.55-
8.85 (br, 3H), 10.38 (br, 1H). [Α] _D ²⁵ = + 9.9 ° (c0.31,1N-HC
l) Melting point: 219-223 ° C HPLC: 6.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 487

Example 131 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- [2- (3,4- dihydroxyphenyl) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.39 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.79 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.21-1.43 (m, 2H), 1.95.
(M, 1H), 2.35 (m, 1H), 2.46 (m,
2H), 2.95 (dd, J = 14, 12Hz, 1
H), 3.07 (dd, J = 14.4 Hz, 1H),
3.17 (m, 2H), 4.76 (ddd, J = 12,
8,4 Hz, 1H), 6.41 (dd, J = 8,1H
z, 1H), 6.57 (d, J = 1 Hz, 1H), 6.
62 (d, J = 8 Hz, 1 H), 7.17 (dd, J =
7.5, 5 Hz, 1H), 7.27 (d, J = 7.5H
z, 1H), 7.66 (dd, J = 7.5, 7.5H
z, 1H), 7.72 (t, J = 4Hz, 1H), 8.
25 (d, J = 8 Hz, 1H), 8.45 (d, J = 5)
Hz, 1H), 8.55-8.84 (br, 3H), 1
0.35 (s, 1H). [Α] _D ²⁵ = + 8.3 ° (c0.21,1N-HC
l) Melting point: 191-195 ° C. HPLC: 6.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 487

Example 132 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridylalanine -N - [(2S) -2,3- dihydroxypropyl] amide _{NMR (DMSO-d 6, δ} ): 0.35 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.76-0.89 (m, 1H), 0.80 (d, J =
7Hz, 3H), 1.21-1.40 (m, 2H),
1.93 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.78 (dd, J = 14, 12Hz,
1H), 2.91-3.05 (m, 2H), 3.16-
3.36 (m, 3H), 3.46 (m, 1H), 4.5
0 (t, J = 6 Hz, 1H), 4.68 (m, 1H),
4.77 (d, J = 7 Hz, 1 H), 7.30 (d, J
= 6 Hz, 2 H), 7.81 (t, J = 5 Hz, 1
H), 8.26 (d, J = 8 Hz, 1H), 8.41
(D, J = 6 Hz, 2H), 8.71 (s, 1H), 1
0.38 (s, 1H). [Α] _D ²⁶ = + 10.9 ° (c0.24, MeO
H) Melting point: 213-217 ° C HPLC: 3.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 425

Example 133 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(2-pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.41 (d, J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.75 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.28 (m, 1H), 1.38 (m, 1H),
1.96 (dq, J = 10, 7 Hz, 1H), 2.35
(M, 1H), 3.03 (dd, J = 14, 11 Hz,
1H), 3.18 (dd, J = 14,5Hz, 1H),
4.35 (d, J = 6 Hz, 2H), 4.90 (m, 1
H), 7.15-7.23 (m, 2H), 7.25 (d
d, J = 7.5, 5 Hz, 1H), 7.32 (d, J =
7.5 Hz, 1 H), 7.62-7.75 (m, 2
H), 8.29-8.42 (m, 2H), 8.44-
8.53 (m, 2H), 8.72 (s, 1H), 10.
38 (s, 1H). [Α] _D ²⁶ = + 3.5 ° (c0.32, 1N-HC
l) Melting point: 230-236 ° C. HPLC: 8.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 442, M-H = 440

Example 134 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- [2- (2- pyridyl) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.38 (d, J = 7
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.78 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.21-1.42 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.33 (m, 1
H), 2.82 (t, J = 7 Hz, 2H), 2.93.
(Dd, J = 14, 10 Hz, 1H), 3.04 (d
d, J = 14, 4 Hz, 1H), 3.41 (m, 2)
H), 4.75 (ddd, J = 10, 8, 4 Hz, 1
H), 7.13-7.25 (m, 3H), 7.28.
(D, J = 7.5 Hz, 1H), 7.61-7.73
(M, 2H), 7.83 (t, J = 6Hz, 1H),
8.26 (d, J = 8 Hz, 1H), 8.44 (br-
d, J = 5 Hz, 1H), 8.49 (br-d, J = 5)
Hz, 1H), 8.71 (s, 1H), 10.38
(S, 1H). [Α] _D ²⁵ = + 11.2 ° (c0.39, 1N-H
Cl) Melting point: 210-212 [deg.] C. HPLC: 6.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 456, MH = 454

Example 135 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine-N-(3- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.42 (d, J = 7
Hz, 3H), 0.67 (d, J = 7Hz, 3H),
0.73 (d, J = 7Hz, 3H), 0.81 (m, 1
H), 1.21 (m, 1H), 1.34 (m, 1H),
1.95 (dq, J = 10, 7 Hz, 1H), 2.34
(M, 1H), 3.00 (dd, J = 14, 11 Hz,
1H), 3.12 (dd, J = 14,5Hz, 1H),
4.25 (dd, J = 15, 7 Hz, 1H), 4.31
(Dd, J = 15,7 Hz, 1H), 4.85 (m, 1
H), 7.28 (dd, J = 7.5, 5 Hz, 1H),
7.26-7.34 (m, 2H), 7.57 (br-
d, J = 7.5 Hz, 1H), 7.65 (dd, J =
7.5, 7.5 Hz, 1H), 8.28-8.39
(M, 2H), 8.41-8.49 (m, 3H), 8.
71 (s, 1H), 10.38 (s, 1H). [Α] _D ²⁵ = + 10.7 ° (c0.37, 1N−H
Cl) Melting point: 236-239 ° C HPLC: 3.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): MH = 440

Example 136 In the same manner as in Example 3- (1), the following compound is obtained. [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N- (4- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.45 (d, J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.75 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 1.21 (m, 1H), 1.37 (m, 1H),
1.98 (dq, J = 10,7 Hz, 1H), 2.36
(M, 1H), 3.03 (dd, J = 14, 11 Hz,
1H), 3.14 (dd, J = 14, 6 Hz, 1H),
4.25 (dd, J = 15, 7.5 Hz, 1H), 4.
30 (dd, J = 15, 7.5 Hz, 1H), 4.89
(Ddd, J = 11,8,6 Hz, 1H), 7.16
(D, J = 6 Hz, 2H), 7.20 (dd, J = 7.
5,5 Hz, 1 H), 7.31 (d, J = 7.5 Hz,
1H), 7.68 (dd, J = 7.5, 7.5 Hz, 1
H), 8.36 (d, J = 8Hz, 1H), 8.40-
8.51 (m, 4H), 8.72 (s, 1H), 10.
39 (s, 1H). [Α] _D ²⁵ = + 15.8 ° (c0.39, 1N-H
Cl) Melting point: 230-235 ° C HPLC: 3.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): MH = 440

Example 137 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-4-pyridylalanine-N- (2-pyridylmethyl) amide NMR (DMSO-d < ₆ >, [delta]): 0.40 (d, J = 7).
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.77 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 1.19-1.42 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.36 (ddd, J
= 11, 10, 3 Hz, 1H), 2.85 (dd, J =
14, 12Hz, 1H), 3.04 (dd, J = 14,
4Hz, 1H), 4.32 (dd, J = 15, 5Hz,
1H), 4.40 (dd, J = 15, 5Hz, 1H),
4.74 (ddd, J = 12, 8, 4 Hz, 1H),
7.20 (d, J = 8 Hz, 1H), 7.26 (dd,
J = 8, 5 Hz, 1 H), 7.32 (d, J = 6 Hz,
2H), 7.70 (ddd, J = 8, 8, 1.5 Hz,
1H), 8.35 (d, J = 8Hz, 1H), 8.43
(D, J = 6 Hz, 2H), 8.46-8.55 (m,
2H), 8.72 (s, 1H), 10.38 (s, 1
H). [Α] _D ²⁵ = + 10.6 ° (c0.36, 1N-H
Cl) Melting point: 241-246 ° C HPLC: 3.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 442

Example 138 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridyl-alanine-N-(3- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.41 (d, J = 7
Hz, 3H), 0.68 (d, J = 7Hz, 3H),
0.75 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.23 (m, 1H), 1.33 (m, 1H),
1.95 (dq, J = 10, 7 Hz, 1H), 2.35
(Ddd, J = 11, 10, 3 Hz, 1H), 2.84
(Dd, J = 14, 12 Hz, 1H), 2.99 (d
d, J = 14.5 Hz, 1H), 4.25 (dd, J =
15,6 Hz, 1H), 4.34 (dd, J = 15,6)
Hz, 1H), 4.69 (ddd, J = 12, 8, 4H
z, 1H), 7.25-7.34 (m, 1H), 7.2
9 (d, J = 7 Hz, 2H), 7.57 (br-d, J
= 7.5 Hz, 1 H), 8.34 (d, J = 8 Hz, 1
H), 8.38-8.52 (m, 4H), 8.72.
(S, 1H), 10.38 (s, 1H). [Α] _D ²⁵ = + 16.7 ° (c0.38, 1N-H
Cl) Melting point: 223-233 ° C HPLC: 3.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 442

Example 139 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- [2- (2-pyridylcarbonyl)
Aminoethyl] amide NMR (DMSO-d ₆ , δ): 0.41 (d, J = 7)
Hz, 3H), 0.70 (d, J = 7Hz, 3H),
0.76 (d, J = 7Hz, 3H), 0.82 (m, 1
H), 1.21-1.40 (m, 2H), 1.95 (d
q, J = 10,7 Hz, 1H), 2.32 (ddd, J
= 10,10,3 Hz, 1H), 2.96 (dd, J =
14, 11 Hz, 1H), 3.04-3.42 (m, 4
H), 3.10 (dd, J = 14.5 Hz, 1H),
4.77 (ddd, J = 11,8,5 Hz, 1H),
7.15 (dd, J = 7.5, 5 Hz, 2H), 7.2
8 (d, J = 7.5 Hz, 1H), 7.57-7.69
(M, 2H), 7.91-8.07 (m, 3H), 8.
24 (d, J = 8 Hz, 1 H), 8.44 (br-d,
J = 5 Hz, 1H), 8.64 (br-d, J = 5H
z, 1H), 8.71 (s, 1H), 8.86 (t, J
= 5 Hz, 1H), 10.38 (s, 1H). [Α] _D ²³ = + 8.0 ° (c0.42, 1N-HC
l) Melting point: 223-229 ° C HPLC: 3.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 20: 80, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 499

Example 140 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N- (2-nicotinoylaminoethyl)
Amide NMR (DMSO-d ₆ , δ): 0.37 (d, J = 7)
Hz, 3H), 0.66 (d, J = 7Hz, 3H),
0.74 (d, J = 7Hz, 3H), 0.79 (m, 1
H), 1.18-1.37 (m, 2H), 1.92 (d
q, J = 10,7 Hz, 1H), 2.30 (m, 1
H), 2.97 (dd, J = 14, 11 Hz, 1H),
3.03-3.35 (m, 4H), 3.08 (dd, J
= 14,5 Hz, 1 H), 4.74 (ddd, J = 1)
1,8,5 Hz, 1H), 7.13 (dd, J = 7.
5,5 Hz, 1 H), 7.27 (d, J = 7.5 Hz,
1H), 7.47 (dd, J = 8, 5Hz, 1H),
7.62 (ddd, J = 7.5, 7.5, 1.5 Hz,
1H), 8.01 (t, J = 4Hz, 1H), 8.18
(Dd, J = 8, 1.5 Hz, 1H), 8.30 (d,
J = 8 Hz, 1H), 8.41 (br-d, J = 5H
z, 1H), 8.64-8.71 (m, 2H), 8.7.
4 (t, J = 4 Hz, 1H), 9.00 (s, 1H),
10.41 (s, 1H). [Α] _D ²³ = + 6.3 ° (c0.43, 1N-HC
l) Melting point: 231-237 ° C HPLC: 7.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 499

Example 141 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-4-pyridylalanine-N- (2-nicotinoylaminoethyl)
Amide NMR (DMSO-d ₆ , δ): 0.41 (d, J = 7)
Hz, 3H), 0.71 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.84 (m, 1
H), 1.21-1.40 (m, 2H), 1.96 (d
q, J = 10,7 Hz, 1H), 2.35 (m, 1
H), 2.80 (dd, J = 14, 12 Hz, 1H),
3.00 (dd, J = 14, 4 Hz, 1H), 3.12
-3.42 (m, 4H), 4.62 (ddd, J = 1
2,8,4Hz, 1H), 7.29 (d, J = 6Hz,
2H), 7.52 (dd, J = 7.5, 5 Hz, 1
H), 8.12 (t, J = 4 Hz, 1H), 8.18
(Br-d, J = 7.5 Hz, 1H), 8.30 (d,
J = 8Hz, 1H), 8.43 (d, J = 6Hz, 2
H), 8.64-8.78 (m, 3H), 9.01 (b)
r, 1H), 10.39 (s, 1H). [Α] _D ²⁶ = + 13.9 ° (c 0.37, 1N−H
Cl) Melting point: 249-253 ° C HPLC: 6.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 499

Example 142 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
-Isobutyl-3-methylsuccinyl] -L-4-pyridylalanine-N- [2- (2-pyridylcarbonyl)
Aminoethyl] amide NMR (DMSO-d ₆ , δ): 0.41 (d, J = 7)
Hz, 3H), 0.70 (d, J = 7Hz, 3H),
0.79 (d, J = 7Hz, 3H), 0.83 (m, 1
H), 1.21-1.40 (m, 2H), 1.95 (d
q, J = 10, 7 Hz, 1H), 2.34 (ddd, J
= 10, 10, 3 Hz, 1H), 2.79 (dd, J =
14, 12Hz, 1H), 2.98 (dd, J = 14,
4Hz, 1H), 3.21 (m, 1H), 3.27-
3.43 (m, 3H), 4.62 (ddd, J = 12,
8,4 Hz, 1 H), 7.28 (d, J = 6 Hz, 2
H), 7.61 (dd, J = 7.5, 5 Hz, 1H),
7.96-8.14 (m, 3H), 8.27 (d, J =
8Hz, 1H), 8.41 (d, J = 6Hz, 2H),
8.65 (d, J = 5 Hz, 1H), 8.72 (s, 1
H), 8.87 (t, J = 4Hz, 1H), 10.38
(S, 1H). [Α] _D ²³ = + 15.8 ° (c0.33, 1N-H
Cl) Melting point: 249-253 ° C HPLC: 6.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 15: 85, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 499

Example 143 The following compound was obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridylalanine -N- (4- pyridylmethyl) amide _{NMR (DMSO-d 6, δ} ): 0.43 (d, J = 7
Hz, 3H), 0.69 (d, J = 7Hz, 3H),
0.76 (d, J = 7Hz, 3H), 0.84 (m, 1
H), 1.27 (m, 1H), 1.36 (m, 1H),
1.97 (dq, J = 10,7 Hz, 1H), 2.37
(Ddd, J = 11, 10, 3Hz, 1H), 2.87
(Dd, J = 14, 12 Hz, 1H), 3.02 (d
d, J = 14.5 Hz, 1H), 4.26 (dd, J =
16,6Hz, 1H), 4.33 (dd, J = 16,6)
Hz, 1H), 4.72 (ddd, J = 12, 8, 5H
z, 1H), 7.18 (d, J = 6Hz, 2H), 7.
32 (d, J = 6 Hz, 2H), 8.37 (d, J = 8)
Hz, 1H), 8.43 (d, J = 6Hz, 2H),
8.45 (d, J = 6 Hz, 2H), 8.58 (dd,
J = 6, 6 Hz, 1H), 8.73 (s, 1H), 1
0.38 (s, 1H). [Α] _D ²⁵ = + 21.4 ° (c0.41,1N-H
Cl) Melting point: 245-251 ° C HPLC: 2.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (ESI): M + H = 442

Example 144 The following compound was obtained as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(2S) -2,3- dihydroxypropyl] amide _{NMR (CDCl 3, δ):} 0.36 (d, J = 7H
z, 3H), 0.72 (d, J = 7Hz, 3H), 0.
75-0.92 (m, 1H), 0.80 (d, J = 7H
z, 3H), 1.21-1.44 (m, 2H), 1.9.
4 (dq, J = 10, 7 Hz, 1H), 2.32 (m,
1H), 2.87-3.05 (m, 2H), 3.13
(Dd, J = 14.5 Hz, 1H), 3.18-3.3
3 (m, 3H), 3.43 (m, 1H), 4.53
(T, J = 6 Hz, 1 H), 4.73-4.86 (m,
2H), 7.18 (dd, J = 7.5, 5 Hz, 1
H), 7.30 (d, J = 7.5 Hz, 1H), 7.5
4-7.72 (m, 2H), 8.33 (d, J = 8H
z, 1H), 8.45 (d, J = 5Hz, 2H), 8.
73 (s, 1H), 10.40 (s, 1H). [Α] _D ²⁵ = + 2.8 ° (c0.12, MeOH) Melting point: 189-194 ° C HPLC: 3.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 425

Example 145- (1) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- (3-hydroxy-3-methylbutyl) amide _{NMR (CDCl 3, δ):} 0.84 (d, J = 6.3
Hz, 3H), 0.87-0.98 (m, 1H), 0.
90 (d, J = 6.4 Hz, 3H), 1.02-1.7
0 (m, 7H), 1.20 (s, 9H), 1.21
(S, 6H), 1.31 (s, 9H), 2.50-2.
86 (m, 2H), 3.19 (dd, J = 14.6,
5.4 Hz, 1 H), 3.23-3.40 (m, 3
H), 4.78 (m, 1H), 5.65 (d, J = 1)
2.2Hz, 1H), 5.66 (d, J = 12.2H)
z, 1H), 7.10-7.30 (m, 3H), 7.6.
2 (ddd, J = 7.8, 7.6, 1.9 Hz, 1
H), 7.69 (br, 1H), 8.48 (br-d,
J = 4.8 Hz, 1H). [Α] _D ²⁰ = + 0.1 ° (c0.52, CHCl
₃ ) Melting point: 81-82 ° C HPLC: 3.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 635

Example 145- (2) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- (2-anilinocarbonyl oxyethyl) amide _{NMR (CDCl 3, δ):} 0.82 (d, J = 6.5
Hz, 3H), 0.90 (d, J = 6.4Hz, 3
H), 0.93 (m, 1H), 1.00-1.70.
(M, 5H), 1.19 (s, 9H), 1.30 (s,
9H), 2.53-2.73 (m, 2H), 3.18.
(Dd, J = 14.8, 5.5 Hz, 1H), 3.30
(Dd, J = 14.8, 5.7 Hz, 1H), 3.50
(M, 2H), 4.09 (m, 1H), 4.16 (m,
1H), 4.83 (m, 1H), 5.65 (br, 2
H), 6.94 (br, 1H), 7.00-7.15.
(M, 2H), 7.18-7.41 (m, 6H), 7.
60 (ddd, J = 7.7, 7.6, 1.8 Hz, 1
H), 7.89 (br, 1H), 8.45 (br, 1)
H). [Α] _D ²⁰ = + 1.1 ° (c0.36, CHCl
₃ ) Melting point: 85-90 ° C HPLC: 8.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 712

Example 145- (3) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- [[2 - [(2S ) -2- hydroxymethyl-1-yl] carbonyloxy] ethyl] amide _{NMR (CDCl 3, δ):} 0.75-0.93 (m,
3H), 0.84 (d, J = 6.5Hz, 3H), 0.
89 (d, J = 6.5 Hz, 3H), 1.04-1.4
8 (m, 3H), 1.20 (s, 9H), 1.31
(S, 9H), 1.71-2.05 (m, 2H), 2.
52-2.68 (m, 2H), 3.13-3.68
(M, 9H), 3.76 (br, 1H), 3.95 (b
r, 1H), 4.20 (br, 1H), 4.80 (m,
1H), 5.63 (d, J = 12.0Hz, 1H),
5.67 (d, J = 12.0 Hz, 1H), 7.17
(Dd, J = 7.7, 5.4 Hz, 1H), 7.27
(D, J = 7.7 Hz, 1 H), 7.47 (br, 1
H), 7.64 (ddd, J = 7.7, 7.7, 1.6
Hz, 1H), 7.85 (br, 1H), 8.47 (b
rd, J = 5.4 Hz, 1H). [Α] _D ²¹ = -13.0 ° (c0.52, CHCl
₃ ) Melting point: 72-77 ° C HPLC: 3.7 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 720

Example 145- (4) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- [(1-hydroxycyclohexyl) methyl] amide _{NMR (CDCl 3, δ):} 0.85 (d, J = 6.4
Hz, 3H), 0.91 (d, J = 6.5Hz, 3
H), 0.97 (m, 1H), 1.01-1.59
(M, 15H), 1.20 (s, 9H), 1.31
(S, 9H), 2.51-2.77 (m, 2H), 3.
17 (m, 1H), 3.21 (d, J = 5.9Hz, 2
H), 3.35 (dd, J = 14.8, 5.4 Hz, 1
H), 4.85 (m, 1H), 5.63 (d, J = 1)
2.1Hz, 1H), 5.68 (d, J = 12.1H)
z, 1H), 7.11-7.21 (m, 2H), 7.2
5 (d, J = 7.7 Hz, 1 H), 7.63 (ddd,
J = 7.7, 7.6, 1.7 Hz, 1H), 7.84
(Br-d, J = 5.8 Hz, 1H), 8.49 (br
-D, J = 5.1 Hz, 1H). [Α] _D ²¹ = + 0.4 ° (c0.50, CHCl
₃ ) Melting point: 91-96 ° C HPLC: 6.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 661

Example 145- (5) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- [2- (iso-butoxycarbonylamino) ethyl] amide _{NMR (CDCl 3, δ):} 0.84 (d, J = 6.5
Hz, 3H), 0.87-1.96 (m, 16H),
1.20 (s, 9H), 1.31 (s, 9H), 2.5
2-2.78 (m, 2H), 3.13-3.42 (m,
6H), 3.81 (d, J = 6.6Hz, 2H), 4.
76 (m, 1H), 5.15 (br, 1H), 5.63
(D, J = 12.2 Hz, 1H), 5.69 (d, J =
12.2Hz, 1H), 7.12-7.36 (m, 3
H), 7.64 (ddd, J = 7.7, 7.7, 1.7)
Hz, 1H), 7.72 (d, J = 6.6Hz, 1
H), 8.50 (d, J = 4.5 Hz, 1H). [Α] _D ²¹ = −2.1 ° (c0.51, CHCl
₃ ) Melting point: 114-117 ° C HPLC: 8.1 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 692

Example 145- (6) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- [2- (N, N ' , N'- triethyl ureido) ethyl] amide _{NMR (CDCl 3, δ):} 0.83 (d, J = 7H
z, 3H), 0.86-1.75 (m, 6H), 0.9
0 (d, J = 7 Hz, 3H), 1.10 (t, J = 7H
z, 9H), 1.19 (s, 9H), 1.30 (s, 9)
H), 2.50-2.77 (m, 2H), 3.05-
3.40 (m, 12H), 4.78 (m, 1H), 5.
63 (d, J = 12 Hz, 1H), 5.68 (d, J =
12Hz, 1H), 7.14 (dd, J = 8, 5Hz,
1H), 7.23 (d, J = 8Hz, 1H), 7.51
-7.81 (m, 3H), 8.48 (d, J = 5Hz,
1H). [Α] _D ²¹ = + 4.4 ° (c0.30, CHCl
₃ ) Melting point: 65-70 ° C. HPLC: 7.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 719

Example 145- (7) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- (2-morpholinoethyl carbonyloxy ethyl) amide _{NMR (CDCl 3, δ):} 0.83 (d, J = 7H
z, 3H), 0.87-1.67 (m, 6H), 0.8
9 (d, J = 7 Hz, 3H), 1.20 (s, 9H),
1.31 (s, 9H), 2.52-2.75 (m, 2
H), 3.18 (dd, J = 14.6 Hz, 1H),
3.28 (dd, J = 14.6 Hz, 1H), 3.33
-3.53 (m, 6H), 3.54-3.71 (m, 4
H), 4.08 (m, 2H), 4.79 (ddd, J =
7,6,6Hz, 1H), 5.63 (d, J = 12H
z, 1H), 5.69 (d, J = 12Hz, 1H),
7.16 (dd, J = 7.5, 5 Hz, 1H), 7.2
6 (d, J = 7.5 Hz, 1 H), 7.57 (br, 1
H), 7.63 (dd, J = 7.5, 7.5 Hz, 1
H), 7.82 (d, J = 7Hz, 1H), 8.47
(D, J = 5 Hz, 1H). [Α] _D ²¹ = −3.9 ° (c0.30, CHCl
₃ ) Melting point: 70-76 ° C HPLC: 3.9 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 706

Example 145- (8) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- (2-N, N- diethylaminoethyl carbonyloxy ethyl) amide _{NMR (CDCl 3, δ):} 0.77-1.76 (m,
12H), 0.84 (d, J = 6.6Hz, 3H),
0.91 (d, J = 6.5Hz, 3H), 1.21
(S, 9H), 1.32 (s, 9H), 2.50-2.
75 (m, 2H), 3.10-3.34 (m, 6H),
3.48 (m, 2H), 4.07 (m, 2H), 4.8
1 (m, 1H), 5.64 (d, J = 11.9 Hz, 1
H), 5.69 (d, J = 11.9 Hz, 1H), 7.
16 (dd, J = 7.7, 4.9 Hz, 1H), 7.2
7 (d, J = 7.7 Hz, 1 H), 7.60 (br, 1
H), 7.64 (ddd, J = 7.7, 7.7, 1.8)
Hz, 1H), 7.79 (d, J = 6.9Hz, 1
H), 8.47 (br-d, J = 4.9 Hz, 1H). [Α] _D ²¹ = -1.2 ° (c0.50, CHCl
₃ ) Melting point: 58-65 ° C HPLC: 6.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 692

Example 145- (9) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- (2-piperidinocarbonyl oxyethyl) amide _{NMR (CDCl 3, δ):} 0.83 (d, J = 6.7
Hz, 3H), 0.85-1.77 (m, 12H),
0.90 (d, J = 6.5 Hz, 3H), 1.20
(S, 9H), 1.31 (s, 9H), 2.51-2.
75 (m, 2H), 3.09-3.52 (m, 8H),
3.92-4.13 (m, 2H), 4.80 (m, 1)
H), 5.64 (d, J = 12.1 Hz, 1H), 5.
67 (d, J = 12.1 Hz, 1H), 7.16 (d
d, J = 7.6, 4.7 Hz, 1H), 7.26 (d,
J = 7.8 Hz, 1H), 7.49-7.66 (m, 1
H), 7.63 (ddd, J = 7.8, 7.6, 1.5)
Hz, 1H), 7.76 (br-d, J = 6.2 Hz,
1H), 8.47 (br-d, J = 4.7 Hz, 1
H). [Α] _D ²¹ = + 1.4 ° (c0.50, CHCl
₃ ) Melting point: 71-76 ° C HPLC: 7.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 704

Example 145- (10) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- (2,2,2-trifluoroethyl) amide _{NMR (CDCl 3, δ):} 0.83 (d, J = 7H
z, 3H), 0.90 (d, J = 7Hz, 3H), 0.
92-1.85 (m, 1H), 1.20 (s, 9H),
1.31 (s, 9H), 2.55-2.77 (m, 2
H), 3.20 (dd, J = 15, 5 Hz, 1H),
3.31 (dd, J = 15, 5 Hz, 1H), 3.70
-4.02 (m, 2H), 4.84 (ddd, J = 7,
5,5 Hz, 1 H), 5.63 (d, J = 12 Hz, 1
H), 5.68 (d, J = 12 Hz, 1H), 7.18
(Dd, J = 7.5 Hz, 1H), 7.26 (d, J =
7Hz, 1H), 7.65 (ddd, J = 7, 7, 2H
z, 1H), 7.95 (d, J = 7Hz, 1H), 8.
04 (br, 1H), 8.45 (br-d, J = 5H
z, 1H). [Α] _D ²⁶ = -8.6 ° (c0.25, CHCl
₃ ) Melting point: 155-159 ° C HPLC: 7.4 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 50: 50, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 631

Example 145- (11) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- (4-hydroxypiperidino) amide _{NMR (DMSO-d 6, δ} ): 0.72-1.95
(M, 16H), 1.20 (s, 9H), 1.30
(S, 9H), 2.49 (m, 1H), 2.63 (b
r, 1H), 3.02-3.44 (m, 4H), 3.0
9 (dd, J = 14, 7 Hz, 1H), 3.72-4.
11 (m, 3H), 5.48 (m, 1H), 5.56-
5.72 (m, 2H), 6.76 (br, 1H), 7.
07-7.20 (m, 2H), 7.58 (br-dd,
J = 7, 7 Hz, 1H), 8.52 (br, 1H). [Α] _D ²³ = + 14.3 ° (c0.29, MeO
H) Melting point: 75-79 ° C HPLC: 6.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 40: 60, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 633

Example 145- (12) In the same manner as in Example 6- (2), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxyamino) succinyl] -L-2
-Pyridylalanine-N-[(2R) -2-hydroxypropyl] amide NMR (CDCl ₃ , δ): 0.43 (d, J = 7H
z, 3H), 0.73 (d, J = 7Hz, 3H), 0.
79 (d, J = 7 Hz, 3H), 0.99 (m, 1
H), 0.99 (d, J = 7 Hz, 3H), 1.20
(S, 9H), 1.24-1.43 (m, 2H), 2.
11 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.90-3.08 (m, 3H), 3.
13 (dd, J = 14.5 Hz, 1H), 3.60
(M, 1H), 4.67 (d, J = 4Hz, 1H),
4.81 (m, 1H), 7.19 (dd, J = 7.5H)
z, 1H), 7.30 (d, J = 8Hz, 1H), 7.
60 (dd, J = 5, 5 Hz, 1H), 7.67 (dd
d, J = 8,7,2 Hz, 1H), 8.35 (d, J =
8Hz, 1H), 8.45 (dd, J = 5, 2Hz, 1
H), 11.54 (s, 1H). [Α] _D ²⁴ = + 6.9 ° (c0.30, MeOH) Melting point: 168-171 ° C HPLC: 3.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 493

Example 145- (13) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- [(2R) -2- hydroxypropyl] amide _{NMR (CDCl 3, δ):} 0.83 (d, J = 7H
z, 3H), 0.89 (d, J = 7Hz, 3H), 0.
92-1.85 (m, 6H), 1.11 (d, J = 7H
z, 3H), 1.18 (s, 9H), 1.30 (s, 9)
H), 2.60 (m, 1H), 2.71 (m, 1H),
2.96 (m, 1H), 3.16-3.48 (m, 4
H), 3.88 (m, 1H), 4.81 (m, 1H),
5.63 (d, J = 12 Hz, 1H), 5.68 (d,
J = 12 Hz, 1H), 7.06 (m, 1H), 7.1
2-7.31 (m, 2H), 7.54-7.69 (m,
2H), 8.48 (br-d, J = 4Hz, 1H). [Α] _D ²⁴ = + 1.8 ° (c0.28, MeOH) Melting point: 77-80 ° C HPLC: 6.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 40: 60, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 607

Example 145- (14) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-2-pyridylalanine-N
- [(2S) -2- hydroxypropyl] amide _{NMR (DMSO-d 6, δ} ): 0.84 (d, J = 7
Hz, 3H), 0.90 (d, J = 7Hz, 3H),
0.93 (m, 1H), 1.01-1.91 (m, 5
H), 1.11 (d, J = 7 Hz, 3H), 1.20
(S, 9H), 1.30 (s, 9H), 2.52-2.
77 (m, 2H), 3.03 to 3.39 (m, 5H),
3.81 (m, 1H), 4.79 (m, 1H), 5.6
2 (d, J = 12 Hz, 1H), 5.68 (d, J = 1
2Hz, 1H), 7.18 (dd, J = 7.5Hz, 1
H), 7.25 (d, J = 7.5 Hz, 1H), 7.6
3 (dd, J = 7.5, 7 Hz, 1H), 7.76
(D, J = 7Hz, 1H), 8.49 (d, J = 5H
z, 1H). [Α] _D ²⁴ = + 11.6 ° (c0.25, MeO
H) Melting point: 78-82 ° C HPLC: 6.5 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 40: 60, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 607

Example 145- (15) In the same manner as in Example 6- (2), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxyamino) succinyl] -L-2
- pyridylalanine -N - [(2S) -2- hydroxypropyl] amide _{NMR (DMSO-d 6, δ} ): 0.44 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.78 (d, J = 7Hz, 3H), 0.95 (d, J
= 7 Hz, 3H), 0.98 (m, 1H), 1.20
(S, 9H), 1.25-1.43 (m, 2H), 2.
11 (dq, J = 10, 7 Hz, 1H), 2.33
(M, 1H), 2.90-3.09 (m, 3H), 3.
12 (dd, J = 14.5 Hz, 1H), 3.59
(M, 1H), 4.65 (d, J = 5Hz, 1H),
4.80 (m, 1H), 7.18 (dd, J = 7.5,
5Hz, 1H), 7.30 (d, J = 7.5Hz, 1
H), 7.59 (dd, J = 5, 5 Hz, 1H), 7.
67 (ddd, J = 7.5, 7.5, 2 Hz, 1H),
8.35 (d, J = 8 Hz, 1H), 8.45 (dd,
J = 5, 2 Hz, 1H), 11.53 (s, 1H). [Α] _D ²⁴ = + 19.5 ° (c0.35, MeO
H) Melting point: 169-173 [deg.] C. HPLC: 6.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 25: 75, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 493

Example 145- (16) The following compounds are obtained in the same manner as in Example 6- (2). [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxyamino) succinyl] -L-2
- pyridylalanine -N- (4- phenoxy recipe piperidino) amide _{NMR (CDCl 3, δ):} 0.57 (m, 3H),
0.74 (d, J = 7Hz, 3H), 0.79 (d, J
= 7 Hz, 3H), 0.91-1.66 (m, 5H),
1.20 (s, 9H), 1.85 (br, 1H), 1.
94 (br, 2H), 2.15 (m, 1H), 2.38
(M, 1H), 2.90-3.54 (m, 4H), 3.
73-4.02 (m, 2H), 4.60 (m, 1H),
5.35 (m, 1H), 6.88-7.03 (m, 3
H), 7.19 (m, 1H), 7.23-7.34.
(M, 3H), 7.67 (dd, J = 7.5, 7.5H
z, 1H), 8.44-8.55 (m, 2H), 11.
55 (br, 1H). [Α] _D ²⁵ = + 52.5 ° (c0.04, MeO
H) Melting point: 80-86 ° C HPLC: 8.6 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 40: 60, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 595

Example 145- (17) In the same manner as in Example 4- (1), the following compound is obtained. [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxy-N-pivaloyloxymethylamino) succinyl] -L-4-pyridylalanine-N
- methylamide _{NMR (DMSO-d 6, δ} ): 0.67-1.82
(M, 6H), 0.83 (d, J = 7Hz, 3H),
0.84 (d, J = 7 Hz, 3H), 1.18 (s, 9
H), 1.29 (s, 9H), 2.42-2.63.
(M, 2H), 2.75 (d, J = 4Hz, 1H),
3.03 (dd, J = 15, 8 Hz, 1H), 3.16
(Dd, J = 15, 7.5 Hz, 1H), 4.65
(M, 1H), 5.61 (d, J = 12Hz, 1H),
5.68 (d, J = 12 Hz, 1H), 6.07-6.
34 (br, 1H), 6.73 (br, 1H), 7.1
6 (d, J = 7 Hz, 2H), 8.50 (d, J = 7H
z, 2H). [Α] _D ²⁵ = + 8.5 ° (c0.37, MeOH) Melting point: 95-101 ° C HPLC: 6.0 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 40: 60, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 563

Example 145- (18) The following compounds are obtained in the same manner as in Example 6- (2). [(2R, 3S) -2-isobutyl-3-methyl-4-
(N-pivaloyloxyamino) succinyl] -L-4
- pyridylalanine -N- methylamide _{NMR (DMSO-d 6, δ} ): 0.46 (d, J = 7
Hz, 3H), 0.72 (d, J = 7Hz, 3H),
0.80 (d, J = 7Hz, 3H), 0.99 (m, 1
H), 1.17-1.43 (m, 2H), 1.20
(S, 9H), 2.12 (dq, J = 10, 7Hz, 1
H), 2.33 (m, 1H), 2.59 (d, J = 5H
z, 3H), 2.80 (dd, J = 14, 11 Hz, 1
H), 2.94 (dd, J = 14,5Hz, 1H),
4.60 (ddd, J = 11,8,5Hz, 1H),
7.28 (d, J = 7 Hz, 2H), 7.85 (q, J
= 5 Hz, 1 H), 8.33 (d, J = 8 Hz, 1
H), 8.43 (d, J = 7 Hz, 2H), 11.53
(S, 1H). [Α] _D ²⁵ = + 13.9 ° (c0.33, MeO
H) Melting point: 194-200 ° C HPLC: 8.3 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 40: 60, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 449

Example 146 In the same manner as in Example 5, the following compound was obtained. [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-4-
Pyridylalanine

Example 147 [(2R, 3S) -4- (N-benzyloxyamino)
2-Isobutyl-3-methylsuccinyl] -L-2-
A solution of pyridylalanine-N-methylamide (552 mg) in N, N-dimethylformamide (10 ml) was added with potassium carbonate (175 mg) and methyl iodide (0.23 m).
l) is added at room temperature. The mixture is stirred overnight. The reaction mixture was poured into saturated brine (30 ml), and ethyl acetate (20 ml) was added.
Extract with mlx3). The extract is washed with 5% aqueous sodium thiosulfate solution (30 ml) and saturated brine (30 ml). The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / methylene chloride = 1:10) to give [(2R, 3S) -4- (N-benzyloxy-N).
-Methylamino) -2-isobutyl-3-methylsuccinyl] -L-2-pyridylalanine-N-methylamide (203 mg) is obtained. NMR (CDCl ₃ , δ): 0.82 (d, J = 7H
z, 3H), 0.88 (d, J = 7Hz, 6H), 1.
01 (m, 1H), 1.40 (m, 1H), 1.56
(M, 1H), 2.60 (m, 1H), 2.73 (d,
J = 5 Hz, 3H), 3.13 (m, 1H), 3.16
(Dd, J = 15,7 Hz, 1H), 3.20 (s, 3
H), 3.32 (dd, J = 15,7 Hz, 1H),
4.80 (m, 1H), 4.84 (s, 2H), 7.1
5 (dd, J = 8, 5 Hz, 1H), 7.23 (m, 1
H), 7.27 (d, J = 8 Hz, 1H), 7.39
(S, 5H), 7.62 (dd, J = 8, 8Hz, 1
H), 7.81 (br-d, J = 5 Hz, 1H), 8.
47 (br-d, J = 5 Hz, 1H). HPLC: 5.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 30: 70, 254 nm, flow rate
1.0 ml / min. , At 30 ° C.) MASS (FB ⁺ ): M + H = 469

Example 148- (1) In the same manner as in Example 3- (1), the following compound is obtained. [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-2-pyridyl alanine -N - [(1-hydroxymethyl-2-hydroxy) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.34 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.76-0.89 (m, 1H), 0.79 (d, J =
7Hz, 3H), 1.21-1.42 (m, 2H),
1.94 (dq, J = 10, 7 Hz, 1H), 2.31
(M, 1H), 2.95 (dd, J = 14, 10 Hz,
1H), 3.14 (dd, J = 14, 5 Hz, 1H),
3.20-3.47 (m, 4H), 3.66 (m, 1
H), 4.63 (t, J = 5 Hz, 1H), 4.79.
(Ddd, J = 10, 8, 5 Hz, 1H), 7.11-
7.26 (m, 2H), 7.29 (d, J = 7.5H
z, 1H), 7.66 (dd, J = 7.5, 7.5H
z, 1H), 8.32 (d, J = 8Hz, 1H), 8.
43 (d, J = 5 Hz, 1 H), 8.71 (s, 1
H), 10.38 (s, 1H). [Α] _D ²⁵ = + 11.3 ° (c0.21, MeO
H) Melting point: 194-199 ° C HPLC: 3.2 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 425

Example 148- (2) The following compounds are obtained in the same manner as in Example 3- (1). [(2R, 3S) -4- (N-hydroxyamino) -2
- isobutyl-3 Mechirusukushiniru] -L-4-pyridylalanine -N - [(1-hydroxymethyl-2-hydroxy) ethyl] amide _{NMR (DMSO-d 6, δ} ): 0.33 (d, J = 7
Hz, 3H), 0.73 (d, J = 7Hz, 3H),
0.76-0.90 (m, 1H), 0.80 (d, J =
7Hz, 3H), 1.21-1.40 (m, 2H),
1.92 (dq, J = 10, 7 Hz, 1H), 2.32
(M, 1H), 2.78 (dd, J = 14, 11 Hz,
1H), 3.02 (dd, J = 14, 4Hz, 1H),
3.24-3.49 (m, 4H), 3.68 (m, 1
H), 4.60-4.73 (m, 3H), 7.31
(D, J = 7 Hz, 1H), 7.47 (d, J = 7.5
Hz, 1H), 8.27 (d, J = 8Hz, 1H),
8.41 (d, J = 7 Hz, 1H), 8.71 (s, 1
H), 10.38 (s, 1H). [Α] _D ²⁵ = + 17.2 ° (c0.21, MeO
H) Melting point: 222-227 ° C. (decomposition) HPLC: 2.8 min. (Nucleosil 5C
18,4mmφx15cm, MeCN: 0.05% TF
Aaq = 1: 10, 260 nm, flow rate
1.0 ml / min. , At R .; T. ) MASS (FB ⁺ ): M + H = 425

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 213/56 333/24 409/12 213 C07F 7/18 A

Claims (3)

[Claims] 1. A formula [Wherein R ¹ is hydrogen or a hydroxy protecting group, R ² is hydrogen, a lower alkyl group or an amino protecting group, R ³ is hydrogen or a 2-thienylthio group, R ⁴ is a 2-pyridyl group or its N-oxide, 4-pyridyl group. , A phenyl group or a 4-methoxyphenyl group, and R ⁵ represents a hydroxy group, a lower alkoxy group or an amino group having a substituent, respectively. Provided that when R ¹ and R ² are each hydrogen, R ⁴
Is a 2-pyridyl group or its N-oxide or 4
-A condition that it becomes a pyridyl group. ] The compound represented by these, or those salt accept | permitted pharmaceutically. 2. A formula [In the formula, R ¹ _a represents an acyl group, R ² _a represents an acyloxymethyl group, and R represents an organic group, respectively. ] The protected hydroxamic acid derivative represented by these or its salt. 3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as a collagenase inhibitor.