WO1999040063A1 - Novel azapeptide type hydroxamic acid derivatives - Google Patents

Abstract

Azapeptide type hydroxamic acid derivatives represented by general formula (I) or pharmacologically acceptable salts thereof and medicinal compositions containing the same. In formula (I) wherein X represents hydrogen or a hydroxyl-protective group; R1 represents hydrogen, hydroxy, amino, mercapto, alkoxy, alkyl, alkenyl, aryl or -(CH¿2?)k-A; R?2¿ represents hydrogen, alkyl or aryl; R3 represents hydrogen, alkyl, aryl, heteroaryl or -(CONH)¿m?-(CHR?11)¿n-Y; and R4 represents alkyl, aryl, heteroaryl, -SO¿2R?12, -CO-(CH¿2?)q -NR?12R12'¿, -CONH-Z-R13 or -(CONH)¿m?-(CHR?11)¿n-Y, or R?3 and R4¿ may together form a nitrogen-containing heterocycle. Because of having a TNFα production inhibitory effect, these compounds are useful in preventing and treating autoimmune diseases, inflammatory diseases, etc., for example, sepsis, MOF, chronic rheumatoid arthritis, Crohn's disease, cachexia, severe adynamia, systemic lupus erythematosus, asthma, type I diabetes and psoriasis.

Description

 Specification

 New azapeptide hydroxamic acid derivatives

 Technical field

 The present invention relates to a novel azapeptide-type hydroxamic acid derivative or a pharmacologically acceptable salt thereof. More specifically, the present invention relates to an azapeptide-type hydroxamic acid derivative or a pharmacologically acceptable salt thereof, which is useful as a production inhibitor of tumor cell necrosis factor (TNFa: tumor necrosis factor α). The present invention also relates to a novel intermediate compound useful for synthesizing the azapeptide-type hydroxamic acid derivative.

 Background art

 TNFα is known as a cytokine that is widely involved in the defense of the body during inflammation and the activation of the immune system, while its continuous and excessive production is represented by multiple organ failure (MOF). It is also known to cause and hate various diseases associated with organ damage.

 MOFs can be used during multiple major invasions (post major surgery, severe trauma, burns, acute inflammation, severe infectious diseases, etc.) during the course of multiple lungs, heart, kidney, liver, central nervous system, blood coagulation, etc. It is understood as a dysfunction that appears simultaneously or continuously in vital organs. MOF is a prominent example of a refractory disease that has a poor prognosis in proportion to the number of dysfunctional organs and a very high mortality rate, but has not yet established a cure for it. .

 In recent years, inhibitors of matrix metalloproteinase (MMP), an enzyme responsible for the processing of membrane-bound TNF to free TNF ct, have specifically inhibited the secretion of free TNF by endotoxin (LPS) stimulation. And has been reported to have a life-saving effect (eg, licGeehan, G. Ϊ. Et al. Nature 370: p.558-561 (1994)).

In view of these findings, using a derivative of droxamate, which has been studied as an MMP inhibitor, has been developed to increase the free TNF a by increasing the free TNF a by inhibiting the production of TNF. Prevention of various intractable diseases Various activities (eg, WO 94 Z 109 0 90) are not yet satisfactory prevention. The emergence of therapeutic agents has not yet arrived.

 Disclosure of the invention

 The present invention has been made based on the background art as described above, and its object is to provide a novel azapeptide-type hydroxamic acid derivative useful as a TNFα production inhibitor or a pharmacologically acceptable derivative thereof. To provide salt.

 Another object of the present invention is to provide a novel intermediate compound useful for the synthesis of the compound.

 That is, the present invention provides a compound represented by the formula (I):

[In the formula, X represents hydrogen or a protecting group for a hydroxyl group, and R ¹ represents hydrogen, a hydroxyl group, amino, mercapto, alkoxy, optionally substituted alkyl, alkenyl, optionally substituted aryl, or — ( CH ₂ ) k — A (k is an integer of any one of 1 to 4, and A is (a) linked by an N atom, and (b) as a further hetero atom at a position not adjacent to the bonded N atom. May contain at least one atom selected from N, 0 and S, (c) with respect to one or both C atoms adjacent to the bonded N atom, substituted by oxo, and (d) benzo May be fused or substituted for one or more other C atoms by lower alkyl or oxo, and for Z or another N atom may be substituted by lower alkyl or phenyl. 5 or 6 membered to N- shows a representative] heterocyclic ring, R ² represents hydrogen, an optionally § Li Ichiru be alkyl or substituted optionally substituted, R ³ is hydrogen, optionally substituted Alkyl, optionally substituted aryl, optionally substituted heteroaryl or R ¹¹

 One (C〇NH) m one (CH) n one Y

(In the formula, R ¹¹ represents hydrogen or an optionally substituted alkyl, Y represents —C〇 ₂ R ¹² , one C〇NR ¹² R ¹² ′ or one COR ¹² (R ¹² and R ¹² ′ are the same or Each represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl, wherein R ¹² and R ¹² ′ may be substituted together with an adjacent nitrogen atom. M may represent 0 or 1, n represents an integer of 0 to 4), and R ⁴ may be substituted Good alkyl, optionally substituted aryl, optionally substituted heteroaryl, one SO ₂ R ¹² , -CO- (CH ₂ ) q _NR ¹² R ¹² '

{q represents 1 or 2, R ¹² and R ¹² ′ are as defined above}, -CONH-Z-R ¹³ {Z represents alkylene having 2 to 4 carbon atoms, and R ¹³ represents a hydroxyl group, amino or NR ¹² R ¹² '[R ¹² and R ¹² ' are as defined above]] or

R ¹¹

 I

 One (CONH) m one (CH) n one Y

(Wherein, R ", Y, m and η are the same as defined above), and R ³ and R ⁴ together with an adjacent nitrogen atom represent a heterocycle which may be substituted. May be formed], or a pharmaceutically acceptable salt thereof.

Further, in the present invention, in the formula (I), R ¹ represents hydrogen, a hydroxyl group, amino, mercapto, alkoxy, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted Good heteroarylthioalkyl, optionally substituted arylthioalkyl, optionally substituted phthalimidalkyl, alkenyl, optionally substituted aryl, or 1 (CH ₂ ) k —A (k Is

A is any integer from 1 to 4, and A is i

 (iii)

 (vii) (viii)

(Wherein, R ⁸ and R ⁹ each represent hydrogen or together form another bond to form a double bond, R ^{1 {)} represents hydrogen, lower alkyl or phenyl, and X ′ represents —C 0 —, — CH ₂ —, —CH (R ¹⁹ ) one, one C (R ¹⁹ ) 2 one, — NH —, —N (R ¹⁹ ) one or one 0—, Y ′ is —0—,- NH— or —N (R ¹⁸ ) —, R ¹⁹ represents lower alkyl), and R ² represents hydrogen, alkyl which may be substituted, Represents an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl or an optionally substituted aryl. , Is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, substituted Teroari one to optionally Rua alkyl, optionally substituted cycloalkyl, optionally substituted Shikuroa Alkylalkyl, optionally substituted aryl, optionally substituted heteroaryl or

R ¹¹

 -(C 0 NH) m-(C H) n-Y

(Wherein, R ¹¹ is hydrogen, alkyl optionally substituted, optionally substituted § reel alkyl represents an alkyl thio alkyl optionally substituted, Y one ^{_{C 0 2 R 12, - C}} ONR ¹² R ¹² ′ or one C OR ¹² (R ¹² and R ¹² ′ may be the same or different and each is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, substituted Represents an optionally substituted heteroarylalkyl, an optionally substituted cycloalkyl or an optionally substituted aryl, wherein R ¹² and R ¹² ′ are substituted together with an adjacent nitrogen atom. M represents 0 or 1, n represents an integer of 0 to 4), and R ⁴ is a substituted or unsubstituted group. Good kill, may be replaced Arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted ^{_{heteroaryl, - S0 2 R 12, -CO-}} (CH 2) q - NR 12 R 12 'ί q represents 1 or 2, R ¹² and R ^12' as defined above is}, -C ONH-ZR ¹³

{Z represents an alkylene having 2 to 4 carbon atoms; R ¹³ represents a hydroxyl group, amino or one NR ¹² R ¹² ′ [R ¹² and R ¹² ′ are as defined above]} or

R ¹¹

 ― (C ONH) m-CCH) n Y

(Wherein, ¹¹ , Y, m and η are the same as defined above), and R ³ and R ⁴ together with an adjacent nitrogen atom form an optionally substituted heterocycle. The present invention also relates to the above-mentioned azapeptide hydroxamic acid derivative or a pharmacologically acceptable salt thereof.

Further, the present invention provides a compound represented by the formula (I) wherein R ¹ is a hydrogen atom or substituted. Salts that are acceptable the Azape peptide-type human Dorokisamu acid derivative or its pharmacology alkyl, in formula (I), the Azape peptide-type human R ² is alkyl optionally substituted A droxamate derivative or a pharmacologically acceptable salt thereof, in the formula (I), wherein the azapeptide type hydroxamic acid derivative wherein R ² is isobutyl or a pharmacologically acceptable salt thereof in the formula (I) , R ³ and the Azape peptide-type human Dorokisamu acid derivative or a pharmaceutically acceptable salt thereof wherein R ⁴ to form a hetero cycle to which may be connexion substitutions together with the adjacent nitrogen atom , in formula (I), also the Azape peptide type arsenate de Rokisamu acid derivative to form a 2-O Kiso quinazolinylmethoxy or morpholino Te summer together with the nitrogen atom to which R ³ and R ⁴ are adjacent To their pharmacologically acceptable salts.

 Further, the present invention provides a compound of the formula (II)

αι)

[Wherein R ¹⁴ represents hydrogen, optionally substituted alkyl or optionally substituted aryl,

Represents a single bond or a double bond, and R ^1S is

Is a single bond, hydrogen, a hydroxyl group, amino, mercapto, alkoxy, optionally substituted alkyl, alkenyl, optionally substituted aryl, one (CH ₂ ) k —A (k is any of 1-4 A is: (a) linked by an N atom; and (b) at least one atom selected from N, 0 and S as a further heteroatom at a position not adjacent to the bonded N atom. (C) A force substituted by oxo on one or both C atoms adjacent to the bonded N atom, and (d) a benzo-condensed or substituted force on one or more other C atoms by lower alkyl or oxo; And / or another N atom, which represents a 5- or 6-membered N-heterocyclic ring which may be substituted by lower alkyl or phenyl) or --COOR ¹⁶ (where R ¹⁶ is hydrogen, optionally substituted alkyl) Or represents an optionally substituted)) or

Is a double bond, represents CH ₂ , R ² represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl, R ^S represents hydrogen, an optionally substituted alkyl, Optionally substituted aryl, optionally substituted heteroaryl or

R ¹¹

 I

 One (CONH) m-(CH) n One Y

(Wherein, R ¹¹ represents hydrogen or an optionally substituted alkyl, and Y represents one C 0 ₂ R ¹² , -CONR ^{, 2} R ¹² ′ or —COR ¹² and R ¹² ′ are the same or different. Each represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl, wherein R ¹² and R ¹² ′ are an optionally substituted heterocycle together with an adjacent nitrogen atom. M represents 0 or 1, n represents an integer of 0 to 4), and R ⁴ represents an optionally substituted alkyl, substituted is optionally Ariru, heteroaryl optionally substituted one ^{_{S0 2 R 12, - CO- (}} CH 2) q -NR 1 R 12 '

{Q represents 1 or 2, R ¹² and R ¹² ′ have the same meanings as defined above.), -CONH-Z-R ¹³ (Z represents an alkylene having 2 to 4 carbon atoms, R ¹³ represents a hydroxyl group, amino or NR ¹² R ¹² '[R ¹² and R ¹² ' are as defined above]] or

R ¹¹

-(CONH) m one (CH) n — Y (Wherein, R ¹ Y, m and η are the same as defined above), and R ³ and R ⁴ together with an adjacent nitrogen atom form an optionally substituted heterocycle. (Hereinafter referred to as intermediate compound (II)).

 Further, the present invention provides a pharmaceutical composition comprising an azapeptide-type hydroxamic acid derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier, and a medicament thereof. Uses, especially TNFα production inhibitors.

 Detailed description of the invention

 The symbols used in the present specification are described below.

The alkoxy in R ¹ and R ¹⁵ preferably has 1 to 6 carbon atoms and may be linear or branched. For example, methoxy, ethoxyquin, η-propoxy, isopropoxy, η-butoxy, tert- Butoxy and the like.

The optionally substituted alkyl in R ¹ and R ¹⁵ is alkyl, arylalkyl, heteroarylthioalkyl, arylthioalkyl, phthalimidalkyl, and one or more, preferably from 1 to 3 each. May be substituted by a number of substituents.

 The alkyl preferably has 1 to 10 carbon atoms and may be linear or branched. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-butyl —Pentyl, isopentyl, neopentyl, n-hexyl, n-octyl, n-decyl and the like.

An arylalkyl is preferably an alkyl moiety having 1 to 6 carbon atoms, which may be straight-chain or branched, and an aryl moiety preferably having a biaryl fused with fuunyl, naphthyl, or ortho-fused. Examples of the group of the formula include those having from 8 to 10 ring atoms and at least one ring being an aromatic ring (for example, indenyl). Specifically, benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (1-naphthyl) ) Propyl, 3- (2-naphthyl) propyl and the like. Heteroarylthioalkyl means that the alkyl portion thereof is preferably a straight-chain or branched chain having 1 to 6 carbon atoms, and the heteroaryl portion is preferably a carbon atom and 1 to 4 hetero atoms. 5- to 6-membered ring group having an atom (oxygen, sulfur or nitrogen), or an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, especially a benz derivative or Examples thereof include those derived by fusing a penylene, trimethylene or tetramethylene group thereto, and stable N-hydroxyl oxide. Examples of the heteroaryl group include pyrrolyl, pyrrolinyl, furyl, phenyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,4-oxaziazolyl, 1,2,4- Oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, bilanyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2.4-triazinyl, 1,2,3-triazinyl, 1,3 , 5—Triazinyl, 1,2,5-year-old xiathiazinyl, 1,2,6-oxathiazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, tianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, chromenyl, isoindolyl The Inn Lil, indazolyl, isoquino, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, Niino Riniru, Ben Zookisajiniru and the like. Preference is given to pyridyl, chenyl and imidazolyl, particularly preferred to phenyl.

 Specific examples of heteroarylthioalkyl include 2-pyrrolylthiomethyl, 2-pyridylthiomethyl, 3-pyridylthiomethyl, 4-pyridylthiomethyl, 2-chernylthiomethyl, 2- (2-pyridyl) thioethyl And 2- (3-pyridyl) thioethyl, 2- (4-pyridyl) thioethyl, 3- (2-pyrrolyl) thiopropyl and the like.

The arylthioalkyl means that the alkyl portion thereof preferably has 1 to 6 carbon atoms and may be linear or branched, and the aryl portion is the same as described above. Specifically, phenylthiomethyl, 3-phenylthiopropyl, 1-naphthylthiomethyl, 2 Mono-naphthylthiomethyl, 2- (1-naphthyl) thioethyl, 2- (2-naphthyl) thioethyl, 3- (1-naphthyl) thiopropyl, 3- (2-naphthyl) thiol pill and the like.

 The alkyl moiety of the phthalimidalkyl preferably has 1 to 6 carbon atoms and may be linear or branched. Specifically, phthalimidmethyl, 2-phthalimidethyl and the like can be mentioned.

The optionally substituted alkyl in R ¹ and R ¹⁵ is, for example, amino, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl (however, alkyl or aryl) The alkyl moiety of alkyl, heteroarylthioalkyl, arylthioalkyl, phthalimidalkyl is not substituted), alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, carboxyl, hydroxysulfo. N, aminosulfonyl, hydroxysulfonyloxy, alkoxycarbonyl, alkamoyl, arylalkyloxy, alkylaminoalkoxy, etc., even if substituted with one or more, preferably 1 to 3 substituents. Yo .

Here, alkoxy and arylalkyl are the same as above. Lower alkyl means a straight or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl, n-pentyl, Examples include isopentyl, neopentyl, n-hexyl and the like. In the alkylthio, the alkyl moiety thereof preferably has 1 to 6 carbon atoms and may be linear or branched, and examples thereof include methylthio, ethylthio, n-propylthio, and isopropylthio. The acyloxy is preferably a linear or branched one having 1 to 6 carbon atoms, and examples thereof include alkanoyloxy such as acetyloxy, propionyloxy, petyriloxy, valeryloxy, bivaloyoxy, and hexanoyloxy. Alkoxycarbonyl is represented by one COOR a, and Ra represents lower alkyl (as above) or arylalkyl (as above). The arylalkyl part in arylalkyloxy is the above aryl JP

The same as benzylalkyl, for example, benzyloxy, phenethyloxy and the like. Alkylaminoalkoxy includes N-alkylaminoalkoxy and N, N-dialkylaminoalkoxy, the alkyl part of which preferably has 1 to 6 carbon atoms and may be straight-chain or branched, and the alkoxy part is preferably May have 1 to 6 carbon atoms and may be linear or branched. For example, methylaminomethoxy, dimethylaminomethoxy, ethylmethylaminomethoxy, 2-methylaminoethoxy, 2-dimethylaminoethoxy, 2-ethylmethylaminoethoxy, 3-methylaminopropoxy, 3-dimethylaminopropyl π-poxy And the like.

The alkenyl in R ¹ and R ¹⁵ preferably has 2 to 6 carbon atoms and includes, for example, vinyl, aryl, 3-butenyl, 5-hexenyl and the like. …

A in — (CH ₂ ) k —A in R ¹ and R ¹⁵ is an N-heterocycle linked by an N atom, and examples thereof include the following groups.

(vii) [Wherein, R ⁸ and R ³ each represent hydrogen or together form another bond to form a double bond, R ^1Q represents hydrogen, lower alkyl or phenyl, and X ′ represents — C 0-, One CH ₂ -,-CH (R ¹⁹ )-, — C (R ¹³ ) ₂ -,-NH-,-N (R ¹⁹ ) — or — 0—, and Y and 1 are 0—, — ΝΗ— Or —N (R ¹³ ) —, and R ′ ⁹ represents lower alkyl.] Here, lower alkyl is as defined above. Specific examples of the heterocyclic ring include, for example, 2-oxo-11-pyrrolidinyl, 110-oxoisoindolin-1-yl, 2-oxoindolin-111-yl, 2,5 —Dioxo-1-1-pyrrolidinyl, 1,2-dimethyl-1,3,5-dioxo-1,2,4-triazolidin-41-yl, 3-methyl-2,5-dioxo-1-1-imidazolidinyl, 3,4,4 1-trimethyl-1,2,5-doxoxo 1-imidazolidinyl, 2-methyl-1,3,5-dioxo1,2,4,1-oxadiazo-1-yl 4-yl, 3-methyl-2,4,5-trioxo- Examples thereof include 1-imidazolidinyl, 2,5-dioxo-l-phenyl-1-1-imidazolidinyl, and 2,6-dioxopiperidino. Rings of the formulas (ii), (iii), (vii) and (viii), especially 1-oxoisoindolin-1-yl, 2-oxoindolin-1-yl, 1,2-dimethyl-13 , 5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl or 3,4,4-trimethyl-2,5-dioxo-1,1-imidazolidini Are preferred.

The optionally substituted alkyl in R ² , R ³ and R ⁴ is alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl. Alkyl and arylalkyl are the same as the alkyl and arylalkyl in R ¹ and R ¹⁵ , respectively.

The heteroarylalkyl means that the alkyl portion thereof may preferably be a straight-chain or branched chain having 1 to 6 carbon atoms, and the heteroaryl portion may be the same as the heteroaryl portion of the heteroarylthioalkyl in R ¹ and R ¹³ . The same is true. For example, 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-chenylmethyl, 2- (2-pyridyl) ethyl, 2- (3-pyridyl) ethyl And 2- (4-pyridyl) ethyl, 3- (2-pyrrolyl) propyl and the like.

 The cycloalkyl preferably has 3 to 7 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The cycloalkylalkyl means that the alkyl portion thereof preferably has 1 to 6 carbon atoms and may be straight-chain or branched, and the cycloalkyl portion is the same as described above. Specific examples include cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like.

R ⁵ ^, one: The optionally substituted alkyl in R ³ and R ⁴ is the same as the optionally substituted alkyl in R ¹ and R ^1S , one or more, preferably 1 to 3 substituents May be substituted.

The optionally substituted alkyl for R ¹¹ is alkyl, arylalkyl, or alkylthioalkyl. Alkyl and arylalkyl are the same as the alkyl and arylalkyl in R ¹ and R ¹⁵ , respectively. Alkylthioalkyl means that the alkyl part thereof preferably has 1 to 6 carbon atoms and may be linear or branched. Specific examples include methylthiomethyl, ethylthioethyl, n-propylthiomethyl, 2-methylthioethyl, 3-methylthiopropyl and the like. The optionally substituted alkyl in R ¹¹ may be substituted by one or more, preferably 1 to 3 substituents similar to the optionally substituted alkyl in R ¹ and R ¹⁵ .

The optionally substituted alkyl in R ¹² , R ¹² ′, R ¹⁴ and R ¹⁸ is alkyl, arylalkyl, heteroarylalkyl, cycloalkyl. These are each alkyl in R ¹ and R ^15, § reel alkyl, heteroalkyl § reel alkyl in R ² and R ^3, is the same as cycloalkyl. These may be substituted by one or more, preferably 1 to 3 substituents similar to the optionally substituted alkyl in R ¹ and R ¹⁵ . The optionally substituted aryl in R ¹ , R ^z , R ³ , R ⁴ , R ¹⁴ , R ¹⁵ and R ¹⁶ is the same as the aryl moiety of the arylalkyl in R ¹ and R ¹⁵ .

 The aryl includes, for example, amino, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl (same as above), alkoxy (same as above), alkylthio (same as above) ), Formyl, acyloxy (as above), oxo, phenyl, arylalkyl (as above), carboxylic acid, hydroxysulfonyl, aminosulfonyl, hydroxysulfonyloxy, alkoxycarbonyl (as above), It may be substituted with one or more, preferably 1 to 3 substituents selected from alkavamoyl, arylalkyloxy (as described above), alkylaminoalkoxy (as described above) and the like.

The optionally substituted aryl in R ¹² and R ¹² ′ is the same as the aryl moiety of the aryl alkyl in R ¹ and R ¹⁵ , preferably phenyl, naphthyl, and more preferably phenyl. . The aryl includes, for example, amino, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl (as above), alkoxy (as above), alkylthio (as above) , Formyl, acyloxy (as above), oxo, phenyl, arylalkyl (as above), carboxyl, hydroxysulfonyl, aminosulfonyl, hydroxysulfonyloxy, alkoxycarbonyl (as above) May be substituted with one or more, preferably 1 to 3 substituents selected from carbamoyl, arylalkyloxy (same as above), alkylaminoalkoxy (same as above) and the like. The reels in R ¹² and R ¹² ′ are

— 0— (CH ₂ ) r-C 0 OR ¹⁷

One (CH ₂ ) s one NR ¹⁸ R ¹⁸ 'and

-0- (CH ₂ ) t — NR ¹⁸ R ¹⁸ '

[Wherein, R ¹⁷ represents hydrogen, lower alkyl (same as above) or arylalkyl (same as above), and R ¹⁸ and R ¹⁸ ′ may be the same or different. And R ¹⁸ and R ′ ⁸ ′ together with an adjacent nitrogen atom may form a substituted or unsubstituted heterocyclo, where r is Represents an integer of 1 to 6, s represents an integer of 0 to 6, and t represents an integer of 1 to 6], and may be substituted with a substituent selected from the group consisting of:

The optionally substituted heteroaryl in R ³ and R ⁴ is the same as the heteroaryl portion of the heteroarylthioalkyl in R ¹ and R ¹⁵ . The heteroaryl is at least one, preferably 1 to 3 of the same as the optionally substituted aryl in R ¹ , R ² , R ³ , R ⁴ , R ″, R ¹⁵ and R ^ie. May be substituted by a number of substituents.

Is 'R ³ and R ⁴ are hetero-cycle to substituted to a connexion formed nitrogen atom and cord adjacent, and R ¹² and R ^12' is connexion formed such together with the adjacent nitrogen atom substituted A heterocycle may have carbon and at least one nitrogen and contain at least one atom selected from nitrogen, oxygen and sulfur as a further heteroatom on the ring. Of the ring-constituting carbon atoms, a 4- to 7-membered ring group which may be substituted by oxo, and a benzene ring or the like utilizing two adjacent carbon atoms constituting the heterocycle. May be condensed. For example, azetidino (1-azetidinyl), pyrrolidino (1-pyrrolidinyl), piperidino, piperazino (1-piperazinyl), morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, 2-oxoquinazolinyl, etc. No. Preferably, they are morpholino, piperazino and 2-oxoquinazolinyl. 2-oxoquinazolinyl is a group represented by the following formula.

^X

[In the formula, Rb represents hydrogen or a low-alkyl (as above)] The heterocycle is one or more, preferably one to three of the same as the optionally substituted aryl in R ¹ , R ² , R ³ , R ⁴ , R ¹⁴ , and R ^16. May be substituted by the substituent.

1 ⁸ Oyobi ¹⁸ 'terrorism cycle to optionally substituted to form together with the adjacent nitrogen atom, are the same as heterocycle in the R ³ and R ^4, for example, Azechijino (1 Azetidinyl), pyrrolidino (1-pyrrolidinyl), piperidino, piperazino (1-piperazinyl), morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, 2-oxoquinazolinyl and the like. Preferably, they are morpholino and piperazino. The heterocycle may be substituted by one or more, preferably 1 to 3 substituents selected from lower alkyl (as above), arylalkyl (as above) and the like.

R ³ and R 'are

R ¹¹

 I

 -(C ONH) m-(CH) n -Y

When they are groups represented by the following, they may be the same group or different groups. The R ¹² in R ¹² and R ⁴ in R ³ are the same rather good be different also, 'and in R ⁴ R ^12' R ¹² in R ³ may be be the same or different .

 The alkylene having 2 to 4 carbon atoms in Z may be linear or branched, and includes, for example, ethylene, trimethylene, tetramethylene, propylene, 1.1-dimethylethylene and the like.

The hydroxyl-protecting group for X includes, for example, arylalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, tetrahydrobiranyl and the like. The arylalkyl which may be substituted is the same as the arylalkyl for R ¹ and R ¹⁵ , and the one or more substituents which may be present are also the same. The aryls that may be substituted are R ¹ , R ² , R ^3, is R ^4, R ^{1 4,} R ^{1 S} and R which may Ariru the same way be substituted in ^ie, it is the same one or more substituents which may be possessed. The optionally substituted heteroaryl is the same as the optionally substituted heteroaryl in R ³ and R ⁴ , and the one or more substituents which may be present are also the same.

 As the protecting group for the hydroxyl group, tetrahydrobiranyl, benzyl and the like are preferable. The azapeptide hydroxamic acid derivative represented by the formula (I) or a pharmacologically acceptable salt thereof may have an asymmetric carbon, and therefore can exist as an optically active form and a racemic form. The body can be separated into each optically active body by a method known per se. When the azapeptide-type hydroxamic acid derivative or a pharmacologically feasible salt further has an additional asymmetric carbon, the compound exists as a diastereomer mixture or a single diastereomer. These can also be separated from each other by a method known per se.

 In addition, the azapeptide-type hydroxamic acid derivative or a pharmaceutically acceptable salt thereof can exhibit polymorphism, and can exist as more than one tautomer. It can exist as a hydrate (eg, ketone solvate, hydrate, etc.).

 Therefore, the present invention includes any stereoisomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof as described above. Active, racemic and diastereomers are also included within the scope of the present invention.

 Pharmacologically acceptable salts of the azapeptide-type hydroxamic acid derivatives include, for example, alkyl metal salts (eg, salts with lithium, sodium, potassium, etc.), alkaline earth metal salts (eg, calcium, Salts with magnesium, etc.), anolemminium salts, ammonium salts, salts with organic bases (eg, salts with triethylamine, morpholine, piperidine, triethanolamine, etc.) and the like.

Other pharmacologically acceptable salts include, for example, inorganic acid addition salts (eg, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts Salts (for example, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, cunic acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, Salts with succinic acid, mandelic acid, and linoleic acid); salts with amino acids (eg, salts with glutamic acid, aspartic acid, etc.);

In a preferred embodiment of the azapeptide hydroxamic acid derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, R ¹ in the formula (I) is hydrogen or an optionally substituted alkyl. Zaptide-type hydroxamic acid derivatives or pharmacologically acceptable salts thereof, azapeptide-type hydroxamic acid conductors wherein R ² is isobutyl in the formula (I) or pharmacologically acceptable salts thereof In the formula (I), R ³ and are taken together with an adjacent nitrogen atom to form 2-oxoquinazolinyl or morpholino, an azapeptide-type hydroxamic acid derivative, or a pharmaceutically acceptable salt thereof. Is mentioned. A method for producing the azapeptide-type hydroxamic acid derivative of the present invention or a pharmacologically acceptable salt thereof will be described below.

Process 1

ΧΟΝΗί

 Process 3

Wherein the R ¹⁴ synonymous (where hydrogen is excluded) is, R ¹⁵ 'has the same meaning as ^{R 1, R 1, R 2} , R 3, R 4 and X are as defined above]

As shown in the above Scheme I, the azapeptide hydroxamic acid derivative of the present invention or a pharmacologically acceptable salt thereof is basically prepared by using carboxylic acid (III) as a raw material and hydrazine (IV). The intermediate compound (II ') is prepared by the C-terminal activation method in peptide synthesis [for example, basics and experiments on peptide synthesis (see Maruzen Shoten, Izumiya et al., Pp. 91)], and the succinic acid derivative (IΓ via conversion to '), human mud Kishiruamin: ΧΟΝΗ ₂ (X can be prepared by reacting with the same meaning). The carboxylic acid (III) used as a raw material is described in the literature (Japanese Patent Application Laid-Open No. 6-506445, Japanese Patent Application Laid-Open No. 4-352757, Japanese Patent Application Laid-Open No. 7-157470, Japanese Patent Application Compounds described in Japanese Unexamined Patent Publication No. 6-65196, WO 96/33968, WO 94-21625, etc.) or prepared by conventional methods based on these documents.

 Hydrazine (IV) is also a compound described in the literature (Tetrahedron, 44, 5525 (1988). J. Chem. So, Perkin Trans 1, 1975. 1712, etc.), or a hydrazine (IV) is used based on these literatures. It is prepared by a technique.

 Hereinafter, details of each step will be described.

Process 1

Step 1 is a step of preparing an intermediate compound (II ') by reacting carboxylic acid (III) with hydrazine (IV). The typical method is shown below.c Step 1-1) Method using mixed acid anhydride The intermediate compound (II ') is obtained by reacting carboxylic acid (III) with isobutyl carbonate and then hydrazine (IV) in the presence of an amine base such as triethylamine or N-methylmorpholine. Can be obtained by As the solvent, a non-aqueous solvent such as tetrahydrofuran (THF), ethyl acetate, N, N-dimethylformamide (DMF) is used, and the reaction can be performed at a low temperature of 15 to 15 ° C. Step 1 2) Method using acid chloride

 The acid chloride is once prepared by reacting the carboxylic acid (III) with oxalyl chloride or thionyl chloride. As the solvent, methylene chloride or a hydrocarbon solvent such as benzene or toluene is used, and the reaction is performed at a low temperature of 15 to -5 or under heating. The intermediate compound (I Γ) can be obtained by reacting the obtained acid chloride with hydrazine (IV) in the presence of an amine base such as triethylamine or pyridine. As the solvent, a non-aqueous solvent such as THF, ethyl acetate, DMF or the like, methylene chloride, or a hydrocarbon solvent such as benzene or toluene is used, and the reaction can be performed at a low temperature or under heating.

Step 1—3) Method using DC C—HOB t method (coupling method)

Bok Riechiruami down or Amin presence of a base such as N- methylmorpholine, carbo phosphate (III), Kishirukarubojii mi de dicyclohexyl the hydrazine (IV) and 1 over human Dorokishibenzu Bok Riazor _{(HO B t · H 2 0} ) ( It can be obtained by reacting a condensing agent such as DCC) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) at room temperature or lower. As a solvent, a non-aqueous solvent such as THF, ethyl acetate, DMF, and pyridin is used.

Step 1-1 4) Method using active ester method

An active ester is once prepared by reacting a carboxylic acid (III) with a phenol derivative such as pentafluorophenol or N-hydroxysuccinic acid imide with a condensing agent such as DCC. As a solvent, an organic solvent such as THF, methylene chloride, benzene, and toluene is used, and the reaction is performed at a temperature lower than room temperature. Subsequently, the obtained activity It can be obtained by reacting the ester with hydrazine (IV) in the presence of an amine base such as triethylamine or N-methylmorpholine. As the solvent, a non-aqueous solvent such as THF or DMF, methylene chloride, or a hydrocarbon solvent such as benzene or toluene is used, and the reaction can be performed at room temperature or lower.

Process 2

 Step 2 is a step of converting the intermediate compound (IΓ) to a succinic acid derivative (II ′ ′). The succinic acid derivative (II ′ ′) can be obtained by reacting the intermediate compound (II ′) with a hydrogen chloride solution or trifluoroacetic acid. As the solvent, an ether-based solvent such as 1,4-dioxane or a hydrocarbon-based solvent such as methylene chloride or benzene or toluene is used, and the reaction can be carried out at a temperature lower than room temperature.

Process 3

In step 3, the succinic acid derivative (I I ') is protected or unprotected with tert-butyl, benzyl, tetrahydrohydranil (Chem. Pharm. Bull. Jpn. 23, 167. 1975) or the like. Droxylamine: a step of reacting with XONH ₂ (X is as defined above). As the reaction conditions, the conditions in Step 1 can be applied. When a protected hydroxylamine is used, the protecting group can be removed after the reaction under ordinary conditions for deprotection of a hydroxyl group.

The introduction of the desired substituents R ³ and R ⁴ can be carried out by using the hydrazine (IV) having the substituent by the method shown in the above scheme I without any special steps. However, for example, it can also be carried out by the method shown in the following scheme II.

[Wherein, R ³ ′ has the same meaning as R ³ (excluding hydrogen), and R ² , R ⁴ , R ¹⁴ ′ and R ¹⁵ ′ have the same meanings as above.]

Process 4

Step 4 is a step of introducing a substituent R ³ ′ from an intermediate compound (Ia) [a compound of the intermediate compound (II ′) wherein R ³ is hydrogen] as a raw material. That is, the intermediate conjugated compound (II 'a) the substituent R ³ in the presence of a base' is reacted with an electrophilic agent or protection agent to be introduced agents, to obtain the intermediate compound (I gamma b) It is.

 Electrophilic agents include commonly used alkylating agents, acid chlorides, carbamoyl chloride, (thio) isocyanate, sulfonyl chlorides, and protective reagents such as benzyloxycarbonyl chloride and di-t-butyl carbonate. Of electrophilic reagents are available. Amines are used as the base. As the solvent, an ether-based solvent such as THF and 1,4-dioxane, or a hydrocarbon-based solvent such as methylene chloride or benzene or toluene is used, and the reaction can be carried out at a temperature of from 15 to room temperature.

In addition, the substituent R ⁴ can be introduced in the same manner as in Scheme II described above.

Intermediate compound (1 1) in R ⁴ gar C_〇_CH ₂ NR ^l2 R ¹² Compound '(R ¹² and R ^12' are as defined above) in which, to the method shown in Scheme III below Can also be prepared.

Scheme 丄 i 丄

[Wherein, H a 1 is halogen, and R ² , R ³ , R ¹² , R ¹² ′, R ¹⁴ ′ and R ¹⁵ ′ are as defined above.]

Process 5

Step 5, for example, intermediate compounds prepared by the method of Step 4 (I gamma c) as a starting material, § Mi ^{emissions: HNR l2 R 12 '(R} 12 and R ^12' as defined above) a nucleophilic agent This is a step of introducing —COCH ₂ NR ^1Z R ¹² (where R ¹² and R ¹² ′ are as defined above) as the substituent R ⁴ .

 This reaction can be carried out without a solvent or in a methylene chloride or a hydrocarbon solvent such as benzene or toluene under heating from room temperature.

In the succinic acid derivative (I ′ ′), the compound in which the substituents R ³ and Z or R ⁴ are —CONR ¹² R ¹² ′ (where R ¹² and R ¹² ′ have the same meaning as described above) (Cho) The compound can be prepared by deprotection, if necessary, following the reaction using isocyanate as an electrophile, or by the method shown in Scheme IV below.

[Wherein, R is —C0 ₂ R ¹² (R ¹² has the same meaning as described above, except for hydrogen), and R ² , R ³ , R ¹² , R ¹² ′, and R ¹⁵ ′ have the same meanings as above.]

Process 6

In step 6, in the succinic acid derivative (IΓ′a) [in the succinic acid derivative (II ′ ′), R ^{4 is} —CO ₂ R ¹² (R ¹² is as defined above, except for hydrogen) Compound] and an amine: HNR ¹² R ¹² ′ (R ¹² and R ¹² ′ are as defined above) to react with the succinic acid derivative (II′′b) [succinic acid derivative (I ′ ′) Wherein R ^{4 is} —CONR ¹² R ¹² ′ (R ¹² and R ¹² ′ are as defined above).

 The solvent used is an ether-based solvent such as THF, 1,4-dioxane, methylene chloride, or a hydrocarbon-based solvent such as benzene or toluene, or a protonic solvent such as an alcohol, and is carried out at room temperature or under heating. be able to.

Incidentally, a succinic acid derivative (II ′) in which the substituent R ^{3 is} —CONR ¹² R ¹² ′ (R ¹² and R ¹² ′ are as defined above) may be prepared in the same manner as in the above scheme IV. it can.

The desired substituent R ¹ is introduced using a carboxylic acid (III) having the substituent. If this is the case, it can be carried out without any special steps by the method shown in Scheme I above, but it can also be carried out by the method shown in Scheme V below, for example.

[Wherein, R ¹ ′ is arylthioalkyl, R ¹⁸ ′ has the same meaning as R ¹⁶ (excluding hydrogen :), and R ² , R ³ , R ⁴ and R ¹⁴ ′ have the same meanings as above.]- ,,

 WO 99/40063

Process 7

 Step 7 is a step in which an intermediate compound (IVe) is obtained using carboxylic acid (V) as a raw material in the same manner as in step 1 of scheme I above. The raw material rubonic acid (V) is a compound described in a literature (Japanese Patent Application Laid-Open No. 4-502008, etc.) or is prepared by a conventional method based on these literatures. Is what is done. Process 8

Step 8 is a step of removing the substituents R ¹⁴ ′ and R ¹⁶ ′ in the intermediate compound (IΓe) to obtain a succinic acid derivative (IΓ′f). For example, when and R ¹⁶ * are a benzyl group, the reaction can be carried out at normal pressure or under pressure by a usual catalytic hydrogenation reaction in the presence of a metal catalyst. As the metal catalyst, palladium, platinum, etc. can be used. As the solvent, an ether solvent such as 1,4-dioxane, a hydrocarbon solvent such as benzene or toluene, or a protic solvent such as alcohol is used. From under heating.

Process 9

 In step 9, the succinic acid derivative (I ′ ′ f) obtained in step 8 is reacted with formaldehyde in the presence of a base to give a succinic acid derivative (II ′ ′ g) which is r-exomethylene carboxylic acid. This is the step of conversion. As the base, amines such as piperidine are used, and the reaction can be carried out in an alcoholic solvent, methylene chloride, or a hydrocarbon-based solvent such as benzene or toluene from room temperature under heating.

Step 1 0

 Step 10 is a step of decarboxylating the succinic acid derivative (IΓ, f) obtained in Step 8 to obtain a succinic acid derivative (IΓ′h) which is a monocarboxylic acid. As the solvent, methylene chloride or a hydrocarbon solvent such as benzene or toluene is used, and the reaction can be performed at room temperature or under heating.

Process 1 1

In step 11, the succinic acid derivative (II'g) obtained in step 9 is reacted with arylthiol as a nucleophile, so that the substituent Ri is an arylthioalkyl. This is the step of obtaining a succinic acid derivative (IΓ ′ i). This reaction can be carried out without a solvent or in a hydrocarbon solvent such as methylene chloride or benzene or toluene under heating from room temperature.

 It should be noted that conversion between various substituents is not only possible in a specific step, but the step is limited as long as it does not affect other functional groups present in the chemical structural formula. Not something.

 The azapeptide-type hydroxamic acid derivative of the present invention synthesized in this manner is appropriately subjected to known separation and purification means, for example, concentration, extraction, chromatography, reprecipitation, recrystallization, and the like. Can be collected at any purity.

 Also, a pharmacologically acceptable salt of the azapeptide hydroxamic acid derivative can be produced by a known method. Further, various isomers of the hydroxamic acid derivative can also be produced by a known method.

 The azapeptide hydroxamic acid derivative of the present invention and a pharmacologically acceptable salt thereof exhibit excellent TNFa production inhibitory activity against mammals (eg, humans, dogs, cats, etc.). Have.

 Therefore, the azapeptide hydroxamic acid derivative and the pharmacologically acceptable salt thereof of the present invention are useful as a TNF production inhibitor. For example, sepsis, MOF, rheumatoid arthritis, Crohn's disease, cachexia, skeletal muscle It is useful for the prevention and treatment of diseases such as asthenia, systemic lupus erythematosus, asthma, type I diabetes, psoriasis, other autoimmune diseases and inflammatory diseases.

 When the azapeptide-type hydroxamic acid derivative of the present invention and a pharmacologically acceptable salt thereof are used as pharmaceuticals, granules, tablets, capsules, injections, and the like can be prepared using a pharmacologically acceptable carrier and the like. It can be orally or parenterally administered as a pharmaceutical composition in the form of plasters, creams, aerosols and the like. An effective amount of the hydroxamic acid derivative and a pharmacologically acceptable salt thereof is added to the above preparation.

The dose of the azapeptide hydroxamic acid derivative and its pharmacologically acceptable salt varies depending on the administration route, the patient's condition, weight, age, etc. It can be set appropriately according to the purpose of administration. Usually, when given orally to adults,

It is preferable to administer 0 to 0, 1 to 1000 mgZkg body weight / day, preferably 0.05 to 250 mgZkg body weight day in one to several parts.

 Example

 Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto.

'Η-NMR was measured at 300 or 500 MHz, and ^{l 3} C-NMR was measured at 75 or 125 MHz. 'Η-NMR chemical shifts used tetramethylsilane as an internal standard, and the relative delta (δ) values were expressed as paper millions (ρ ρm). Coupling constants indicate trivial multiplicity in Hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m ( Multiplet), dd (double toe doublet), brs (broad singlet), brd (broad doublet) and so on.

Reference example 1

 4—t e r t —butoxy 2 R-isobutylsuccinic acid

 The title compound was produced according to the method described in WO95 / 0631, JP-T-6-5066445.

 [] D-+ 10.9 ° (c = l.25, MeOH); literature value: [na]. = + 1 0. 4 ° (c-1.0. JieOH)

Reference example 2

 4-t e rt —butoxy 2 R—isobutylsuccinic acid N—hydroxysuccinimide

To a solution of 4-tert-butoxy-2R-isobutylsuccinic acid (1.98 g, 8.59 mmol) obtained in Reference Example 1 in tetrahydrofuran (13 ml) was added N-hydroxysuccinimide (0.10 g. 8.67). mmol), and a solution of dicyclohexylcarbodiimide (1.78 g, 8.20 mmol) in tetrahydrofuran (7 ml) was added dropwise under ice cooling. Reaction mixing The mixture was stirred for 1.5 hours under ice-cooling, then transferred to a refrigerator and allowed to stand for 18 hours. The obtained mixture was returned to room temperature, and the precipitated urea was removed by filtration. The filtrate was concentrated. Hexane was added again to remove the rare, to give the title compound (2.33 g, yield 83¾) as a pale yellow liquid.

 ^-M (CDCls) face. 300MHz: 3.25-3.10 (m. 1H), 2.82 (in, 4Η),

2.73 (dd, J: 16.7. 8.0 Hz. 1H), 2.9 (dd. J = 16.7. 6.4 Hz, 1H),

1.82-1.69 (m, 2H), 1.46 (s, 9H). 1.31-1.20 (m. 1H), 1.00-0.90 (m. 6H). Reference Example 3

 4 1-benzyloxy 3-benzyloxycarbonyl 2 R-isobutylsuccinic acid

 The title compound was produced according to the method described in JP-T-4-15202008. Reference example 4

 4-tert e-butoxy 2-R-isobutyl-1-3-fluoromethyl succinic acid

 The title compound was produced according to the methods described in JP-A-6-61596 and JP-A-7-157470.

Reference example 5

 4-tert e-butoxy-3-methyl-2R-isobutylsuccinic acid

 The title compound was produced according to the methods described in JP-A-4-3525757 and JP-A-7-157470.

Reference example 6

2S-Hydrazino-1-N-methyl-3-phenylpropionamide hydrochloride The title compound can be obtained by a known method (Tetrahedron. 1988, 44.5525). —Butyroxycarbonyl) hydrazino] 1-3-phenylpropionic acid benzyl ester was synthesized as follows. (1) 2 S— [N, Ν'-bis- (tert-butyloxycarbonyl) hydrazino] -1-3-phenylpropionic acid 2 S- [N, N'-bis- (tert-butyloxycarbonyl) hydrazino] -13-phenylpropionic acid benzyl ester (14.1 g. 30.0 nimol) in ethyl acetate (440 ml) in 5% palladium A carbon catalyst (2.06 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to obtain the target compound (11.2 g, yield: 98 mg) as a white foam.

_{lH-NMR (CDC1 3) 5ppm} , 300MHz: 14.02-9.20 (br s, 1H),

7.41-7.09 (m.5H), 6.21 and 6.11 (br s.1H total).

4.72-4.18 and 4.18-3.97 (m, 1R total),

 3.41 (dd, J = 14.4, 4.1 Hz. 1H), 3.15 (apparent t. J = 12.3 Hz. 1H).

1.50, 1.47 and 1.41 (s. 18H total). [Rotamer peak was observed]

 (2) 2 S- [N, N'-bis- (tert-butyroxycarbonyl) hydrazino] -1-N-methyl-3-phenylpropionamide

 2S— [N.N′—bis (tert-butyloxycarbonyl) hydrazino] —3-phenylpropionic acid (10.8 g, 28.4 mmol) and N, N obtained in (1) of Reference Example 6 —Vivaloyl chloride (4.4 ml. 35.7 ol) was added to a solution of diisopropylethylamine (11 ml, 63.1 mmol) in tetrahydrofuran (200 ml) under ice-cooling, and the mixture was stirred for 30 minutes. A 40% aqueous methylamine solution (54 ml) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a 1N aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated, and the resulting residue was subjected to silica gel column chromatography. The desired compound (9.89 g, yield 89) was obtained as an oily substance by purifying with Graphite (hexane ethyl acetate = 21).

 ^ -NMR (CDCls) 5ppm, 300MHz: 8.53 and 8.33 (br s. 1H total).

7.37-7.10 (m, 5H). 5.87 and 5.78 (br s. 1H total).

5.40-5.08 and 4.93-4.23 (m. 1H total) .3.82-3.54 (m. 1H),

3.14—2.91 (m. 1H), 2.82 (d, J = 6.7 Hz. 3H).

1. 7. 1.39 and 1.30 (br s. 18H total). [Rotamer peak was observed] (3) Hydrogen chloride was bubbled into 2S-hydrazino-1-N-methyl-13-phenylpropionamide hydrochloride ethyl acetate (600 ml) under ice cooling for 20 minutes. In addition, 2S— [N, N'-bis- (tert-butyloxycarbonyl) hydrazino] —N-methyl_3-phenylpropionamide (9.57 g, obtained in (2) of Reference Example 6) 2 4.3 mraol) and stirred for 2 hours. After concentrating the reaction mixture, the obtained crystals were washed with ethyl acetate to give the title compound (5.03 g, yield 90%) as white crystals.

 'H-NMS (D SO-de) ^ ppm. 300MHz: 9.76-8.73 (m, 2H),

8.45 (q, J = 4.3 Hz, 1H), 7.36-7.12 (m, 5H) .6.52-4.54 (m.1H),

3.81 (apparent t. J = 6.4 Hz. 1H). 2.96 (dd, J = 13.6, 5.8 Hz, 1H).

2.91-2.73 (m, 1H). 2.60 (d.J = 4.3 Hz, 310.

Reference Example 7

 2-Naphthylmethylhydrazine hydrochloride

 (1) 2-Naphthaldehyde (tert-butyloxycarbonyl) hydrazone Using 2-naphthaldehyde and tert-butyl carbazate in a known manner (J. Chem. Soc. Perkin Trans. 1, 1975, 1712). ).

'H-NMR (DMS0-d ₆ ) dppm, 300MHz: 10.99 (br s, 1H). 8.16 (s, 1H).

8.00-7.80 (m, 5fl), 7.60-7.40 (m, 2H), 1.49 (s, 9H).

 (2) N— (t er t-butyloxycarbonyl) -N '-(2-naphthylmethyl) hydrazine

 The compound was synthesized by a known method (J. Chem. Soc. Perkin Trans. 1.1975. 1712) using 2-naphthaldehyde (tert-butyloxycarbonyl) hydrazone obtained in (1) of Reference Example 7.

^J H-NME (DMS0-de) 5 ppm. 300MHz: 8.25 (br s, 1H), 7.90-7.75 (m, 4H), 7.52-7.38 (m. 3H), 4.91-4.78 (m. 1H), 4.03 (d, J = 4.6 Hz, 2H),

1.38 (s, 9H).

(3) 2-Naphthylmethylhydrazine hydrochloride To a solution (25 ml) of N- (tert-butyloxycarbonyl) -1- (2-naphthylmethyl) hydrazine (2.00 g, 7.40 mmol) obtained in (2) of Reference Example 7 in 4 mL of hydrochloric acid was added 4N hydrochloric acid. Dioxane (18 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 19 hours. Ether was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain the title compound (1.44 g, yield 79%) as a pale yellow solid.

 ^ -NM (D SO-de) <5ρριπ. 300MHz: 9.21 (br s. 1H), 8.00-7.00 (m. 4H), 7.65-7.40 (m. 3H). 4.20 (m, 2H).

Reference Example 8

 Isobutyl hydrazine hydrochloride

 It was synthesized in the same manner as in Reference Example 7.

 'H-NM (DMSO-de) <ppm. 300MHz: 7.30 (br s. 1H).

2.72 (d, J = 7.0 Hz. 2H), 2.00-1.81 (m, 1H). 0.91 (d. J = 6.7 Hz, 6H).

 N-benzyl-N-methylaminocarbonylmethylhydrazine hydrochloride

 (1) N— (tert—butyroxycarbonyl) —N′—benzylyl N ′ — (methoxycarbonylmethyl) hydrazine

 N- (tert-butyloxycarbonyl) 1 N, 1-benzylhydrazine (3.46 g., 15.6 rel.) In N, N-dimethylformamide solution (150 ml) was added to a solution of potassium carbonate (3.23 g., 23.4 ol.). ) And methyl bromoacetate (1.77 ml. 18.7 mmol) were added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, extracted with ether, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane Z ethyl acetate = 3/1 ) To give the oily target compound (3.01 g, yield 66).

_{lH-NME (CDC1 3) 5ppm} , 300ΪΗζ:.. 7.40-7.28 (. m 5H) 6.66 (br s, 1H), 4.11 (. s 2H), 3.73 (s, 3H), 3.68 (. s 2H) 1 .0 (s. 9H).

(2) N— (tert-butyloxycarbonyl) i N '— benzyl i N' — (methylaminocarbonylmethyl) hydrazine N- (tert-butyloxycarbonyl) -N'-benzyl-N '-(methoxycarbonylmethyl) hydrazine (2.90 g, 9.85 mmol) obtained in (1) of Reference Example 9 was 40% methylamide Methanol solution (100 ml) was added, and the mixture was stirred at room temperature for 15 hours. The target compound (yield quantitative) was obtained as a white solid by concentrating the reaction mixture under reduced pressure.

 'H-NM (CDCls) <5 pm. 300MHz ： 8.01-7.95 (m, 1H), 7.40-7.28 (m, 5H). 5.66 (br s, 1H). 3.92 (s, 2H), 3.36 (s, 2H), 2.80 (d. J = 4.8 Hz. 3H). 1.36 (s, 9H).

 (3) N-benzyl N'-methylaminocarbonylmethylhydrazine hydrochloride N- (tert-butyloxycarbonyl) -N 'obtained in (2) of Reference Example 9

—Benzyl—N ′ — (methylaminocarbonylmethyl) hydrazine was added with 4 N dioxane hydrochloride (100 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, ether (200 ml) was added to the residue, and the precipitate was collected by filtration to give the title compound (2.06 g, yield 91 g) as a white solid.

 • H-NMR (DMSO-de) 5ppin, 300MHz: 9.71 (br s, 3H), 8.17-8.11 (m. 1H).

7.42-7.32 (m, 5H), 4.09 (s, 2H), 3.57 (s.2H),

 2.60 (d. J = 4.5 Hz. 3H).

Reference example 10

 Fazafenylalanine phenyl ester

 (1)-(tert butyloxycarbonyl) azafenylalanine phenyl ester

A solution of N- (tert-butyroxycarbonyl) -N'-benzylhydrazine (10.0 g. 45.0 mmol) and pyridine (4.00 ml, 49.5 mmol) in tetrahydrofuran (150 ml) was cooled under ice-cooling to obtain a mixture of phenyl carbonate ( 5.93 ml, 47.2 mraol) was slowly added dropwise, and the mixture was further stirred at the same temperature for 1 hour. Ethyl acetate was added to the reaction solution, which was washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate, water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By washing the obtained solid with hexane, a white solid As a result, the target compound (14.0 g, yield 96 mg) was obtained.

 Ή-ΝΜΕ (CDCls) 5ppm, 300MHz: 7.40-7.05 (m, 10H), 6.44 (br s, 1H), 4.85 (br s, 1H), 4.77 (br s. 1H), 1.46 (s, 9H).

 (2) azaphenylalanine phenyl ester

 4N dioxane hydrochloride (100 ml) was added to the N- (tert-butyloxycarbonyl) aza phenylalanine phenyl ester (13.8 g, 42.5 g) obtained in Reference Example 10 (1), and The mixture was stirred at room temperature for 1 hour. Ether was added to the reaction mixture, and the precipitate was collected by filtration. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (as a white solid). 9.47 g. Yield 92%) was obtained.

 ^ -NMR (CDCla) <5ppm. 300MHz: 7.40-7.05 (m, 10H), 4.75 (br s. 2H), 4.19 (br s. 2H).

Reference example 1 1

 Fazafuranalanine N-methylamide

 (1) N— (tert—butyloxycarbonyl) azafeniralanine N'-methylamide

 It was synthesized by a known method (method described in Japanese Patent Application Laid-Open No. 8-31889) using N- (tert-butyloxycarbonyl) -N'-benzylhydrazine.

 (2) Fazafuranalanine N-methylamide

 Reference Example 11 Using N- (tert-butyloxycarbonyl) aza-fuenylalanine N′-methylamide obtained in (1) of Example 11, it was synthesized by the same method as (2) of Reference Example 10. .

- image _{(CDC1 3) 5ppm, 300MHz:} 7.40-7.25 (m, 511), 6.38 (br s, 1H).

4.71 (s, 2H), 3.36 (s, 2H), 2.85 (d, J = 4.9 Hz.3H).

Example 1

N- (4-tert-butoxy-2R-isobutylsuccinyl) azaphenyl Alanine phenyl ester

 A solution of 4-tert-butoxy-2R-isobutylsuccinic acid (500 nig, 2.17 mmol) obtained in Reference Example 1 in tetrahydrofuran (15 ml) was added at 130 to 120 with 4-methylmorpholine (0.24 ml). 2.17 mmol), and the mixture was stirred for 5 minutes. A solution of isobutyl chlorocarbonate (297 nig, 2.17 mmol) in tetrahydrofuran (5 ml) was added, and the mixture was stirred for 30 minutes. To this reaction mixture was added a solution of the azaphenylalanine phenyl ester (526 mg, 2.17 mmol) obtained in Reference Example 10 in tetrahydrofuran (5 ml) at 130 to 120 ° C, and the mixture was warmed to room temperature. The mixture was stirred for 65 hours. The insolubles generated were removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel gel chromatography (hexane Z ethyl acetate = 101, 5 Z 1). Thus, the amorphous title compound (514 mg, yield 52) was obtained.

 ! H- NMB (CDCls) 5 pm, 300MHz: 7.80-7.55 (m, 1H). 7.50-7.00 (m, 10H). 4.76 (br s. 2H), 2.75-2.50 Cm, 2H), 2.40-2.20 ( m, 1H), 1.32 (s, 9H).

1.70-1.20 (m.2H). 1.20-1.00 (m, 1H), 1.00-0.75 (m, 6H).

Example 2

 N- (4-Hydroxy-1-R-isobutylsuccinyl) azaphenylalanine phenylester

 Under ice-cooling, trifluoroacetic acid (10 ml) was added to N- (4-tert-butoxy-2R-isobutylsuccinyl) azafuranalanine phenyl ester (514 g, 1.13 mmol) obtained in Example 1 and the mixture was added as it was 1. Stir for 5 hours. After addition of chloroform to the reaction mixture, the residue obtained by concentrating under reduced pressure was purified by silica gel chromatography (chloroform / methanol = 20/1) to obtain an amorphous material. The title compound (402 mg, yield 89) was obtained.

 'H-NMS (CDCla) <5ppm. 300MHz: 12.30 (br s, 1H), 10.50 (br s, 1H).

10.65 (br s, 1H), 7.50-6.95 (m, 10H), 4.83 (br s.2H).

4.54 (br s, 2H), 2.66 (m.1H), 2.43 (dd.J = 16.6, 7.9 Hz, 1H),

2.26 (dd. J = 16.6, 7.9 Hz. 1H), 1.44 (m, 2H). 1.12 (m, 1H). 0.78 (d.J = 6.2 Hz, 3H), 0.72 (d.J = 6.2 Hz. 3H).

Example 3

 N- (4-hydroxy 2 R-isobutylsuccinyl) azaphenylalanine N'-methylamide

 Under ice-cooling, 40% methylamine solution (5 ml) was added to N- (4-hydroxy-2R-isobutylsuccinyl) azaphenylalanine phenyl ester (200 mg, 0.50 ππαοΐ) obtained in Example 2. , And the mixture was stirred for 30 minutes at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (5 ml) and a solution of trifluoroacetic acid (86.0 mg, 0.75 mmol) in methylene chloride (2 ml) were added to the obtained residue, followed by stirring for 30 minutes. The precipitate was collected by filtration, washed successively with methylene chloride, 1N hydrochloric acid, and ethyl acetate, and dried under reduced pressure to give the title compound (120 mg, yield 71) as a white solid.

 Ή-NMR (D SO-de) δ ppm, 30011Hz: 9.96 (s, 1H), 7.40-7.15 (m, 5H),

4.90 (br s.1H), 4.16 (br s, 1H) .2.59 (d.J = 4.3 Hz, 3H).

2.50-2.05 Cm, 3H), 1.23 (m, 2H), 0.98 (m. 1H).

0.72 (d, J-6.7 Hz, 3H), 0.70 (d, J = 6.7 Hz, 3H).

Example 4

 N— [Ν '— (4—t ert—butoxy 2 R—isobutylsuccinyl) amino] morpholine

A solution of 4-tert-butoxy-2R-isobutylsuccinic acid (585 mg, 2.54 mmol) obtained in Reference Example 1 in N, N-dimethylformamide (10 ml) was added at room temperature to 11-hydroxybenztriazole. _{(HOBt. H 2 0. 470 mg} , 3.07 mmol), BOP reagent (1.35 g, 3.05 negation ol) and N- Mechirumoruhori emissions (0.33 ml. 3.05 mmol), and the mixture was stirred for 2 0 min. To this mixture was added N-aminomorpholine (0.50 g. 4.90 mmol) at room temperature, and the mixture was stirred for 4 hours. After water (100 ml) was added to the reaction mixture, the mixture was extracted with ether, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as an oil. 720 mg, Yield A rate of 90 was obtained.

 ^ -NME (DMSO-de) 5 ppm. 300MHz, 80 ° C: 8.68 (brs, 1H),

3.62-3.58 (ra, 4H) 2.80-2.70 (m, 4H), 2.49-2.47 (m, 1H),

2.40-2.31 (m, 1H), 2.21-2.12 (m.1H), 1.60-1.39 (m.2H), 1.39 (s, 9H). 1.18-1.06 (in.1H) .0.89-0.84 (π.6H ).

Example 5

 N- (4-tert-butoxy-1 2R-isobutylsuccinyl) -N ', N'-diphenylhydrazine

 Using 4-tert-butoxy-2R-isobutylsuccinic acid and N, N-diphenylhydrazine hydrochloride obtained in Reference Example 1, it was synthesized in the same manner as in Example 4 to obtain the title compound as a brown solid (yield 21 ¾) was obtained.

_{'H-NMR (CDC1 3)} (5 pm, 300MHz:. 8.01 (br s 1H), 7.33-6.92 (m, 5H).

2.81-2.61 (m, 2H), 2.34 (dd, J = 16.7, 2.5 Hz.1H), 1.75-1.58 (m.2H), 1.27-1.12 (m, 1H) .1.00-0.83 (m.6H).

Example 6

 N- [N '-(4-hydroxy-1 2R-isobutylsuccinyl) amino] morpholine

 To a methylene chloride solution (50 ml) of N- [Ν '-(4-tert-butoxy-2R-isobutylsuccinyl) amino] morpholine (693 mg, 2.20 mmol) obtained in Example 4 was added ice Under cooling, hydrogen chloride gas was blown for 10 minutes, and the mixture was stirred for 1 hour. The solvent of the reaction mixture was distilled off under a stream of nitrogen, and the residue was dried under reduced pressure to obtain the title compound. The title compound was used crude in the next reaction (Example 11-12).

Example 7

 N— (4-hydroxyl 2 R—isobutylsuccinyl) mono N ′, N′—diphenylhydrazine

Methylene chloride of N- (4-tert-butoxy-2R-isobutylsuccinyl) -1-N ', N'-diphenylhydrazine (48 mg, 0.12 rol) obtained in Example 5 To the solution (0.15 ml) was added dropwise trifluoroacetic acid (0.60 ral) under ice-cooling, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100/1, 50/1) to give the title compound (dark brown solid). 38 mg and a yield of 93 mg were obtained.

 Ή-NMR (DMSO-de) δ ppm.300MHz: 12.25 (br s.1H), 10.66 (s, 1H), 7.37-6.80 (m, 10H), 2.85-2.68 (m.1H), 2.40-2.27 ( m.1H),

1.55-1.03 (m, 2H), 1.30-1.10 (m, 1H), 1.00-0.80 (in, 6H).

Example 8

 N— (4-Benzyloxy—3-benzyloxycarbonyl) 2R—Isobutyl succinyl) 1N′—Benzyl-N′—Methylaminocarbonylmethylhydrazine

 Example 4 was carried out using 4-tert-butoxy-2R-isobutylsuccinic acid obtained in Reference Example 1 and N-benzyl-N-methylaminocarbonylmethylhydrazine hydrochloride obtained in Reference Example 9. In the same manner as in the above, the title compound (yield: 56 に よ り!) Was obtained as a white solid.

 'H-NMR (CDCla) 5ρρπι. 500MHz: 7.95-7.94 (m. 1H). 7.35-7.22 (m, 15H). 6.83 (s, 1H), 5.15 (d. J-12 Hz. Lfl). 5.11 ( d, J = 12 Hz.1H),

5.05 (d.J = 12 Hz, 1H) .5.03 (d.J = 12 Hz.1H), 3.98 (m.1H).

3.81 (d, J = 13 Hz.1H), 3.71 (d, J = 10 Hz.1H), 3.40-3.30 (m.2H) .2.73 (d, J = 4.9 Hz.3H) .2.72-2.68 (m .1H), 1.36-1.27 (m.1H).

1.03-0.96 (m, 1H), 0.90-0.81 (m. 1H), 0.68 (d, J = 6.5 Hz, 3H).

0.62 (d. J = 6.5 Hz. 3H).

Example 9

 N-benzyl-1-N '-(4-hydroxy-1-R-isobutylsuccinyl) -1-N-methylaminocarbonylmethylhydrazine

N— (4-benzyloxy-3-benzyloxycarbonyl-1R—isobutylsuccinyl) obtained in Example 8 —N′—benzyl-1-N′—methylaminocarb A 10% palladium carbon catalyst (60 mg) was added to an ethanol solution (60 ml) of bonylmethylhydrazine (577 mg, 1.01 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After filtering off the catalyst, toluene (10 ml) was added to the residue obtained by concentrating the filtrate under reduced pressure, and the mixture was heated under reflux for 20 minutes. The title compound (152 mg, 43% yield) was obtained as a white solid by purifying the reaction mixture as it was by silica gel column chromatography (chloroform / methanol = 9Z1, 1/1).

Ή-NMR (DMS0-d _e ) 5 ppm. 300MHz: 9.42 (s, 1H), 8.31-8.30 (m, 1H),

 7.37-7.23 (m, 5H), 3.94 (d. J = 12 Hz, 1H), 3.88 (d. J-12 Hz. IE).

 2.57 (d.J = 4.7 Hz, 3H) .2.41-2.36 (m.lfl), 1.91—1.87 (m, 2H).

 1.26-1.19 (m, 1H) .1.01-0.98 (m, 2H), 0.68 (d, J = 5.3 Hz.3H),

 0.66 (d, J = 5.3 Hz, 3H).

Example 10

 N- (4-benzyloxy-3—benzyloquincarbonyl-2R-isobutyrsuccinyl) azafeniralanine N'-methylamide

 4-benzyloxy-13-benzyloxycarbonyl-12R-isobutylsuccinic acid (1.56 g. 3.91 orchid ol) obtained in Reference Example 3 was dissolved in benzene (20 ml), and oxalyl chloride (1.02 ml. 11.7 mmol) was dissolved in benzene (20 ml). In addition, the mixture was heated and stirred at 60 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the solvent was distilled off to prepare an acid chloride.

 Prepared first in the tetrahydrofuran solution (20 ml) of azapheniralanine N-methylamide (0.70 g, 3.91 mmol) and N-methylmorpholine (0.86 ml. 7.81 mmol) obtained in Reference Example 11 A tetrahydrofuran solution (10 ml) of the obtained acid chloride was added dropwise during cooling, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution, which was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate hexane: = 1/1, 2/1) to give the title compound (1.46 g, yield 676) as a glassy oil.

lE-MR (CDCls) 5 ppm. 300MHz: 7.40-7.15 (m. 15H),- 6.09 (br d, J = 4.6 Hz, 1H), 5.37 (d, J = 15.1 Hz. 1H),

 5.17 (d, J = 12.1 Hz. 1H), 5.12 (d. J = 12.3 Hz. 1H),

 5.06 (d, J = 12.3 Hz.1H), 5.04 (d, J = 12.1 Hz, 1H),

 4.19 (d, J-15.1 Hz, 1H), 3.85 (d, J = 10.4 Hz. 1H),

 2.76 (d, J = 4.6 Hz, 3H). 2.70-2.60 (m. 1H). 1.60-1.45 (m, 1H),

 1.20-1.05 (m. 1H). 0.90—0.80 (in. 1H). 0.70 (d, J = 6.4 Hz, 3H),

 0.45 (d.J = 6.4 Hz, 3H).

Example 1 1

 N- (4-Hydroxy-1 2R-Isoptyl-3-carboxysuccinyl) aza phenylalanine N'-Methylamide

 Ethanol solution of N- (4-benzyloxy-13-benzyloxycarboxy-2R-isobutylsuccinyl) azafuerilalanine N'-methylamide (1.35 g, 2.41 mmol) obtained in Example 10 (30 ml), 10% palladium-carbon catalyst (100 mg) was added, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The title compound was obtained as an ethanol solution by removing the catalyst by filtration, and subjected to the reaction of Example 12. Example 1 2

 N- (4-Hydroxy-1-R-isobutyl-3-methylenesuccinyl) azaphenylalanine N'-methylamide

Example 11 Piperidine (0.26 ml. 26.5 mmol) was added to an ethanol solution of N- (4-hydroxy-2R-isobutyl-3-carboxysuccinyl) aza-fernilalanine N'-methylamide obtained in Example 1 and added at room temperature for 1 hour. After stirring for 5 minutes, a 37% aqueous solution of formalin (1.0 ml) was added, and the mixture was stirred at room temperature for 14 hours and then refluxed for 1 hour. The reaction solution was diluted with ethyl acetate, washed with 0.5 N hydrochloric acid and water, and the organic layer was back-extracted with a saturated aqueous potassium carbonate solution. The aqueous layer was acidified with concentrated hydrochloric acid, extracted again with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the title compound (0.53 g, The yield was 64%). ^l H-NM (CDCls) (5 pm, 300MHz: 7.98 (br s. 1H). 7.30-7.15 (a, 5H), 6.44 (s, 1H). 6.00 (br s. 1H), 5.83 (s. 1H ),

5.00 (br d. J-13.9 Hz. 2H). 4.41 (br d, J = 13.9 Hz. 2H).

3.25-3.15 (m. 1H). 2.67 (d. J = 4.0 Hz. 3H), 1.80-1.65 (m, 1H),

1.30-1.45 (m, 2H), 0.83 (d, J = 5.9 Hz, 3H), 0.75 (d, J = 5.9 Hz. 3H).

 N— (4-hydroxy 2 R—isobutyl-13 (R or S) —phenylthiomethylsuccinyl) azafeniralanine N′—methylamide

 N- (4-Hydroxy-2R-isobutyl-3-methylenesuccinyl) azafunerilanine N'-methylamide (0.87 g, 2.51 mmo 1) obtained in Example 12 was mixed with thiophenol (10 ml). Then, the mixture was heated and stirred at 60 ° C for 2 days in a sealed state. The reaction solution was poured into getyl ether (200 ml), and the precipitate was collected by filtration to give the title compound (0.42 g, yield 37) as a white solid.

 ^-MR (CDC) <5ppm. 300ΪΗζ-. 7.40-6.90 Cm. 10H). 6.59 (br s. 1H), 4.84 (d.J = 12.9 Hz.1H). 3.21 (d, J = 12.9 Hz, 1H) ),

2.95-2.75 (m.1H). 2.64 (br s, 2H), 2.33 (br s, 3H).

2.00-1.80 (m, 1H). 1.40-1.20 (m. 2H),

0.84 (d. J = 6.4 Hz. 3H). 0.66 (d, J = 6.4 Hz. 3H).

Example 14

 N— (4—t ert—butoxy 2 R—isobutylsuccinyl) — N ′ — (2-naphthylmethyl) hydrazine

2-Naphthylmethylhydrazine (930 mg. 5.40 bandol) and disopropylethylamine (0.94 ml, 0.54 mmol) obtained in Reference Example 7 were mixed with tetrahydrofuran (26 ml). Under ice-cooling, a solution of 4-tert-butoxy-2R-isobutylsuccinate N-hydroxysuccinimide (1.20 g. 3.67 mmol) obtained in Reference Example 2 in tetrahydrofuran (8 ml) was slowly added. After the dropwise addition, the mixture was stirred at room temperature for 1.5 hours. Dilute hydrochloric acid was added to the reaction mixture, extracted with chloroform, and anhydrous magnesium sulfate was added. The residue obtained by drying under reduced pressure and concentrated under reduced pressure is purified by silica gel column chromatography (ethyl ethyl hexanoacetate 10 × 1, 5/1) to give the title compound (colorless transparent liquid). 848 mg, yield 60%).

 'HNR (DMSO-de) (5ppm, 300MHz: 9.42 (br s, 1H), 7.90-7.70 (m. 4H), 7.55-7.40 (m. 3H), 5.31 (br s, 1H). 4.10-3.90 (m. 2H).

2.40-2.30 (m, 1H). 2.14 (dd. J = 15, 6.5 Hz. 1H). 1.40-1.10 (m, 11H), 1.04-0.90 (m. 1H), 0.75-0.60 (m. 6H).

Example 15

 N— [Ν'-I (4-tert-butoxy-1 R-isoptylsuccinyl) amino] —L-phenylalanine N ''-Methylamide

 4-tert-butoxy-2R-isobutylsuccinate N-hydroxysuccinimide obtained in Reference Example 2 and 2S-hydrazino-1-N-methyl-3-phenylpropione obtained in Reference Example 6 Using amide hydrochloride and diisopropylethylamine, the title compound (yield: 76 mg) was obtained as a white solid in the same manner as in Example 14.

'H-NMR (DMS0-d _fl ) <5 ppm, 300MHz: 9.38 (s. 1H),

7.71 (q, J = 4.7 Hz. 1H), 7.32-7.13 (m. 5H). 4.89 (brs, 1H),

3.54 (apparent t, J = 6.4 Hz, 1H). 2.87 (dd. J = 13.7, 5.9 Hz. 1H).

2.77 (dd.J = 13.7, 6.8 Hz, 1H), 2.60-2.45 (m. 1H),

2.52 (d.J-4.8 Hz, 3H), 2.35 (dd, J-15.8. 8.2 Hz.1H),

2.15 (dd.J = 15.8, 6.2 Hz, 1H), 1.51-1.30 (m, 2H), 1.12-0.97 (in.1H), 1.36 (s.9H) .0.83 (d, J = 6.3 Hz, 3H) , 0.80 (d, J = 6.3 Hz.3H).

Example 16

 N- [Ν'-I- (4-tert-butoxy-2R-isobutyl-13- (R or S) -phthalimidomethylsuccinyl) amino] -L-phenylanilanine N ''-methylamide

4-tert-butoxy-2R-isobutyl-3-phthal obtained in Reference Example 4 Using imidomethylsuccinic acid and 2S-hydrazino-N-methyl-13-phenylpropionamide hydrochloride obtained in Reference Example 6, the title compound was obtained as a white solid by the same method as in Example 4. The yield was 93%).

^{! H-NMR (CDCla) 5} pm 500MHz:. 7.97 (br s, 1H), 7.83-7.82 (m, 2H).

7.76-7.72 (m, 2H), 7.52 (br s, 1H), 7.36-7.26 (m.5H),

4.26 (br s, lfl), 3.89-3.85 (m, 1H), 3.75-3.74 (m, 1H),

3.65-3.61 (ID.lH), 3.32-3.29 (m.1H), 2.96-2.77 Cm, 5H),

2.56-2.51 (m, IE), 1.75-1.70 (m, 1H), 1.50-1.3 (m, 1H), 1.28 (s.9fl), 1.11-1.06 (m.1H) .0.84 (d.J = 6.6 Hz, 3H). 0.82 (d, J-6.6 Hz. 3H).

 N-benzyl-N '-(4-tert-butoxy-1R-isobutylsuccinyl) hydrazine

 Using the 4-tert-butoxy-2R-isobutylsuccinate N-hydroxysuccinimide and benzylhydrazine obtained in Reference Example 2, the title compound was obtained as a pale yellow oil in the same manner as in Example 14 (2.92 g, yield 67 mg).

 ^ -NMR (DMSO-de) <5 pm. 300MHz: 9.42 (s, 1H), 7.25-7.15 (m, 5H).

5.16 (br s. 1H), 3.82 (s, 2H), 2.55-2.40 (m, 1H),

2.35 (dd, J = 15.5.7.9 Hz.1H), 2.16 (dd.J = 15.5.6.5 Hz, 1H),

1.38 (s. 9H). 1.45-1.30 (m. 2H), 1.10-0.95 (m. 1H),

0.81 (d.J = 5.9 Hz, 3H) .0.77 (d.J = 5.9 Hz.3fl).

Example 18

 N- (4-tert-butoxy-2R-isobutylsuccinyl) -N'-isobutylhydrazine

To a mixed solution of isobutylhydrazine hydrochloride (359 rag) obtained in Reference Example 8, tetrahydrofuran (9 ml), water (4.5 ml), and a 1N aqueous solution of sodium hydroxide (4.50 ml. 4.50 mmol). Under ice-cooling, 4-tert-butoxy-1 2R-ybutyl succinate N-hydroxysuccinimide obtained in Reference Example 2 (739 mg, 2. A solution of 23 mmol) in tetrahydrofuran (4 ml) was slowly added dropwise, followed by stirring at room temperature for 1.5 hours. Dilute hydrochloric acid was added to the reaction mixture, extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (ethyl ethyl hexanoacetate, 20Z 1,1 0 / 1. purification by 5/1) to give the title compound as a clear colorless liquid (490 _m g, yield 73 ¾).

-Thigh (D S0-d _e ) (5ppm, 300MHz: 9.44-9.30 (m, 1H). 4.83-4.70 (m.1H) .2.61-2.10 (m.5H), 1.73-1.60 (m, 1H). 1.50-1.38 (m. 2H),

1.05-1.00 (m. 1H). 0.91-0.70 (m, 12H).

Example 19

 N-Benzyl-N '-(4-tert-butoxy 2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) hydrazine hydrochloride

A solution of 4-tert-butoxy-3-phthalimidomethyl-2R-isobutylsuccinic acid (6.62 g, 17.0 ol) obtained in Reference Example 4 in N, N-dimethylformamide (100 ml) was cooled with ice. _{lower, H0Bt 'H 2 0 (2.60} g, 17.0 mmol), BOP reagent (9.00 g, 20.4 mmol) and N- methyl乇Ruhori emissions (6.00 ml, 54.3 mmol) and the mixture was stirred for 2 0 minutes. After benzylhydrazine (4.15 g. 34.0 mmol) was added to the reaction mixture, the mixture was stirred for 12 hours. The reaction mixture was poured into ice water, extracted with chloroform, washed with saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (hexane / hexane). Purification using ethyl acetate = 2/1) and oily N-benzyl N'-I (4-tert-butoxy-I 2 R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) hydrazine (7.0 g) , Yield 83.

 ! H-NM (CDCls) 5ppm, 300ΪΗζ: 7.83 (m, 3H), 7.72 (m. 2R),

7.40-7.27 (m, 6H). 4.05 (d, J = 12.6 Hz, 1ΰ).

4.00 (d.J = 12.6 Hz.1H), 3.84 (dd, J = 14.2.5.2 Hz.1H),

3.74 (dd, J = 14.2.5.2 Hz, 1H), 3.00 (m, 1H) .2.53 (m.1H), 1.87 (m. 1R), 1.47 (m. 1H), 1.28 (s, 9H). 1.10 (m. 1H),

0.85 (d.J = 6.6 Hz, 3H), 0.81 (d.J = 6.6 Hz, 3H).

 The obtained hydrazine (7.00 g, 14.2 dragonol) was dissolved in getyl ether (100 ml), 4N dioxane hydrochloride (3.6 ml) was added under ice cooling, and the mixture was stirred for 30 minutes. Hexane (100 ml) was added to the reaction mixture, and the resulting precipitate was collected by filtration, washed with hexane, and dried to give the title compound (7.0 g).

 ^ -NMR (CDC) 5 ρπι. 300MHz ： 11.67 (br s. 1H), 7.70 (m. 6H),

7.33 Cm. 3H), 4.74 (d. J = 12.8 Hz. 1H), 4.60 (d. J = 12.8 Hz. 1H), 3.93 (dd. J = 13.8 Hz, 8.6 Hz, 1H).

3.45 (dd, J = 13.8 Hz, 3.9 Hz. 1H), 2.96 (m. 2H),

1.66 (t. J = 10.0 Hz, 1H). 1.22 (s, 9H), 0.81 (d, J = 5.8 Hz. 3H).

0.74 (d.J = 5.8 Hz, 3H).

Example 20

 N- (4—t ert—butoxy-1 2 R—isobutyl-1 3 (R or S) —phthalimidomethylsuccinyl) —N'—phenylhydrazine

 Under the same conditions as in Reference Example 2, 4-penta-butoxy-13-phthalimidomethyl-2R-isobutylsuccinic acid obtained in Reference Example 4 was replaced with N-hydroxysuccinic acid imide to give pentafluorophenyl succinic acid. The resulting compound was reacted with phenol to prepare a penfluorofluorophenyl ester, and the title compound was obtained as a white amorphous substance (yield: 77%) in the same manner as in Example 14 using the active ester and phenylhydrazine.

 ! H-MR (CDCls) <5 ppm, 300MHz: 8.50 (d. J = 4.4 Hz. Ill),

7.95-7.80 (m, 2H). 7.80-7.65 (m, 2H), 7.30-7.10 (m. 2H).

6.95-6.80 (m, 3H), 6.33 (d.J-4.4 Hz.1H), 4.00-3.80 (m.2H).

3.10-3.00 (m.1H), 2.90-2.75 (m, 1H). 1.90-1.75 (m, 1H),

 1.70-1.50 (m, 1H), 1.31 (s.9H), 1.30-1.10 (m, 1H),

0.96 (d. J = 6.5 Hz, 3H). 0.89 (d, J = 6.5 Hz. 3H). The compounds of Examples 21 to 31 shown below were reacted with the corresponding hydrazine hydrochloride under the same conditions as in Example 20 in the presence of N-methylmorpholine or N, N-diisopropylethylamine. It was synthesized by reacting.

Example 2 1

 N-p-benzyloxybenzyl-N '-(4-1-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) hydrazine p-benzyl As a result, the title compound (yield: 61 mg) was obtained.

 'H-NM (CDCls) δρριη. 300 MHz: 7.84-7.79 (m, 3H), 7.71-7.69 (m, 2H) .7.41-7.26 (m.7H), 6.94-6.91 (m, 2H), 5.02 (s , 2H).

3.96 (apparent t, J-13.0 Hz. 2H). 3.80 (dd.J = 14.2, 5.4 Hz. 1H) .3.73 (dd.J = 14.2, 5.4 Hz. 1H), 3.03-2.96 (m, 1H), 2.57-2.49 (m, 1H), 1.78 (ddd, J = 12.0, 11.1. 4.0 Hz.1H), 1.52-1.43 (m, 1H).

1.28 (s, 9H), 1.05 (ddd, J = 10.0, 6.6, 3,5 Hz, 1H).

0.86 (d.J = 6.6 Hz, 3H). 0.82 (d, J = 6.6 Hz, 3H).

Example 22

 N- (4-tert-butyn-2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) -N '-(2-pyridylmethyl) hydrazine

 Using 2-pyridylmethylhydrazine hydrochloride, the title compound was obtained as amorphous (yield 56 mg).

 ^ -NM (CDCla) <5ppm, 300MHz ： 8.58 (d. J = 4.4 Hz, 1H),

8.20 (br s, 1H). 7.84-7.80 (m, 2H). 7.74-7.68 (m, 2H),

 7.64 (dd, J = 7.6. 1.7 Hz. 1H), 7.34 (d. J = 7.8 Hz. 1H).

 7.18 (dd, J = 7.1.5.4 Hz.1H) .5.30 (br s, 1H), 4.21 (s, 2H),

 3.80 (d, J = 5.9 Hz, 2H), 3.05-3.00 (m, 1H), 2.57-2.52 (m, 1H).

 1.27 (s. 9H), 0.82 (d. J = 6.6 Hz, 3H). 0.79 (d, J = 6.6 Bz. 3H).

Example 2 3 N— (4-tert-butoxy-1R-isobutyl-3 (R or S) —phthalimidmethylsuccinyl) -1-N '— (2-nitrobenzyl) hydrazine

 Using 2-nitrobenzylhydrazine hydrochloride, the title compound was obtained as an amorphous (yield: 88?).

_{'H- M (CDC1 3) <} ppm 300MHz:... 8.01-7.98 (. M 2H), Ryo .85- 7.82 (m, 2H) 7.73-7.70 (. ID 3H), 7.57 (dd J = 6.6. 1.4 Hz, 2H), 7.45-7.41 Cm. 1H), 5.30 (br s, 1H). 4.37—4.33 (m, 2H), 3.79 (dd. J = 14.3. 5.1 Hz. 1H). 3.70 (dd, J = 14.3, 6.7 Hz, 1H), 2.97-2.90 (m.1H) .2.52 (br s.1H) .1.72-1.68 Cm.2H), 1.27 (s.9H) .1.05 (m, 1H),

0.80 (d.J = 5.8 Hz, 3H), 0.78 (d.J = 5.8 Hz, 3H).

Example 2 4

 N— (4 _t ert—butoxy-1 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) 1 N ′ — (1-naphthylmethyl) hydrazine

 Using 1-naphthylmethylhydrazine hydrochloride, the title compound was obtained as white amorphus (yield 58 mg).

 Difficult (CDC) <5ppm. 300MHz: 8.33 (d. J = 8.4 Hz, 1H),

7.90-7.75 (m.5H), 7.75-7.65 (m.2H). 7.60-7.35 (m.4H),

5.10 (br s.1H) .4.52 (d, J-12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 3.87 (dd, J 14.2, 5.3 Hz.1H), 3.79 (dd, J = 14.2, 6.9 Hz. 1H).

3.10-3.00 (m.1H). 2.60-2.50 (m.1H). 1.90-1.75 (ra.1H).

1.60-1.5 (m, 1H), 1.28 (s.9H), 1.20-1.05 (m.1H).

0.87 (d.J = 6.6 Hz, 3H). 0.83 (d, J = 6.6 Hz, 3H).

Example 2 5

 N— (4-tert-butoxy-2R-isobutyl-13 (R or S) —phthalimidomethylsuccinyl) -1-N '-(2-naphthylmethyl) hydrazine

Using 2-naphthylmethylhydrazine hydrochloride, the title compound (yield 79 mg) was obtained as white amorphous. _{^{1 H-NMR (CDC1 3)}} ^ ppm 300MHz:. 7.90-7.65 (. M 8H),

7.55 (d, J = 8.4 Hz, 1H) .7.40-7.30 (m, 2H), 5.21 (br s, 1H).

4.20 (apparent d, J = 4.1 Hz, 2H). 3.80-3.60 (m, 2H),

3.05-2.90 (m.1H), 2.60-2.45 (m, 1H) .1.85-1.70 (m, 1H),

1.50-1.30 (in. Lfl), 1.25 (s, 9H). 1.50-1.00 Cm. 1H).

0.81 (d, J = 6.5 Hz, 3H). 0.76 (d, J = 6.5 Hz, 3H).

Example 26

 N '-(4-biphenylmethyl) -N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) hydrazine p-phenylpenzylhydrazine hydrochloride, white The title compound was obtained as amorphous (yield: 62!).

_{Ή-NMR (CDC1 3) 5ppm} 300MHz:... 7.85-7.75 (. In 2H), 7.75-7.65 (m, 2H), 7.60-7.50 (m, 4H) 7.50-7.25 (m, 5H) 5.11 (d J = 5.9 Hz, 1H).

4.15—4.00 (m. 2H). 3.80 (dd, J = 13.9, 4.6 Hz, 1H).

3.74 (dd, J = 13.9, 6.4 Hz, 1H), 3.05-2.95 (m, 1H), 2.60-2.50 (m.1H) .1.85-1.70 (m.1H) .1.55-1.40 (m, 1H). 1.27 (s. 9H), 1.20-1.05 (m, 1H). 0.86 (d, J = 6.6 Hz. 3H), 0.82 (d. J = 6.6 Hz. 3H).

Example 2 7

 N- (4-tert e-butoxy-1 R-isobutyl-1-3 (R or S) -phthalimidomethylsuccinyl) -N'-phenethylhydrazine

 The title compound (yield: 77%) was obtained as white amorphous using funetylhydrazine hydrochloride.

¹ H-NMR (CDCls) 5 ppm, 300 MHz: 7.98 (brs, 1H), 7.90-7.80 (m.2H). 7.80-7.65 (m.2H), 7.35-7.10 (m, 5H), 3.91 (dd. J = 14.2. 5.1 Hz, 1H). 3.80 (dd.J = 14.2. 6.6 Hz, 1H), 3.20-3.10 (m. 2H). 3.10-2.95 (m. Lfl). 2.83 (t.J = 7.7 Hz 2H), 2.65-2.50 (ra, 1H), 1.90-1.75 (m, 1H).

1.65-1.50 (m, 1H). 1.30 (s, 9H). L 20— 1.05 (m. 1H). 0.88 (d. J = 6.6 Hz. 6H).

Example 2 8

 N- (4-tert-butoxy-1 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N '-(3-phenylpropyl) hydrazine

 The title compound (yield 57) was obtained as white amorphous using 3-phenylpropylhydrazine hydrochloride.

_{^ -NMR (CDC1 3) δ ριπ} , 300MHz:. 8.02 (br s, 1H) 7.90-7.75 (. M 2H), 7.75-7.65 (m, 2H), 7.30-7.10 (. M 5H), 3.89 (dd , J = 14.2.5.3 Hz, 1H), 3.78 (dd.J = 14.2, 6.6 Hz, 1H), 3.05-2.95 (m.1H),

2.91 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H) .2.65-2.50 (m.1H). 1.90-1.70 (m, 3H), 1.60-1.45 (m, 1H) , 1.30 (s, 9fl), 1.15-1.05 (m, 1H), 0.88 (d. J = 6.6 Hz. 6H).

Example 2 9

 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) -N '-(cyclohexylmethyl) hydrazine Using cyclohexylmethylhydrazine hydrochloride as the title compound (Yield 67 mg) was obtained.

_{^ -NMR (CDC1 3) δρρπι,} 300MHz:.. 7.88-7.82 (m, 3H), 7.75-7.69 (. M 2H), 4.75 (br s, 1H) 3.91 (dd, J = 14.2 6.6 Hz.

3.81 (dd.J = 14.2, 6.6 Hz, 1H), 3.01 (m, 1H),

2.59 (d. J = 6.2 Hz, 2H), 1.81-1.63 (m. 9H). 1.35-1.12 (m, 3H).

1.30 (s, 9H), 0.88 (d, J = 6.5 Hz. 6H).

Example 30

 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N'-neopentylhydrazine

Using neopentyl hydrazine hydrochloride, the title compound was obtained as a white amorphous substance (yield: 75). ^ -NMR (CDCls) 5ppm. 300MHz: 7.96 (br s, 1H). 7.90-7.75 (m, 2H), 7.75-7.65 (m. 2H). 3.92 (dd. J = 14.2, 5.3 Hz. 1H),

3.82 (dd.J = 14.2, 6.6 Hz. Lfi), 3.10-2.95 (m, 1H),

2.68 (d.J = 11.0 Hz, 1H), 2.62 (d.J = 11.0 Hz, 1H),

2.65-2.55 (m, 1H) .1.85--1.75 (m.1H), 1.65-1.45 (m.IB). 1.30 (s.9H). 1.20-1.05 (m, 1H), 0.96 (s, 9H) ₍ 0.88 (d, J = 6.8 Hz. 6H).

Example 3 1

 N— (4—t ert—butoxy-1 2 R—isobutyl-1 3 (R or S) —phthalimidomethylsuccinyl) 1 N′-t ert-butylhydrazine

 The title compound (83 X yield) was obtained as a white solid using tert-butyl hydrazine hydrochloride.

_{lH-NMR (CDC1 3) 5ppm} , 300MHz:. 8.05 (br s, 1H), 7.90-7.80 (m, 2H), 7.80-7.65 (m, 2H) 3.96 (. dd, J = 14.3, 5.0 Hz 1H) ,

3.78 (dd.J = 14.3.6.1 Hz.1H), 3.05-2.95 (m.1H), 2.70-2.60 (m.1H), 1.90-1.75 (m.1H) .1.65-1.50 (m.1H), 1.30 (s, 9H), 1.20-1.05 (m. 1H). 1.15 (s. 9H). 0.90 (d. J = 6.5 Hz, 3H). 0.89 (d. J = 6.5 Hz. 3H).

Example 3 2

 N- (4-tert-butoxy-1 2R-isobutylsuccinyl) aza- (2-naphthyl) aranyl-L-alanine benzyl ester

To a solution of triphosgene (228 mg, 0.77 mmol) in methylene chloride (15 ml) was added L-alanine benzyl ester hydrochloride (448 mg, 2.08 mmol) and diisopropylethylamine (0.73 ml, 4.20 mmol) in methylene chloride. The solution (20 ml) was added dropwise at room temperature and stirred for 10 minutes. N- (4-tert-butoxy-2R-isobutylsuccinyl) -1-N '-(2-naphthylmethyl) hydrazine (741 mg, 1.93 mmol) obtained in Example 14 and diisopropylethyl were added to the reaction mixture. A solution of amine (0.36 ml, 2.10 mmol) in methylene chloride (20 ml) was added dropwise, and the mixture was stirred at room temperature for 10 minutes. Add water to the reaction mixture, extract with ethyl acetate, wash with water, and dry with anhydrous sulfuric acid. And concentrated under reduced pressure, and the residue obtained is purified by silica gel column chromatography.

The residue was purified by — (hexane ethyl acetate = 20, 1, 10/1, 5Z 1) to obtain the title compound (545 mg, yield: 48¾) as a pale yellow candy-like solid.

'H-NMR (D S0-d ₆ ) 5 ppm, 300 MHz: 10.24 (br s. 15). 7.90-7.60 (m. 4H), 7.50-7.22 (m, 8H), 6.70 (br s. 1H). 5.25-5.00 (m, 3H).

4.48-4.25 (m.2H), 2.30-2.14 (m.1H) .1.41-0.88 (m, 15H).

0.65-0.55 (m, 6H).

Example 3 3

 N— (4-tert e-butoxy-1R-isobutylsuccinyl) aza— (1-1naphthyl) alanyl-L-alanine

 Example 3 N- (4-tert-butoxy-2R-isobutylsuccinyl) aza (2-naphthyl) azalanyl-L-alanine benzyl ester obtained in Example 2 (323 mg, 0.55 tmol) in tetrahydrofuran (10 10% palladium on carbon catalyst (100 mg) was added to a mixed solution of methanol (10 ml) and methanol (10 ml), and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to obtain the title compound. The product was subjected to the reaction of Example 34 as crude.

Example 3 4

 N- (4-tert-butoxy-2R-isobutylsuccinyl)-(2-naphthyl) alanyl-L-alanine N'-benzylamide

Example 33 N- (4-tert-butoxy-2R-isobutylsuccinyl) aza (2-naphthyl) azalanyl-L-alanine obtained in 3 was dissolved in methylene chloride (10 ml). Benzylamine (0.14 ml, 1.32 negation ol), BOP reagent (290 mg, 0.65 6 mmol) , HOBt · H 2 0 (100 mg, 0.65 mmol) and the mixture was stirred for 1 at room temperature for 4 hours. Dilute hydrochloric acid (100 ml) was added to the reaction mixture, extracted with chloroform, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel gel chromatography (chloroform methanol = 10/0, 95/5) to give the title compound (217 mg, yield 6) as a white solid. 7! ¾).

 ^ -NMR (CDCla) c5 pm, 500MHz: 7.93 (s, 1H), 7.75-7.67 (m. 3H).

61 (s. 1H), 7.44-7.42 (m. 2H), 7.34-7.20 (m, 7H), 6.75-6.66 (m. 1H),

5.37-5.20 (m, 1H) .4.44-4.30 (m.4H), 2.70-2.63 (m, 1H),

 2.29- 2.23 (m.2H) .1.41 (d, J = 7.2 Hz.3H), 1.36 (s.9H).

1.28-1.23 (m, 1H). 1.19-1.12 (m. 1H), 0.98-0.93 (m, 1H).

 0.60 (d.J = 6.5 Hz, 3H), 0.49-0.42 (m, 3H).

Example 3 5

 N-(4 — t er t —butoxy 2 R-isobutylsuccinyl) azaphanyl alanyl L-alanine benzyl ester

 Using the N-benzyl-N '-(4-tert-butoxy-2R-isobutylsuccinyl) hydrazine obtained in Example 1 in the same manner as in Example 32, the title compound ( Yield 76%).

_{1 H-NMR (CDC1 3)} ^ ppm 300MHz:.. 7.40-7.20 (m, 10H) 7.14 (. S 1H),

 6.70 (br d, J = 7.2 Hz. 1H), 5.37 (br d. J-14.8 Hz. 1H),

5.24 (d, J = 12.4 Hz, IB), 5.14 (d, J = 12.4 Hz. 1H).

 4.60 (quint, J = 7.2 Hz, 1H) .4.21 (br d, J = 14.8 Hz, 1H).

 2.77 (dd.J = 17.8. 12.0 Hz, 1H), 2.30-2.15 (m, 2H),

 1.43 (d.J = 7.2 Hz.3H), 1.50-1.40 (m, 1H), 1.37 (s.9H).

 1.30- 1.20 (m. 1H). 1.10-1.00 (m. 1H). 0.78 (d. J = 6.4 Hz. 3H).

0.63 (d, J = 6.4 Hz. 3H).

Example 3 6

 N- (4-tert-butoxy-2R-isobutylsuccinyl) azaleucyl-L-alanine benzyl ester

Using N- (4-tert-butoxy-2R-isobutylsuccinyl) -N'-isobutylhydrazine obtained in Example 18 as a pale yellow solid, in the same manner as in Example 32 Title compound (Yield 50 50 was obtained. ¹ H-NMR (DMSO-de) ^ ppm. 300 MHz: 10.30 (m, 1H), 7.40-7.25 (m, 5H).

6.63-6.40 (a 1H) .5.20-5.02 (m.2H) .4.31-4.15 (m, lfl),

3.60-3.38 Cm, lH), 2.92-2.68 (m, 1H), 2.60-2.20 (m, 3H).

1.80-1.67 (m. 1.51-1.30 Cm. 11H). 1.28 (d, J = 7.2 Hz. 3H),

1.19-1.00 (m. 1H). 0.94-0.72 (m. 12H).

Example 3 7

 N— (4—t ert—butoxy-1 2 R—isobutyl-3 (R or S) —phthalimid-methylsuccinyl) azapheniralanine N′—methylamide

 Example 3 Using N-benzyl-N '-(4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) hydrazine hydrochloride obtained in Example 19 In the same manner as in 2, the title compound was obtained as a white powder (yield 62. However, methylamine hydrochloride was used instead of L-alanine benzyl ester hydrochloride.

_{'H-NMR (CDC1 3)} <5 pm 300MHz:.. 7.83 (. M 2H) 7.74 (m, 2H),

7.41 (br s.1H). 7.28 (m. 510, 6.30 (br s, 1H),

 5.23 (d. J = 14.7 Hz. 1H). 4.45 (d. J = 14.7 Hz, 1H), 3.96 (m. 2H).

 2.93 (m, 1H), 2.86 (d, J = 4.6 Hz. 1H). 2.47 (m. 1H). 1.71 (m. 1H).

 1.30 (m. 1H). 1.20 (s, 9H). 0.81 (d, J = 6.4 Hz. 3fl).

 0.72 (d. J = 6.4 Hz. 3H).

 The compounds of Examples 38 to 40 below were prepared using the N-benzyl-N '-(4-tert-butoxy-1 2R-isobutyl-3 (R or S) -phthalimidmethyl) obtained in Example 19 Succinyl) hydrazine hydrochloride was used as a starting material to synthesize according to the method of Example 32.

Example 3 8

N— (4-tert-butoxy-1 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) azaphenyl The title compound (yield: 80%) was obtained as a white powder.

 ^ -NME (CDCI3) ^ ρρπι, 500MHz: 7.83-7.81 (m, 2H), 7.73-7.72 (m, 2H), 7.51 (br s, 1H), 7.35-7.26 (m.10H), 6.84-6.79 ( m, 1H),

5.26-5.24 (m, 1H) .5.22-5.11 (m.2H), 4.64-4.62 (m.1H),

4.41-4.32 (m.1H) .4.03-3.97 (m.2H), 2.93-2.89 (in.1H).

2.45-2.42 (m, 1H), 1.74-1.67 (m.1H). 1.46 (d.J = 7.3 Hz.3H),

1.39-1.23 (m. 2H), 1.20 (s, 9H), 0.81 (d, J = 6.4 Hz, 3H),

0.69 (d.J = 6.4 Hz, 3E).

Example 3 9

 N— (4—t ert—butoxy 2 R—isobutyl-1 (R or S) —phthalimid-methylsuccinyl) azaphenyl

 L-alanine benzyl ester 'L-alanine methyl ester, hydrochloride was used instead of hydrochloride. The title compound (yield quantitative) was obtained as a white powder.

 'E-NMR (CDCI3) 5ppm, 500MHz: 7.84-7.83 (m, 2H), 7.75-7.71 Cm, 2H), 7.54 (br s, 1H) .7.33-7.24 (m.5H), 6.80-6.75 (m . 1H),

5.35-5.22 (m. 1H). 4.58-4.55 (m. 1H) .4.46-4.34 (in. IE).

4.03-3.99 (m.2H) .3.73 (s, 3H), 2.94-2.90 (m.1H) .2.45-2.3 (m, 1H), 1.75-1.69 (m, 1H). 1.45 (d, J = 7.3 Hz, 3H), 1.40-1.34 (m. 1H).

1.28-1.23 (m. 1H), 1.22 (s. 9H), 0.82 (d, J = 6.3 Hz. 3H).

0.70 (d, J = 6.3 Hz. 3H).

Example 40

N-(4-1 ₆ 1 "1-butoxy 2 R-isoptyl 3 (R or S)-phthalimidmethylsuccinyl) azapheniralanyl-glycine benzyl ester

L-alanine benzyl ester 'glycine benzyl ester D-toluenesulfonate was used instead of hydrochloride. The title compound as a white solid (Yield 54).

^! H-NMS (CDCI3) 5ρρπι, 300MHz: 7.80 (m, 2H), 7.72 (m. 2H).

7.66 (br s. 1H), 7.30 (m, 5H), 6.78 (br s. 1H),

 5.16 (d, J = 12.3 Hz, 1H) .5.11 (d, J = 12.3 Hz.1H), 4.55 (br s, 1H) .4.22 (dd, J = 18.0, 5.7 Hz.1H) .4.05 (dd, J = 18.0.5.7 Hz.1H).

3.92 (d. J = 5.4 Hz. 1H), 2.91 (m. 1H), 2.51 (m. 1H). 1.22 (s, 9H).

0.80 (d. J = 6.4 Hz, 3H), 0.70 (d, J = 6.4 Hz. 3H).

Example 4 1

 N- (4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidmethylsuccinyl) azaphenylalanine N'-phenylamide N-benzyl-N 'obtained in Example 19 (4-tert-butoxy-2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) hydrazine hydrochloride (190 mg. 0.36 dragonol) in methylene chloride solution (10 ml), diisopropylethylamine (0.07 ml, 0.39 mmol) and then phenyl isocyanate (0.04 ml. 0.39 mmol), and the mixture was stirred at room temperature for 2.5 hours. Dilute hydrochloric acid (50 ml) was added to the reaction mixture, extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (190 mg. 87).

 Ή-NMR (CDCla) ^ m. 500 MHz: 8.46 (br s, 1H). 7.86-7.83 (m. 2H).

7.75-7.74 (m.2H) .7.58-7.54 (m.1H) .7.50 (br s.1H).

7.34-7.26 (m, 8H), 7.04-7.01 (m, 1H), 5.49-5.35 (m.1H).

 4.50- 4.36 (m. 1H) .4.03-4.02 (m. 2H) .3.00-2.96 (m. 1H).

 2.51- 2.50 (m. 1H) .1.75-1.71 (m. 1H) .1.45-1.31 (m. 1H),

1.34-1.31 (m, 1H), 1.26 (s, 9H), 0.85 (d, J = 6.4 Hz, 3H),

0.75 (d, J = 6.4 Hz, 3H).

Example 4 2

N— (4-tert-butoxy-1 R-isobutyl-1-3 (R or S) — lid Luimi domethylsuccinyl) azafeniralanine benzyl ester

 N-benzyl-N ′ obtained in Example 19— (4_tert-butoxy 2 R-isobutyryl 3 (R or S) —furimidium methyl succinyl) hydrazine hydrochloride (623 mg, 1.26 mmol) ) In tetrahydrofuran solution (20 ml)

(0.50 ml. 6.30 mmol) and then benzyloxycarbonyl chloride (0.20 ml. 1.40 mmol) were added, and the mixture was stirred for 3 hours under ice-cooling, then raised to room temperature and stirred for 5 hours. Dilute hydrochloric acid (50 ml) was added to the reaction mixture, extracted with ethyl acetate, washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hexane and dried to give the title compound (750 mg, yield 95%;) as a white solid.

 lH-NMR (CDC) 5ppm, 300MHz: 8.58 (br s, 1H). 7.77-7.70 (m. 4H), 7.33 (m. 10H), 5.11 (m. 4H). 4.59 (s, 2H). 3.37 ( m, 1H),

2.74 and 2.55 (m, 1H total), 1.26 and 1.21 (s. 9H total).

0.76 (d, J = 5.6 Hz, 3H). 0.63 (d, J = 5.6 Hz. 3H). [Rotamer peak was observed]

Example 4 3

 N-benzyloxycarbonyl N— [Ν '-(4-tert-butoxy-2R-isobutylsuccinyl) amino] 1 L-phenylalanine N' '1-methyl amide

 A method similar to that of Example 42 using N-CN '-(4-tert-butoxy-2R-isobutylsuccinyl) amino] -l-phenyl-2-alanine N' '-methylamide obtained in Example 15 This yielded the title compound as a pale yellow oil (yield 31 mg).

 ^ -NMR (DMSO-de) 5 ppm. 300MHz ： 10.23 (s, 1H),

8.43-8.25 and 8.25-8.00 (m. 1H total) .7.44-7.12 (m, 10H),

 5.02 (s, 2H), 4.65-4.35 (m, 1H), 3.26-3.09 (m, 1H).

2.85 (dd.J = 14.0, 6.7 Hz, 1H), 2.81-2.66 (m. 1H). 2.60-2.46 (m, 4H), 2.33-2.10 (m. 1H), 1.72-1.26 (m. 2R). 1.21- 0.96 (in, 1H),

 0.96-0.80 (m. 2H), 0.80-0.48 (m, 4H). [Rotamer peak was observed] Example 4 4

 N—benzyloxycarbonyl N— [Ν '-(4-tert-butoxy 2 R-isobutyl-3 (R or S) —phthalimid-methylsuccinyl) amino] — L-phenylalanine N' '— Methylamide

 N- [Ν '-(4-tert.butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) amino] obtained in Example 16 1 L-fe

 Five

The title compound (95% in yield) was obtained as a white solid in the same manner as in Example 42, using dilulanine N ′ ′-methylamide.

_{^ - MR (CDC1 3) <} 5ppm, 500MHz: 8.93 (. Br s 1H), 8.53 (. Br s 1H).

8.36 (br s, 1H), 7.85-7.73 (m.4H), 7.40-7.20 (ID.8H),

6.96-6.92 (m, 2H), 5.6-5.38 (m, 1H) .5.06-5.01 (m.1H).

4.95-4.86 (m. 1H). 4.30-4.26 (m, 1H), 4.10-4.04 (m. 1H),

3.90-3.69 (m, 1H). 3.37-3.16 (m, 1H), 2.97-2.68 (m. 5H),

1.81-1.76 (m. 1H). 1.72-1.67 (m, 1H). 1.38-1.23 (ID. Hire),

1.13- 1.09 (m, 1H). 1.04-1.00 (m. 1H). 0.92-0.85 (m. 6H). [Rotamer peak was observed]

Example 4 5

 N-Benzyl-1-N '-(4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) -1-N- (p-Methoxybenzenesulfonyl) hydrazine

Example 19 N-benzyl-N '-(4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) hydrazine hydrochloride (514 nig. 0.97 miDol) obtained in Example 9 In a tetrahydrofuran solution (10 ml), add pyridine (0.40 ml. 4.95 minol), 4-dimethylaminopyridine (120 mg. 0.98 mmol) and p-methoxybenzenesulfonyl chloride (600 mg, 2.90 ιηΐποΐ) under ice-cooling. Plus 1 Stirred for hours. After raising the temperature to room temperature and stirring for 22 hours, dilute hydrochloric acid (100 ml) was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl hexanoacetate = 3 Z 1, 1/1) to give the title compound (485 mg, yield 75 mg;) as a white solid.

 ^ -NMR (CDCla) 5ρρπι. 300MHz: 8.23 (s, 1H). 7.97 (d, J = 8.9 Hz. 2H), 7.84-7.80 (m, 2H), 7.75-7.71 (m, 2H), 7.40-7.21 (m. 5H),

7.01 (d, J = 8.9 Hz, 2H), 4.82 (d, J = 14 Hz.1H),

4.68 (d, J = 14 Hz, 1H), 3.85 (s, 3H), 3.44-3.41 (m. 1H),

2.74-2.71 (m. 1H). 2.49—2.42 (m. 1H), 1.58-1.51 (m. 1H),

1.30-1.22 (m, 1H), 1.22 (s, 9H), 0.94-0.86 (m. 2H).

0.68 (d, J-6.0 Hz, 3H) .0.64-0.62 (m, 3H).

 The compounds of Examples 46 to 59 shown below were synthesized in the same manner as in Example 41.

Example 4 6

 N— (4-tert-butoxy 2 R—isobutyl-3 (R or S) —phthalimidmethylsuccinyl) azaphenylalanine N ′ — (p-fluorophenyl) amide

 N-benzyl-N '-(4_tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) hydrazine hydrochloride obtained in Example 19 is reacted with p-fluorophenyl isocyanate. As a result, the title compound (yield 945) was obtained as a white solid.

 Ή-ΝΜΒ (CDCls) 5 pm. 300MHz: 8.46 (br s. 1H). 7.90-7.80 (m, 2H), 7.80-7.70 (m, 2H) .7.55-7.45 (m, 2H). 7.42 (br s , 1H).

7.35-7.20 (m, 5H), 6.98 (t, J = 8.7 Hz, 2H).

5.42 (br d, J = 12.7 Hz, 1H), 4.37 (br s. J = 12.7 Hz. 1H),

4.15-3.95 (m, 2H), 3.00-2.90 (m, 1H), 2.55-2.30 (m, 1H), 1.85-1.70 (m, 1H). 1.50-1.20 (m. 2H), 1.24 (s, 9H),

0.85 (d, J = 6.2 Hz, 3H), 0.74 (d.J = 6.2 Hz. 3H).

Example 4 7

 N— (4-tert-butoxy 2 R—isobutyl-3 (R or S) —phthalimidmethylsuccinyl) azapenylglycine N′—methylamide N— (4-tert obtained in Example 20 —Butoxy 2 R—Isobutyl-3

The title compound (yield quantitative) was obtained as a white amorphous by reacting (R or S) -phthalimidomethylsuccinyl) -N'-phenylhydrazine with methyl isocyanate.

 'H-NMR (CDCla) 5ppin, 300MHz: 9.19 (s, 1H), 7.90-7.80 (m.2H),

7.80-7.70 (m, 2H), 7.40-7.15 (m.5H). 5.65 (d.J = 4.7 Hz.1H),

4.28 (dd. J 14.7, 6.7 Hz. 1H), 4.04 (dd. J = 14.7, 4.4 Hz, 1H), 3.05-2.95 (m, 1H), 2.84 (d. J = 4.7 Hz. 3H). 2.80- 2.70 (m, 1H),

1.85-1.70 (m.1H), 1.55-1.40 (m, 1H), 1.30-1.10 (m, IE), 1.28 (s, 9H), 0.87 (d.J = 6.5 Hz, 3H), 0.82 (d. J = 6.5 Hz, 3H).

Example 4 8

 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) aza (0-benzyl) tyrosine N'-methylammit '

 Example 21 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N, 1- (p-benzyloxy) benzylhydrazine obtained in 1 was added to benzylhydrazine. The title compound was obtained as a white solid by reacting with methyl (yield 54).

_{'H-NMR (CDC1 3)} <ppm 300MHz:.. 7.84-7.80 (m, 2H), 7.75-7.71 Cm 2H),

7.45 (br s, 1H), 7.41-7.30 (m.5H), 7.22 (d, J = 8.7 Hz, 2H).

 6.90 (d, J-8.7 Hz. 2H), 5.13 (d.J = 13.6 Hz. IB), 5.00 (s, 2H),

4.43 (d.J = 13.6 Hz, lfl), 4.03-3.91 (m.2H). 2.94 (dd, J-11.5, 6.3 Hz. 1H). 2.84 (d, J = 4.5 Hz, 3H).

2.52-2.45 (m, 1H). 1.24 (s.9H) .0.83 (d, J = 6.5 Hz, 311).

0.75 (d, J = 6.5 Hz. 3H).

Example 4 9

 N- (4-tert-butoxy-2 R-isobutyl-1-3 (R or S) -phthalimid-methylsuccinyl) other (2-pyridyl) alanine N'-methylammit "

 Example 22 N- (4-tert-butoxy-2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N '-(2-pyridylmethyl) hydrazine obtained in Example 2 was treated with methyl isocyanate. The title compound (yield 54 ^) was obtained as a white solid by the reaction.

 • H-NR (CDCla) 5ppm, 300MHz: 8.64 (s, 1H). 8.49 (d, J = 4.8 Hz, 1H),

7.86-7.82 (m.2H), 7.76-72.m (2H). 7.65 (td.J = 7.7.1.6 Hz, 7.

29 (d.J = 7.9 Hz.1H), 7.17 (dd.J = 7.3, 5.1 Hz.1H),

 6.49 (d, J = 4.0 Hz, 1H), 5.10 (d, J = 17.0 Hz, 1H),

 4.72 (d, J = 17.0 Hz, 1H), 4.15 (dd, J = 14.5. 8.5Hz, 1H).

 3.91 (dd, J = 14.4, 3.9 Hz.1H), 3.03-2.96 (m.1H),

 2.85 (d, J = 4.5 Hz. 3H). 2.66-2.58 (m, 1H), 1.30 (s. 9H),

 0.76 (d, J = 6.4 Hz, 3H), 0.74 (d, J = 6.4 Hz, 3H).

Example 5 0

 N- (4—t er t —butyn — 2 R—isobutyl-13 (R or S) —phthalimidmethylsuccinyl) other (2-ditrophenyl) alanine N'—methylamid

Example 23 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) -N '-(2-ditrobenzyl) obtained in Example 3 was added to hydrazine with methyl isocyanate. Was reacted to give the title compound (yield 61!) As a pale yellow solid. _{Ή-NR (CDC1 3) dp} , 300MHz: 7.98 (.. D J = 7.1 Hz 1H).

7.90-7.83 (m, 2H), 7.76-7.72 (m. 3H). 7.61 (dd. J = 7.6. 1.1 Hz, 1H), 7.42 (dd. J = 8.4. 1.1 Hz, 1H). 6.39 (br s , 1H),

5.23 (d.J = 16.1 Hz.1H). 4.93 (d.J = 16.1 Hz.1H),

4.04 (dd, J 14.6, 8.5 Hz, 1H), 3.95 (dd, J 14.6, 4.2 Hz. 1H), 2.97 (quint, J = 5.4 Hz, 1H). 2.83 (d, J = 4.6 Hz, 3H),

2.53 (quint. J-5.1 Hz. 1H). 1.76-1.67 (m, 1H). 1.42-1.29 (m, 2H) .1.25 (s, 9H), 0.82 (d, J = 6.1 Hz, 3H). 0.81 (d. J = 6.1 Hz, 3H).

Example 5 1

 N— (4-tert e _butoxy 2 R—isobutyl-3 (R or S) —phthalimid-methylsuccinyl) other (1—naphthyl) alanine N'—methylamide '

 Example 24 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N '-(1-naphthylmethyl) obtained in 4) Methyl isocyanate in hydrazine The title compound (74% yield) was obtained as a white solid.

 'H-NMS (CDCls) <5ppm. 300MHz: 8.25 (d, J = 8.3 Hz, 1H).

7.90-7.75 (m, 6H). 7.60-7.40 (m, 2H), 7.40-7.30 (m, 2H),

7.20 (br s, 1H). 6.38 (br s, 1H), 5.90-5.70 (m. IB),

4.90-4.70 (m, 1H) .4.00-3.85 (m, 2H), 2.90 (d, J = 4.6 Hz, 3H),

2.95-2.85 (m, 1H), 2.40-2.30 (m. 1H). 1.70-1.55 (m. 1H),

1.40-1.20 (m, 2H), 1.20 (s. 9H). 0.75 (d, J = 6.3 Hz. 3H),

0.66 (d, J = 6.3 Hz, 3H).

Example 5 2

-(4-tert-butoxy-2R-isobutyl-1-3 (R or S) -phthalimid-methylsuccinyl)-(2-naphthyl) alanine N'-methylamido ' N- (4-tert-Butoxy-1 2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -1-N '-(2-naphthylmethyl) obtained in Example 25 The title compound (yield 92 ^) was obtained as a white solid by the reaction.

 ! H-NM CCDCI3) 5ppm. 300MHz: 7.85-7.65 (m. 8H), 7.55-7.30 (m. 4H),

6.27 (br s, 1H). 5.40-5.20 (m. 1H), 4.80-4.60 (m, 1H),

 3.95-3.80 (m, 2H), 2.95-2.80 (m, IB), 2.89 (d, J = 4.6 Hz.3H).

 2.50-2.35 (m, 1H), 1.75-1.60 (m.1H) .1.35-1.10 (m.3H) .1.21 (s.9H).

0.71 (d.J = 6.4 Hz, 3H), 0.59 (d, J = 6.4 Hz, 3H).

Example 5 3

 N- (4-tert-butoxy-2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) aza- (4-biphenyl) alanine N'-methyl amide

 Example 26 N '— (4-biphenylmethyl) -N- (4-tert-butoxy-1-2R-isobutyl-13 (R or S) -phthalimid-methylsuccinyl) -N- (4-biphenylmethyl) obtained in Example 6 Methyl isocyanate was added to hydrazine. The reaction gave the title compound as a white solid (yield 92%).

 ^ -NMR (CDCls) <5 pm. 300 MHz: 7.85-7.75 (m.2H), 7.75-7.65 (m.2H), 7.60-7.45 (m.5H) .7.45-7.25 (m.5H), 6.31 ( br s, 1H),

5.30-5.15 Cm.1H) .4.65-4.45 (in, 1H) .4.05-3.90 (m.2H).

3.00-2.90 (m. Lfl), 2.88 (d.J = 4.6 Hz. 3H) .2.55-2.45 (m. 1H).

1.85-1.70 (m.1H), 1.50-1.35 (m, 1H), 1.24 (s, 9H), 1.35-1.20 (m, 1H) .0.83 (d, J = 6.4 Hz.3H) .0.74 (d, J = 6.4 Hz, 3H).

Example 5 4

N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomophenylanilanine N'-methylamide N- () obtained in Example 27 4-tert-butoxy-2 R-isobutyl-3 The title compound (yield: 80%) was obtained as a white solid by reacting (R or S) -phthalimidmethylsuccinyl) -N'-phenethylhydrazine with methyl isocyanate.

 ^ -NMR (CDCls) 5 pm, 300MHz: 7.90-7.80 (m.2H), 7.80-7.70 (m, 2H). 7.35-7.15 Cm, 5H), 6.08 (br s, 1H), 4.20-4.05 (m . 1H),

4.07 (dd.J = 14.6.8.4 Hz.1H). 3.96 (dd, J = 14.6. 4.1 Hz.1H), 3.65-3.50 (m, 1H) .3.00-2.85 (m, 3H), 2.82 (d. J 2 4.7 Hz, 3H),

2.50-2.0 (m.1H), 1.80-1.65 (m, 1H), 1.40-1.20 (m, 2H). 1.27 (s.9H) .0.92 (d, J = 6.5 Hz.3H), 0.91 ( d, J = 6.5 Hz, 3H).

Example 5 5

 N- (4-tert-butoxy-1 2 R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) azahomophenylalanine N'-phenylamide N- (4-tert-butoxy) obtained in Example 27 — 2 R—isobutyl-3

(R or S) -phthalimidomethylsuccinyl) The title compound (99% yield) was obtained as a white amorphous by reacting 1N'-phenylhydrazine with phenyl isocyanate.

_{'fl-NM (CDC1 3)} <5ppm 500MHz:... 8.18 (br s, lfl) 7.87-7.85 (. m 2H), 7.75-7.74 (. m 2H) 7.53 (. d, J = 7.9 Hz 2H) 7.42 (br s, 1H).

7.33-7.21 (m. 7fl), 7.01 (t, J = 7.4 Hz. 1H). 4.25-4.20 (m, 1H).

4.10 (dd. J = 15, 7.8 Hz. 1H), 4.03 (dd. J = 15. 4.0 Hz, 1H).

3.58-3.53 (m, 1H), 3.06-2.97 (m.2H), 2.95-2.90 (in.1H),

2.47-2.45 (m, 1H), 1.65-1.60 (m.1H), 1.40-1.36 (m, 1H), 1.27 (s.9H) .0.94 (d.J-6.6 Hz, 6fl).

Example 5 6

N- (4-tert-butoxy-2R-isobutyl-1-3 (R or S) -phthalimid-methylsuccinyl) other (3-phenylpropyl) glycine N'-methylamide Example 28 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -fluoromidmethylsuccinyl) -N '-(3-phenylpropyl) obtained in 8-isocyanic acid was added to hydrazine. The title compound (96% in yield) was obtained as a white semi-solid by reacting with methyl.

_{Ή-ΝΜΕ (CDC1 3) (} 5ppm 300MHz:.... 7.90-7.80 (m, 2H), 7.80-7.70 (m, 2H), 7.60 (br s 1H) 7.30-7.10 (m 5H), 5.99 (br s, 1H),

4.00-3.90 (m, 2H), 3.80-3.65 (m.1H), 3.60-3.45 (m.1H),

3.00-2.90 (m.1H), 2.95-2.75 (to, 3H), 2.81 (d, J = 4.6 Hz.3H),

2.70-2.60 (m, 2H). 2.60-2.50 (m. 1H), 1.65-1.50 (m. 1H), 1.27 (s. 9H). 1.40-1.25 (in.1H), 0.93 (d, J = 6.5 Hz. 3H), 0.92 (d, J = 6.5 Hz. 3H).

 N- (4-tert-butoxy-1 2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) azacyclohexylalanine N'-methylamide N- (4-tert-butoxy) obtained in Example 29 — 2 R—Isoptyl-3

The title compound (yield 48) was obtained as a white solid by reacting (R or S) -phthalimidomethylsuccinyl) 1-N '-(cyclohexylmethyl) hydrazine with methyl isocyanate.

. 'Eta - hide _{(CDC1 3) 5ppm, 300MHz:} 7.87-7.83 (. M 2H), 7.77-7.72 (m, 2H), 6.07 (br s, 1H), 4.05-4.02 (. M 2H) 3.61-3.59 (m. 1H), 3.25 (m, 1H) .3.02-3.00 (m, 1H). 2.80 (d, J = 4.6 Hz. 3H). 2.63 (m. 1H).

1.73-1.71 (n. 1H), 1.65-1.50 (m. 9H), 1.40-1.16 (m, 3H). 1.26 (s, 9H). 0.97 (d. J = 4.8 Hz. 3H). 0.94 (d, J = 4.8 Hz, 3H).

Example 5 8

N— (4-tert-butoxy 2 R—isobutyl-13 (R or S) -phthalimidmethylsuccinyl) azaneopentylglycine N′—methylamide N— (4− tert 1-butoxy 2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl 1-N'-neopentyl-dola The title compound (yield quantitative) was obtained as a white semi-solid by reacting gin with methyl isocyanate.

 'H-NMR (CDCh) 5ppm, 300MHz: 7.90-7.80 (m, 2H), 7.80-7.70 (m, 2H),

6.20 (br s, 1H), 4.10 (dd.J = 14.6, 8.5 Hz, 1H).

 4.01 (dd, J = 14.6. 4.1 Hz, 1H), 3.90-3.70 (m. 1H), 3.10-2.90 (m. 2H). 2.81 (d, J = 4.6 Hz, 3H), 2.65-2.50 (m. 1H) .1.95-1.80 (m.1H),

1.75-1.60 (m. 1H), 1,45-1.30 (m. 1H). 1.26 (s. 9H),

1.00-0.85 (m, 15H).

Example 5 9

 N— (4—t ert—butoxy-1 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) aza— (t errt—butyl) glycine N′—phenylamide

 Example 31 Reaction of N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N'-tert-butylhydrazine obtained in 1 with phenyl isocyanate As a result, the title compound was obtained as a white solid (yield: 93%).

Thigh _{(CDC1 3) 5ppm 300MHz:.} . 8.33 (. Br s lfl) 7.90-7.80 (. M 2H).

 7.80-7.70 (m, 2H). 7.61 (br s.1H), 7.55-7.40 (m.2H),

 7.30-7.15 (m. 2H). 6.99 (t, J = 7.3 Hz, 1H). 4.30-4.10 (m. 1H).

 4.10-3.95 (m.1H) .3.15-3.00 (m, lfl) .2.75-2.55 (m, 1H),

 1.90-1.60 (m.2H), 1.52 (s, 9H), 1.30-1.10 (m.1H), 1.23 (s.9H).

 1.00 (d, J = 6.4 Hz. 3H). 0.96 (d. J = 6.4 Hz. 3H).

Example 6 0

Ν'-benzyl-N- (4-tert-butoxy-2R-isobutyl_3 (R or S) -phthalimidomethylsuccinyl) -N'-bivaloylhydrazine N-benzyl N obtained in Example 19 '― ((4-tert-butoxy-1R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) -hydrazine Using the hydrochloride and bivaloyl chloride, the title compound was obtained as a white amorphous (yield 85) in the same manner as in Example 42.

_{! H-NMR (CDC1 3)} 5ppm, 500MHz: 8.89 (br s, 1H), 7.84-7.81 (. M 2H), 7.75-7.72 (m, 2H), 7.29-7.24 (m, 4H), 7.17-7.14 (m, 1H),

5.41-5.03 (m, 1H), 4.85-4.7 (m.1H) .3.81-3.65 (m.2H).

2.93-2.90 (m, 1H), 2.69- 2.65 (m.Ifl), 1.82-1.77 (m.1H).

1.57-1.52 (in.1H), 1.35 (s, 9H), 1.29-1.24 (m.Ifl), 1.22 (s.9H),

0.85 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H).

Example 6 1

 Ν '—Benzoyl N, 1-benzyl-1-N— (4-tert-butoxy 2 R—isobutyl-13 (R or S) —phthalimid-methylsuccinyl) hydrazine N-benzyl obtained in Example 19— N, 1- (4-tert-butoxy-2R-isobutyl-13 (R or S) -fluoromidmethylsuccinyl) hydrazine hydrochloride and benzoyl chloride were prepared in the same manner as in Example 42. The title compound was obtained as a white amorphous (yield: 95%).

 XH-NR (CDCla) 5 pm. 500MHz: 8.83 (br s, 1H),

7.72 (dd. J = 5.5. 3.1 Hz. 2H), 7.60-7.56 (m. 2H). 7.39-7.21 (m. 8H), 5.72-4.63 (m, 2H), 3.45-2.50 (m, 2H), 2.76-2.68 (ID.lH),

2.45-2.37 (m, 1H), 1.60-1.50 (m. 1H), 1.29-1.23 (m. 1H), 1.19 (s, 9H), 0.89-0.80 (m. 1H), 0.70-0.49 (m. 6H ). [Rotamer peak was observed] Example 6 2

 N- (4-tert e-butoxy 2 R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) azaphenylalanine N '— [4- (4-Methylpiperazino) phenyl] amide

To a solution of 4- (N-methylbiperazino) aniline (205 mg, 1.07 bandol) in tetrahydrofuran (5 ml) at 0 ° C was added carbonyldiimidazole (183 mg, 1.13 mmo 1), and the mixture was allowed to come to room temperature. And stirred for 1.5 hours. The N— obtained in Example 19 was added to this solution. Benzyl-N '— (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) hydrazine hydrochloride (265 mg, 0.500 ol) and diisopropylethylamine (0.10 ml. 0.57 mmol) )) (5 ml), and the mixture was stirred at room temperature for 16 hours. Water (100 ml) was added to the reaction mixture, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the residue was subjected to silica gel column chromatography-(chloroform / methanol-80%). / 5) to give the title compound (294 mg, yield 83 mg;) as a white solid.

 lH-original (CDCls) δρριη, 500MHz ： 8.24 (br s, 1H). 7.85-7.84 (m, 2H).

7.76-7.73 (m.2H), 7.50 (br s, 1H) .7.44 (d, J = 9.0 Hz.2H),

7.35-7.25 (m, 5H), 6.88 (d.J-9.0 Hz. 2H). 5.43-5.36 (m, 1H),

4.6-4.39 (m, 1H) .4.04-4.00 (m.2H), 3.16-3.14 (m.4H),

2.98-2.95 (m, 1H), 2.58-2.56 (m, 4H), 2.51-2.48 (m.1H) .2.34 (s, 3H) .1.76-1.71 (m, 1H) .1.41-1.37 (m.1H ). 1.30-1.25 (m, 1H) .1.25 (s.9H). 0.84 (d.J = 6.6 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H).

Example 6 3

 N- (4-tert-butoxy-1 R-isobutyl-1-3 (R or S) -phthalimidomethylsuccinyl) azapheniralanine N '-(3-pyridylmethyl) amide

 Using N-benzyl-N, 1- (4-1-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) hydrazine hydrochloride and 3-pyridylmethylamine obtained in Example 19 The title compound (yield: 49 mg;) was obtained as a white amorphous substance in the same manner as in Example 62.

 ^-MR (CDCla) δρρπι. 500MHz: 8.54 (d. J = 1.9 Hz. 1H),

8.41 (dd.J = 4.8, 1.5 Hz, 1H), 7.81-7.79 (m.2H), 7.74-7.72 (m, 2H). 7.48 (br s.1H), 7.32-7.05 (m.7H), 7.04 -6.96 (m. 1H),

5.36-5.28 (m, 4.56 (dd, J-15, 6.0 Hz, 1H). 4.46 (dd.J = 15, 5.6 Hz, 1H), 4.48-4.40 (m. 1H). 3.92-3.88 (m, 2H).

2.93-2.89 (m, 1H). 2.44-2.40 (m, 1H). 1.70-1.62 (m. 1H).

1.32-1.19 (m. 2H). 1.15 (s, 9H). 0.78 (d. J-6.5 Hz, 3H),

0.67 (d, J = 6.5 Hz. 3H).

Example 6 4

 N '—Benzyl—N' —Promoacetyl-N— (4-tert —Butoxy-1 2R—Isobutyl-13 (R or S) —Phthalimidomethylsuccinyl) hydrazine

 Using N-benzyl-N '-(4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) hydrazine hydrochloride and acetyl bromide obtained in Example 19 The title compound (89% in yield) was obtained as a white solid in the same manner as in Example 42.

 MHz-NMR (CDCls) δ ριη. 500MHz: 8.79 (br s, 1H). 7.84-7.82 (m. 2H), 7.76-7.73 (m, 2H), 7.38-7.05 (m, 5H), 5.61-5.32 ( m.1H).

4.01-3.95 (m.2H) .3.82 (d, J = 4.5 Hz.1H). 3.79 (d.J = 4.5 Hz.1H), 3.60-3.32 (m.1H), 2.94-2.88 (m.1H) 2.68-2.61 (m, 1H),

1.82-1.77 (m, 1H), 1.51-1.47 (m, 1H) .1.31-1.26 (m, 1H), 1.24 (s.9H) .0.89-0.79 Cm, 6H). (Rotamer peak was observed. ]

Example 6 5

 N, —Benzyl-1-N- (4-tert-butoxy-1 R-isobutyl-3 (R or S) —phthalimidomethylsuccinyl) -1-N ′ —morpholinoacetylhydrazine

N'-benzyl-N'-bromoacetyl-N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) hydrazine obtained in Example 6 (218 mg. 0.355 (mmol) (0.078 ml, 0.894 mmol) was added to a methylene chloride solution (10 ml) of the resulting solution, and the mixture was stirred at room temperature for 13 hours. Dilute hydrochloric acid (50 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (185 rag, yield 84 84) as a white solid.

_{^{1 H-NM (CDC1 3)}} 5ppm, 500MHz: 8.94 (br s, 1H), 7.84-7.82 (m, 2H), 7.75-7.71 (. M 2H), 7.38-7.17 (m, 5H), 5.04-4.98 (m, 1H),

 4.84- 4.78 (ni.1H), 3.79-3.74 (m.5H). 3.60-3.55 Cm.1H).

3.36-3.28 (m, 2H), 2.92-2.89 (m.1H) .2.63-2.59 (in.5H).

 1.85- 1.79 (m, 1H), 1.50-1.46 (m. 1H), 1.24 (s, 9H), 1.22-1.16 (m. 1H). 0.88 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H).

Example 6 6

 N * —Benzyl-N, 1- (4-benzylpiperazino) acetyl-N— (4-tert-butoxy-2 R—Isoptyl-3 (R or S) —phthalimidmethylsuccinyl) hydrazine

 Example 6 N'-benzyl-N'-bromoacetyl-N- (4-tert-butoxy-2R-isobutyl-1 (R or S) -phthalimidomethylsuccinyl) hydrazine and 4-benzyl obtained in 4 The title compound (97% in yield) was obtained as a white amorphous substance in the same manner as in Example 65 using piperazine.

 'H-NMR (CDCls) δρριη. 500MHz: 9.13 (s. 1H). 7.84-7.81 (m, 2H).

7.74-7.73 (m, 2H). 7.35-7.24 (m, 9H) .7, 19-7.16 (m.lfl),

5.02 (d, J = 15 Hz. 1H). 4.83 (d, J-15 Hz. 1H).

3.74 (dd, J = 14.4.8 Hz. 1H), 3.65-3.61 (m, 1H). 3.52 (s, 2H).

3.32 (s, 2H), 2.94-2.90 (m.1H) .2.61-2.50 (m.9H), 1.80-1.75 (m.1H) .1.44-1.39 (m.1H), 1.24 (s.9H), 1.22-1.15 (m, 1H),

0.85 (d, J = 6.5 Hz, 3H), 0.81 (d.J = 6.5 Hz. 3H).

Example 6 7

 N- (4-hydroxy 2 R isobutyl succinyl) aza-one (2-naphthyl) aralan-L-alanine benzyl ester

N- (4-I-tert-butoxy-2R-isobutyrsk obtained in Example 3 Trifluoroacetic acid (0.6 ml) was added to a methylene chloride (0.15 ml) solution of cynyl) aza- (2-naphthyl) aranyl-L-alanine benzyl ester (210 mg, 0.36 mmol) under ice-cooling, and then to room temperature. Raise 1. Stir for 5 hours. The reaction mixture was concentrated under a stream of nitrogen and dried, and the residue was purified by silica gel column chromatography (chloroform / methanol = 1/0, 100/1) to give the title compound (165 mg, Yield 94) was obtained.

'H-NMR (DMS0-d _s ) <5 ppm. 300 MHz: 12.35 (br s, 1H). 10.31 (br s, 1H), 7.92-7.65 (m, 4H), 7.50-7.25 (m. 8H). 6.60 (br s, 1H).

5.25-4.94 (m. 3H), 4.50-4.18 (m, 2H), 2.0-2.20 (m, 1H),

1.40-0.85 (m, 6H), 0.61-0.40 (m. 6fl). [A peak of Rotamer was observed] The compounds of Examples 68 to 79 shown below were synthesized according to the method of Example 67 described above. Was conducted.

Example 6 8

 N-(4-Hydroquinone 2 R-isobutylsuccinyl) aza (2-naphthyl) araranyl L-alanine N '-benzylamide

 Example 3 N- (4-tert-butoxy-2R-isobutylsuccinyl) aza (2-naphthyl) obtained in 4 N- (4-naphthyl) alanyl-L-alanine N′-Synthesized from benzylamide, and crude It was subjected to the reaction.

Example 6 9

 N- (4-Hydroxy-1 2R-isobutylsuccinyl) azaphenylylalanyl — L-alanine benzyl ester

 N- (4-tert-butoxy-2R-isobutylsuccinyl) azaphenylalanyl obtained from Example 35; synthesized from L-alanine benzyl ester, which was used crude for the reaction of Example 108. Provided.

Example 7 0

N- (4-Hydroxy-2R-isobutylsuccinyl) azaleucyl-L-alanine benzyl ester The title compound (94% yield) was obtained as a white solid by synthesizing from N- (4-tert-butoxy-2R-isobutylsuccinyl) azaleucyl-L-alanine benzyl ester obtained in Example 36.

^£ Η-Ν Ε (DMS0-d ₆ ) 5ppm, 300MHz: 12.35 (br s. 1H), 10.35 (br s, 1H). 7.46-7.20 (m. 5H), 6.50-6.30 (m, 1H). 5.20 -5.01 (m, 1H).

4.27-4.05 (m, 1H), 3.60-3.45 (m. 1H). 2.89-2.70 (m. 1H).

2.70-2.25 (m. 3H). 1.80-1.60 (m, 1H), 1.51-1.30 (m, 2H).

1.26 (d, J = 7.4 Hz.3H), 1.20-1.05 (m.1H), 0.91-0.70 (m, 12H).

Example 7 1

 N- (4-Hydroxy-2R-isobutyl-l-3 (R or S) -phthalimid methylsuccinyl) azadinuranine N'-methylamide

 N— (4—tert—butoxy—2R—isobutyl-3 obtained in Example 37

(R or S) -Phthalimidomethylsuccinyl) synthesized from azafuranalanine N'-methylamide to give the title compound (62% yield) as a white solid.

Ή-NMR (MeOH-d ₄ ) (5ppm. 300MHz: 7.88-7.80 (m. 4H), 7.31 (m. 5H), 5.01 (m, 1H), 4.42 (m. 1H), 4.15 (m. 1H) 3.89 (m, 1H). 3.00 (m. 1H), 2.84 (s, 3H). 2.64 (m. Lfl). 1.71 (t, J = 9.2 Hz. 1H), 1.27 (m, 1H).

0.84 (d. J = 5.9 Hz. 3H), 0.77 (d. J = 5.9 Hz. 3H).

Example Ί 2

 N- (4-hydroxy-2R-isobutyl-1-3 (R or S) -phthalimid methylsuccinyl) azaphenylalanine benzyl ester

 N- (4-tert-butyn- 1 2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) obtained in Example 42 was synthesized from azafudinalanine benzyl ester to give the title compound as a white solid ( A yield of 95%) was obtained. ^ -NR (Me0H-d4) δ pm, 300MHz: 7.69 (s, 4H), 7.20-7.15 (m.7H), 6.93-6.46 (m, 3H), 5.02 (m, 2H). 2.95 (m, 1H) ), 2.38 (m, 1H),

1.49 (t, J = 11.6 Hz, 1H), 0.64 (br s.3H) .0.55 (br s, 3H). peak was observed]

Example 7 3

 N— (4-hydroxy 2 R—isobutyl-3 (R or S) —phthalimid methylsuccinyl) azaphenylalanine N′—phenylamide

 Example 41 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) obtained in 1) was synthesized from azaphenylalanine N'-phenylamide, which was crude. It was subjected to 140 reactions.

Example 7 4

 N-Benzyl-1-N '-(4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) -N- (p-Methoxybenzenesulfonyl) hydrazine

 N-benzyl-N ′ obtained in Example 4 5 N '-(4-16-13 "-butoxy 21 ^ -isobutyl-13 (R or S) -phthalimid-methylsuccinyl) -N- (p-methoxy Benzenesulfonyl) The compound was synthesized from hydrazine and subjected to the reaction of Example 1339 as crude.

Example 7 5

 N— (4-hydroxy 2 R—isobutyl-3 (R or S) —phthalimid methylsuccinyl) azafuranilanyl-1-L-alanine benzyl ester N— (4-tert-butoxy-2) obtained in Example 38 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azafeniralalanil L-l-alanine benzyl ester was synthesized and subjected to the reaction of Example 135 as crude.

Example 7 6

N— (4-hydroxy 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) azafuranilanyl—L-alanine methyl ester N— (4-tert-butoxy) obtained in Example 39 2 R—isobutyl—3 (R or S) —phthalimidmethylsuccinyl) azaphenyl It was synthesized from alanine methyl ester and subjected to the reaction of Example 13 33 as crude. Example 7 7

 N- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimid methylsuccinyl)

 N- (4-tert-butoxy-1-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) obtained in Example 40 was synthesized from azafeniralara2luglycine benzyl ester to give a white solid. As a result, the title compound (yield 54) was obtained.

 'H-NMR (DMSO-de) (5ppm. 300MHz: 10.31 (s, 1H). 7.85 (m, 4H),

7.36-7.24 (m. 10H). 6.80 (br s, 1H), 5.11 (s, 2H). 4.80 (br s, 1H), 4.40 (br s, 1H), 3.93 (m. 2fl). 2.86 (m , 1H), 2.59 (m, 1H).

1.57 (m, 1H), 1.31 (m, 1H). 1.10 Cm. 0.76 (d.J = 6.0 Hz, 3H).

 0.72 (d. J = 6.0 Hz. 3H).

Example 7 8

 N-benzyloxycarbonyl N- [Ν '-(4-hydroxyl-2R-isobutylsuccinyl) amino] -L-phenylalanine N', monomethylamide Obtained in Example 43 Ν-benzyloxycarbonyl-Ν- [Ν '-(4-tert-butoxy-2R-isobutylsuccinyl) amino] -l-L-phenylalanine N' '-methylamide, yellow The title compound (quantitative yield) was obtained as an oil.

iH-M (DMS0-d ₆ ) <5ppm. 300MHz ： 11.14-9.76 (m, 1H),

8.60-8.34 and 8.34-7.98 (m, 1H total). 7.40-7.13 (m. 10H),

5.02 (s, 2H), 4.74-4.36 (m.1H). 3.28-3.03 (m, IS),

2.87 (dd.J = 13.9, 6.9 Hz, 1H) .2.82-2.63 (m.1H), 2.63-2.46 (ID.3H), 2.46-2.30 (m, 1H), 2.30-2.08 (m.1H), 1.70-1.32 (m, 2H),

1.26-1.00 (m. 1H). 0.96-0.82 (m, 3H), 0.82-0.39 (m. 3H). [Rotamer peak was observed] Example Ί 9

 Ν—Benzyloxycarbonyl— Ν— [Ν'-I- (4-hydroxy-2R-Isobutyl-13 (R or S) -phthalimid-methylsuccinyl) amino] -L-phenylalanine N ',-Methylamide

 Example 4 4-benzyloxycarbonyl- カ ル ボ ニ ル _ [Ν '-(4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidmethylsuccinyl) amino] -l-phenyl obtained in Example 4 The compound was synthesized from L-alanine N, '-methylamide and subjected to the reaction of Example 104 as crude.

Example 8 0

 N- (4-Hydroxy-2R-isobutyl-l-3 (R or S) -phthalimid-methylsuccinyl) azaphenylalanine N '-(4-fluorophenyl)

 N- (4_tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) azaphynilalanine obtained in Example 46 was synthesized from N '-(-fluorophenyl) imide, The crude product was subjected to the reaction of Example 141.

Example 8 1

 N- (4-Hydroxy 2 R-isobutyl-1 (R or S) -phthalimid methylsuccinyl) azapenylglycine N'-methylamide

 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) obtained in Example 47 Synthesized from azaphenylglycine N, -methylamide, crude The reaction of Example 1 16 was used.

Example 8 2

N- (4-Hydroxy-2R-isobutyl-3 (R or S) -phthalimid methylsuccinyl) aza (0-benzyl) tyrosine N, monomethylamide N- (4- tert-butoxy 2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl It was synthesized from syn-N, monomethylamide and subjected to the reaction of Example 117 as crude. Example 8 3

 N— (4-hydroxy 2 R—isobutyl-13 (R or S) —phthalimid methylsuccinyl) aza— (2-pyridyl) alanine N′—methylamide N— obtained in Example 49 -tert -butoxy 2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) aza- (2-pyridyl) aranin N '-synthesized from methylamide and crude The reaction was provided. Example 8 4

 N— (4-hydroxy 2 R—isobutyl 13 (R or S) —phthalimid methylsuccinyl) other (2-ditrophenyl) alanine N′—methylami N— (4— obtained in Example 50 tert-butoxy 2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) aza (2-ditrophenyl) alanine N'-methylamide was synthesized and subjected to the reaction of Example 11-19 as crude. did.

Example 8 5

 N— (4-hydroxy 2 R—isobutyl-3 (R or S) —phthalimid methylsuccinyl) other (1-naphthyl) alanine N′—methyl amide N— (4-tert— obtained in Example 51 Butoxy 2 R—Isoptyl—3 (R or S) —Phthalimidomethylsuccinyl) N- (1-naphthyl) aranin N ′ —Synthesized from methylamide and used crude for the reaction in Example 12-21. did. Example 8 6

N— (4-hydroxy-2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) aza (2-naphthyl) alanine N′—methylamide N— obtained in Example 52 4-tert-butoxy-2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) aza (2-naphthyl) aranan N'-Methylamide Synthesized from methylamide, crude reaction of Example 1 2 2 Was served. Example 8 7

 N- (4-Hydroxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) aza- (4-biphenyl) aranan N'-methylamide N- (4) obtained in Example 53 — Tert-butoxy— 2 R—isobutyl-13 (R or S) —phthalimid-methylsuccinyl) — (4-biphenyl) alanine N ′ —synthesized from methylamide and crude It was subjected to.

Example 8 8

 N- (4-Hydroxy-1 2 R-isobutyl_3 (R or S) —phthalimid methylsuccinyl) azahomophenylanilanine N'—methylamide

 Example 5 N- (4-tert-butoxy-2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomophenylylalanine N'-methylamide obtained in 4 It was synthesized and subjected to the reaction of Example 124 as crude.

Example 8 9

 N- (4-Hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomophenylalanine N'-phenylamide

 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomopheniralanine N ′ obtained in Example 55 was synthesized from N′-phenylamide, and was used as crude in Example 12. It was subjected to the reaction of 5. Example 9 0

 N— (4-hydroxy 2 R—isobutyl-1 3 (R or S) —phthalimid methylsuccinyl) aza-1 (3-phenylpropyl) glycine N′—methylamido '

Example 56 Synthesis of N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) other (3-phenylpropyl) glycine N'-methylamide obtained in 6 The crude product was subjected to the reaction of Example 126. Example 9 1

 N— (4-hydroxy-2R—isobutyl-13 (R or S) —phthalimid methylsuccinyl) azacyclohexylalanine N'—methylamide

 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) obtained in Example 57 7-azacyclohexylalanine

The compound was synthesized from N'-methyl amide and subjected to the reaction of Example 127 as crude. Example 9 2

 N— (4-hydroxy-2 R—isobutyl-1 (R or S) —phthalimidomethylsuccinyl) azaneopentylglycine N′—methylamide

 Example 58 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azaneopentylglycine obtained in 8 Synthesis from N'-methylamide It was subjected to the reaction of Example 128 as it was.

Example 9 3

 N- (4-hydroxy-1 R-isobutyl-1-3 (R or S) -phthalimid methylsuccinyl) azaglycine N'-phenylamide

 Synthesized from N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) other tert-butylglycine N'-phenylamide obtained in Example 59 The crude product was subjected to the reaction of Example 12 29.

Example 9 4

 Ν '—benzyl-1- 一 (4-hydroxy- 2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) 1-N' —bivaloylhydrazine

 N'-benzyl-Ν- (4-tert-butoxy-1 2 R-isobutyl-3 (R or S) -fumidylmethyl succinyl) obtained in Example 60 1 N'-pivalylhydrazine And subjected to the reaction of Example 142 as crude.

Example 9 5

N'-Benzyl-N'-Benzyl-N- (4-Hydroxy-2R-Isobutyl 1- (R or S) -phthalimidomethylsuccinyl) hydrazine N'-benzoyl-N'-benzyl-N- (4-tert-butoxy-1 2R-isobutyl) obtained in Example 61 3 (R or S) -phthalimidmethylsuccinyl) It was synthesized from hydrazine and subjected to the reaction of Example 144 as crude.

Example 9 6

 N— (4-Hydroxy-2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) azafeniralanine N '-[4- (4-Methylbiperazino) phenyl] amide

 Example 6 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -furimid-methylsuccinyl) azafinalalanine N '-[4- (4-methylbiperazino) phenyl obtained in 2 And subjected to the reaction of Example 144 as crude.

Example 9 7

 N- (4-Hydroxy 2 R—Isoptyl-3 (R or S) —Phthalimid methyl succinyl) azapheniralanine N, — (3-pyridylmethyl) Amin K

 Example 6 From N— (4-tert-butoxy-2R—isobutyl-3 (R or S) —furimidomethylsuccinyl) azafuenylalanine N ′ — (3-pyridylmethyl) amide obtained in 3 It was synthesized and subjected to the reaction of Example 144 as crude.

Example 9 8

N'-Benzyl-N- (4-hydroxyl-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N'-morpholinoacetylhydrazine N'-benzyl obtained in Example 65 N- (4-tert-butoxy-2 R-isobutyryl-3 (R or S) -phthalimid-methylsuccinyl) -N'-morpholinoacetylhydrazine It was used for the reaction. Example 9 9

 N'-Benzyl-N '-(4-Benzylpiperazino) acetyl-N- (4-Hydroxy-l2R-Isobutyl-13 (R or S) -Phthalimidmethylsuccinyl) Hydrazine

 N'-benzyl-N '-(4-benzylpiperazino) a cetyl-N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl obtained in Example 6 6 ) It was synthesized from hydrazine and subjected to the reaction of Example 147 as crude.

Example 1 100

 N- [4- (Ν'-Hydroxyamino) — 2 R—iso.butylsuccinyl] aza— (2-naphthyl) alanyl-L—alanine benzyl ester

 Pyridine solution (145 mg, 0.27 mmol) of Ν- (4-hydroxy 2 R-isobutylsuccinyl)-(2-naphthyl) aranyl-l-alanine benzyl ester (145 mg, 0.27 mmol) obtained in Example 6 7 ), B0P reagent (157 mg, 0.35 mmol), hydroxylamine hydrochloride (76 mg, 1.1 mmol) and 4-methylmorpholine (0.18 ml, 1.60 mmol) were sequentially added, and the mixture was stirred at room temperature for 2.5 hours. . The reaction mixture was diluted with methylene chloride, washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Formula Z methanol = 100/1, 50%). The title compound (86 mg, yield 58 mg) was obtained as a white solid by purifying with 1,1 and 20-1).

¹ H-NME (D SO-de) ^ pm, 300MHz: 10.50 (br s. 1H), 10.22 (br s. 1H), 8.72 (br s, 1H). 7.95-7.63 (m, 4H), 7.52- 7.21 (in.8H),

5.11-4.96 (m. 3H), 4.42-4.10 (m. 2H). 2.31-2.11 (m. 1H).

2.07-1.90 (m.lH), 1.42-0.80 (m.6H) .0.60-0.45 (m.6H);

^{1 3 C-NME (DMSO-} de) 75 MHz:..... 173.3, 167.9, 157.2, 136.1, 135.0, 132.7 132.2, 128.3 127.8, 127.5, 127.4, 126.7 126.4, 125.8 125.5, 65.5, 50.8, 49.2 41.3 , 36.3. 35.0, 24.7. 23.2. 21.2, 16.7; MS [SIMS (+)] m / z 549 (MHO.

Example 10 1

 N— [4- (Ν'-hydroxylamino) — 2 R—isobutylsuccinyl] aza- (2-naphthyl) alanyl-L—alanine N '' — methylamide

 Ν— [4 _ (Ν ′) — hydroxyamino) —2R-isobutylsuccinyl] aza-1 (2-naphthyl) aranyl-L-alanine benzyl ester obtained in Example 100 (41.0 nig, 0.08 mmol) A 40% methylamine methanol solution (0.20 ml) was added dropwise to a methanol solution (0.15 ml) of the solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated, and the residue obtained was concentrated by silica gel column chromatography (chloroform form methanol = 100%). The title compound (13 mg, yield 33 mg) was obtained as a white solid by purifying with 1, 50/1, 20 1).

^! H-NMR (DMS0-d _e ) δ ρπι. 300 MHz: 10.59 (br s, 1H). 10.08 (br s, 1H). 8.82 (br s, 1H), 7.91-7.31 (m. 8H), 7.20- 6.84 Cm. 1H). 4.35 (m, 1H), 5.08 (m. 1H), 4.20-4.00 (m, 1H), 2.61 (d, J = 4.4 Hz. 3H),

2.31-2.16 (m, 1H), 2.10-1.95 (m. 1H) .1.35-0.80 (m. 6H).

0.69-0.45 (m, 6H).

Example 10

 N- [4- (Ν'-hydroxyamino) -1 2 R-isobutylsuccinyl] aza-1 (2-naphthyl) alanyl-L-alanine

 Ν- [4- (Ν'-hydroxyamino) -12R-isobutylsuccinyl] obtained in Example 100 (2-naphthyl) aranyl-L-alanine benzyl ester (110 mg, 0.20 mmol) To a solution of this in tetrahydrofuran (10 ml) was added 10% palladium carbon catalyst (12 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Further, a catalyst (24 mg) was added, and the mixture was stirred for 43 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give the title compound (27 mg, yield 31%) as a white solid.

'H-NME (DMSO-de) 5 pm, 300MHz: 12.34 (br s, 1H), 10.47 (s.-1H), 10.20 (s, 1H), 8.75 (br s, 1H), 7.90-7.81 (m.3H). 7.70 (s.1H),

 7.52-7.41 (m, 3H) .6.14-5.95 (m.1H) .5.12-5,00 (m, lfl),

 4.40-4.28 (m. 1H) .4.12-4.07 (m. 1H), 2.50-2.41 (m. 1H),

 2.24 (dd, J = 15, 11 Hz, 1H) .2.01 (dd.J = 15. 4.5 Hz,

 1.33 (d.J = 7.4 Hz, 3H), 1.30-1.24 (m.1H). 1.10-1.06 (m.1H),

 0.94-0.85 (a 1H), 0.59-0.54 (i, 6H);

¹³ C-NMR (DMSO-de), 75 MHz: 174.85, 173.44, 167.89, 157.13. 135.13.

132.70.132.22.127.54, 127.43, 127.37.126.66, 126.45, 125.85.

125.50, 50.96.49.08, 41.44.37.54, 35.05, 24.77, 23.18, 21.26, 17.11; MS [SIMS (+)] m / z 459 (MH ⁺ ).

Example 1 0 3

 N- [4-(N, 1-hydroxyamino) 1 2 R-isobutylsuccinyl] aza- (2-naphthyl) alanyl-L-alanine N, 1-benzylamine

 Using N- (4-hydroxy-2R-isobutylsuccinyl) aza (2-naphthyl) aranyl-L-alanine N′-benzylamide obtained in Example 68, a method similar to that of Example 100 was used. The title compound (70) was obtained as a white solid.

 lH-NMR (DMSO-de) 5ppm. 300MHz: 10.54 (br s. 1H). 10.10 (s. 1H),

8.79 (br s, 1H), 8.26-8.24 (m, 1H). 7.89-7.78 (m.3H), 7.69 (s, 1H), 7.50-7.40 (m, 3H) .7.34-7.09 (m, 5H) , 7.13-7.00 (m. 1H).

5.15-5.03 (m, 1H), 4.38-4.27 (m.3H), 4.26-4.16 Cm.1H),

2.50-2.42 (m. 1H). 2.26 (dd, J = 15.10 Hz, 1H).

 2.04 (dd, J = 15, 4.1 Hz, 1H), 1.26-1.24 (m, 1H), 1.13-1.05 (m.1H), 0.94-0.89 (m, 1H) .0.60-0.52 (m, 6H);

¹³ C-NMR (DMS0-d ₆ ). 125 MHz: 173.54, 173.10.168.00, 157.05, 139.45.135.11, 132.77.132.32.128.23.127.65, 127.50, 127.44.126.86.

126.63, 125.95. 125.64. 50.94. 50.23, 41.88. 41.28. 37.94. 35.10, 24.86, 23.21, 21.31, 18.20;

MS [SIMS (+)] m / z 548 (MH ⁺ ).

Example 1 0 4

 N—benzyloxycarbonyl N— [Ν '— [4— (Ν' '— hydroxyamino) 1-2R—isobutyl-3 (R or S) —phthalimidmethylsuccinyl] amino—L— Phenylalanine N '' '— methylamide

 7—Venzyloxycarbonyl obtained in Example 7 Ν— [Ν '-(4-Hydroxy 2 R—Isoptyl-3 (R or S) —phthalimid-methylsuccinyl) amino] —Fenilalanine The title compound (yield: 59 mg) was obtained as a white solid in the same manner as in Example 100, using N ′ ′-methylamide.

 ^ -N R (DMSO-de) <5 pm. 300MHz. 80: 7.79 (s. 4H),

7.30-7.14 (m. 10H), 5.06 (d, J = 13 Hz. 1H), 4.96 (d. J = 13 Hz. 1H), 4.70-4.65 (m. 1H). 3.89-3.81 (m. Iff) . 3.48-3.41 (m. 1H),

3.33 (dd.J = 14.6.3 Hz. Lfl) .3.00-2.94 (m.1H), 2.78-2.70 (π, 2H) .2.58-2.56 (m, 3H). 1.60-1.45 (m.2H), 1.10-1.04 (m, 1H),

0.82 (d. J = 6.5 Hz. 3H). 0.77 (d. J = 6.5 Hz, 3H);

MS [SIMS (+)] m / z 658 (MH +).

Example 1 0 5

 N- [N'-1- [4 -— (Ν'-hydroxyamino) -1 2 R-isobutyl-1 3 (R or S) —phthalimidomethylsuccinyl] amino] —L-phenylalanine N '' '-methylami Do

Ν-benzyloxycarbonyl obtained in Example 104 Ν- [Ν '-[4- (Ν''-hydroxyamino)-1 R-isobutyl-3 (R or S) -phthalimide Methylsuccinyl] amino] 1-L-phenylalanine N ','-Methyl amide (310 mg. 0.47 mniol) in methanol (30 ml), 10% palladium on carbon catalyst (120 mg), hydrogen atmosphere The mixture was stirred at room temperature for 18 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give the title compound (242 mg. 98).

lH-NMR (DMS0-d _e ) <5 pm, 500MHz: 10.45 (s, 1H), 9.63 (s. 1H),

 .67 (br s, 1H), 7.84-7.81 (m, 4H), 7.76-7.74 (m. 1H).

7.27-7.18 (m, 5H), 5.10-5.08 (m, 1H), 3.83 (dd.J = 13, 11 Hz.1H).

3.58-3.56 (m. 3.20 (dd, J = 13.10 Hz, 1H).

2.86 (dd. J = 15, 6.8 Hz, 1H). 2.78 (dd. J = 15, 6.9 Hz, 1H),

2.72-2.68 (m, 1H), 2.51 (s.3H) .2.47-2.43 (m.1H) .1.50-1.46 (m, 1H), 1.36-1.31 (m.1H), 0.91-0.87 (m.1H ), 0.79-0.78 (in. 6H);

I ³ C-纖(DMSO-de) 75 MHz: ........ 171.43 171.29, 167.17 167.01 137.55, 134.20 131.38 129.04 127.95, 126.12, 122.87, 64.63, 43.91 2.54, 39.67, 37.87, 36.82, 25.16, 24.94, 23.97. 20.91;

MS [SIMS (+)] m / z 524 (MH ⁺ ).

Example 1 0 6

 N- [2R-isobutyl-1-41- (Ν'-tetrahydropyran-1-2-yloxyamino) succinyl] azarazyl-1 L-alanine benzyl ester

 The Ν- (4-hydroxy-2R-isobutylsuccinyl) azaleucyl-L-alanine benzyl ester (142 mg. 0.32 mmol) obtained in Example 70 was mixed with N, N-dimethylformamide (5 ml) and methylene chloride. (2 ml) in a mixed solvent, and 0-tetrahydropropyran-1-ylhydroxylamine (7500 mg. 0.64 mmol), BOP reagent (170 mg, 0.38 octol) and 4-methylmorpholine were dissolved in the mixture. (0.08 ml, 0.72 mmol) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added ethyl ether, washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silylation gel column chromatography (cloform form Z methanol = 50/1, Purification by 20/1) gave the title compound (143 rag, yield 81 mg) as a white solid.

¹ H-NME (D SO-de) <5 ppm, 300MHz: 11.20 (br s. 1H). 10.29 (br s, 1H), 7.48-7.20 (m. 5H). 7.18-6.90 (m. 1H), 5. 0-5.00 (m, 2H), 4.85-4.70 (m.1H), 4.21-4.02 (m, 1H), 4.00-3.75 (m, 1H).

3.60-3.40 (m.2H) .2.85-2.64 (m, 1H), 2.64-2.50 (m.1H),

2.40-2.07 (m.2H), 1.80-1.33 (m.9H) .1.33-1.21 (m, 3H).

1.18-1.00 (m, 1H). 0.90-0.70 (m. 12H).

Example 1 0 7

 N— [4— (N, 1-hydroxyamino) 1-2R—isobutylsuccinyl] aza mouth isyl-L-alanine benzyl ester

 Chlorination of N- [2R-isobutyl-4- (Ν'-tetrahydropyran-1-2-yloxyamino) succinyl] azaleucyl-1L-alanine benzyl ester (67 mg, 0.12 ιηιποΐ) obtained in Example 106 To a methylene solution (0.3 ml) was added dropwise trifluoroacetic acid (0.8 ml) under ice-cooling, and the mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was concentrated under a stream of nitrogen, and the residue was purified by silica gel column chromatography (chloroform-form Zmethanol = 100, 1, 50/1) to give the title compound (13) as a white solid. mg, yield 23).

lH-thigh (D S0-d _e ) 5ppm. 300MHz: 10.51 (br s, lfl), 10.29 (br s, 1H), 8.72 (s, 1H). 7.40-7.25 (m. 5H), 7.12-7.00 ( m. 1H), 5.17-5.00 (m, 2H). 4.18-4.05 (m. 1H), 3.60-3.40 (m. 1H) .2.84-2.70 (ra, 1H).

2.63-2.50 (m, 1H), 2.34-2.03 (m, 2H), 1.80-1.62 (m. 1H),

1.50-1.34 (m.2H), 1.33 (d.J = 7.3 Hz, 3H), 1.16-1.00 (m, 1H).

0.95-0.76 Cm, 12H);

MS [SIMS (+)] m / z 465 (MH ⁺ ).

Example 1 0 8

N- [2R-Isobutyl-41- (Ν'-tetrahydrodropyrane-2-yloxyamino) succinyl] azaphenylalanyl L-alanine benzyl ester 6— (4-hydroxyloxy) obtained in Example 69 —2R-Isobutylsuccinyl) azaphenyl-2-alanyl L-alanine benzyl ester was used to obtain the title compound as amorphous (yield: 64 mg) in the same manner as in Example 106. _{^ - MR (CDC1 3) t5ppm} , 300MHz: 7.40-7.20 (m, 10H).

5.30 (br d. J = 14.7 Hz. 1H). 5.22 (d, J = 12.4 Hz. 1H).

5.13 (d, J = 12.4 Hz. 1H). 4.90—4.75 (m. 1H). 4.60-4.45 (m, 1H),

4.23 (br d, J-14.7 Hz 1H). 3.90-3.75 (m. 1H), 3.65-3.55 (m, 1H),

2.80-2.10 (ID.3H), 1.46 (d, J = 7.0 Hz.3H) .1.85-1.20 (m.8H),

1.15—0.95 (m, 1H), 0.78 (d, J = 6.2 Hz, 3H). 0.63 (d. J = 6.2 Hz, 3H).

 N— [4-1 (Ν'-hydroxyamino) 1-2R—isobutylsuccinyl] aza phenylalanyl L-alanine benzyl ester

 As in Example 107, using Ν— [2R-isobutyl-41- (ー ′ -tetrahydropyran-1-2-yloxyamino) succinyl] azaphenyl-2-alanyl L-alanine benzyl ester obtained in Example 108 According to the method described above, the title compound (yield: 50 mg) was obtained as a white solid.

 'H-NMR (DMSO-de) <5 ppm, 300KHz: 10.50 (s, 1H), 10.23 (s, 1H),

8.72 (s, 1H). 7.40-7.15 (m. 10H), 5.17 (d. J = 12.7 Hz, 1H).

5.09 (d.J = 12.7 Hz.1H), 5.05-4.80 (m.1H) .4.25-4.00 (DJ.2H),

2.60-2.40 (m. 1H), 2.27 (dd, J = 15.0, 10.8 Hz, 1H).

2.04 (dd, J = 15.0, 3.6 Hz. 1H). 1.37 (d. J = 7.3 Hz, 3H).

1.40-1.10 (in. 2H), 1.05-0.90 (m. 1H), 0.73 (d. J = 6.5 Hz, 3H).

0.69 (d. J = 6.5 Hz, 3H);

¹³ C-NMR (DMSO-de) .75 MHz: 173.41, 173.25, 167.95, 157.16.137.63, 136.09.128.28, 127.94.127.88, 127.76, 127.48.126.81, 65.43, 50.89.49.40. , 23.25, 21.41. 16.73;

MS [SIMS (+)] m / z 499 (¾H ⁺ ).

 Example 1 1 o

N- [4- (Ν '' 1benzyloxyamino) 1 2 R-isobutylsuccinyl] — Ν,, Ν 'diphenylhydrazine To a pyridine solution (0.5 ml) of N- (4-hydroxy-2R-isobutylsuccinyl) -1-', N'-diphenylhydrazine (32,0 mg. 0.01 mmol) obtained in Example 7, A B0P reagent (54.0 mg. 0.12 mmol), 0-benzylhydroxylamine hydrochloride (45.0 mg, 0.28 mmol) and 4-methylmorpholine (0.03 ml, 0.28 mmol) were sequentially added, and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the reaction mixture, which was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / chloroform form = 2 / 1,1 / 1 / Purification by (1, 1/0) afforded the title compound (21 mg. Yield 47 mg) as a white solid.

'Η-赚 (DMS0-d ₆ ) <5ppm. 300MHz ： 11.10 (br s. 1H). 10.70 (br s, 1H). 7.50-7.30 (m. 5H). 7.30-6.86 (m, 10H) , 4.87-4.70 (m, 2H),

2.92-2.75 (m, 1H). 2.32-2.00 (m. 2H), 1.50-1.30 (m. 2H),

1.20-1.00 (m, 1H), 1.00-0.75 (m, 6H).

Example 1 1 1

 N- [4-(Ν '' -hydroxyamino) 1 2 R-isobutylsuccinyl] ― Ν ', N' -diphenylhydrazine

 Example 11 of の — [4- (Ν ′,-benzyloxyamino) —2R—isobutylsuccinyl] -1-′, N′—diphenylhydrazine (18.0 mg. 0.04 mmol) obtained in 10 To a methanol solution (2 ml) was added 10% palladium-carbon catalyst (7 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The catalyst in the reaction mixture was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (formaldehyde methanol: 50/1, 20/1) to give a light red solid. The title compound (10 mg, yield 70 mg) was obtained.

^X HNR (DMS0-de) 5ρρπι. 300MHz: 10.67 (br s, 1H), 10.47 (br s, 1H). 8.31 (br s. 1H). 7.34-6.82 (m. Hired), 2.90-2.75 (m . 1H),

 2.30-2.00 (m. 2H). 1.50-1.35 (in, 2H), 1.20-1.00 Cm. 1H).

0.95-0.72 (m. 6H); ¹³ C-NMR (DMSO-de). 75 MHz: 173.6. 167.1, 145.7. 128.9, 41.0, 37.9,

 35.4, 25.3, 23.3, 21.7;

MS [SIMS (+)] m / z 356 (MH ⁺ ).

Example 1 1 2

 N— [Ν '— [4- (Ν' '— benzyloxyamino) —2R—isoptylsuccinyl] amino] morpholine

 Using the Ν- [Ν '-(4-hydroxy-2R-isobutylsuccinyl) amino] morpholine obtained in Example 6, in the same manner as in Example 110, the title compound (yield 52 ¾) was obtained.

 'H-NMR (DMSO-de) δρρπ, 300MHz ： 11.01 and 10.96 (s. 1H total).

9.05 and 8.43 (s, 1H total) .7.37-7.33 (m, 5H), 4.76-4.73 (s, 2H total) .3.59-3.56 (m, 4H) .2.72-2.69 (m.4H) .2.56-2.50 (m, 1H).

2.29-2.08 (m, 1H), 2.00-1.92 (m. 1H). 1.48-1.36 (m, 2H),

1.14-0.97 (in, 1H), 0.90-0.80 (m. 6H). [Rotamer peak was observed] Example 1 1 3

 N-EN '-[4— (Ν' '-hydroxyamino) -1-R-isobutylsuccinyl] amino

 Example 11 Using Ν— [Ν ′ — [4- (Ν ′ ′-I ^ C benzyloxyamino) -12R-isobutylsuccinyl] amino) morpholin obtained in Example 11 The title compound (yield: 61 mg) was obtained as a white solid in the same manner as in 1.

'H-NMR (DMS0-d _a ) (ppin. 300MHz: 10.39 (br s, 1H), 9.04 (br s, 1H).

 8.69 (br s. 1H), 3.60-3.57 (m. 4H) .2.72-2.69 (m. 4H),

 2.55-2.50 (m, 1H), 2.26-1.92 (m.2H) .1,49-1.31 (m.2H),

1.13-0.98 (m, 1H), 0.90-0.80 (m, 6H); [Bottomer peak was observed] 1 ^S C-NMR (DMS0-d ₆ ). 75 MHz: 176.72, 171.28, 167.13. 65.77, 54.46,

 40.68.38.35, 35.71, 33.84, 25.32, 23.27, 21.74;

MS [SIMS (+)] m / z 274 (MH ⁺ ). Example 1 1 4

 N- [Ν'-I [41- (Ν ''-benzyloxyamino) 1-2 R-isobutylsuccinyl] amino] 1-benzyloxycarbonyl L-phenylalanine N ',, methylamino Do

 Example 7 8-benzyloxycarbonyl obtained in 8 Ν— [Ν '— (4-hydroxy-1 2R-isobutylsuccinyl) amino] 1 L 1 phenylalanine Ν' 1 methyl amide The title compound was obtained as a white foamy substance (yield: 46 mg) in the same manner as in Example 110 using the above.

 'fi-NK (D SO-de) 5ppm. 300ΪΗζ: 11.06 (s, 1H), 10.25 (br s. 1H).

8.45-8.27 and 8.27-7.98 (m. 1H total), 7.48-7.01 (m. 15H).

5.02 (s, 2H), 4.74 (s, 2H), 4.64-4.30 (m, 1H), 3.27-3.07 (m. 1H).

2.99-2.70 (m. 2H) .2.57-2.43 (m. 3H),

 2.32-2.12 and 2.12-1.88 (m. 2H total), 1.68-1.27 (m, 2H),

 1.12-0.93 (m, 1H). 0.93-0.78 and 0.78-0.46 (m. 6H total). [Rotamer Ope ak was observed]

Example 1 1 5

 N-EN '-[4-(Ν' '—Hydroxyamino) 1 2 R—Isoptylsuccinyl] amino] —L-phenylalanine Ν, *' Monomethylamide

 Example 11 Ν-CN ′ 1 [41- (Ν ′ ′ — benzyloxyamino) —2R-isobutylsuccinyl] amino obtained in Example 14—Ν-benzyloxycarbonyl—L-phenylanilanin N The title compound (yield: 68 mg) was obtained as a white solid in the same manner as in Example 11 using '' '-methylamide.

 'H-NMR (DMSO-de) 5ppm. 300MHz: 10.36 (d. J = 1.4 Hz. 1H).

9.40 (d, J = 4.8 Hz. 1H). 8.68 (d, J = 1.8 Hz. 1H).

7.63 (q. J = 4.7 Hz. 1H). 7.34-7.12 (m. 5H), 4.90 (t, J = 4.4 Hz, 1H). 3.58-3.48 (m. 1H), 2.86 (dd, J: 13.8. 5.9 Hz, 1H).

2.76 (dd.J = 13.8, 7.0 Hz, 1H), 2.66-2.55 (m.1H), 2.55-2.444 (m, 3ft). 2.07 (dd, J = 14.4.6.6 Hz, 1H), 1.95 (dd.J = 14.4, 7.7 Hz.1H),

1.48-1.32 (m, 2H) .1.08-0.93 (m, 1H),

0.80 (apparent t. J = 6.0 Hz, 6H).

Example 1 1 6

 N— [4— (Ν'—hydroxyamino) 1 2 R—Isoptyl-3 (R or S) —phthalimidomethylsuccinyl] azaphenylglycine

 Example 10 Using 10- (4-hydroxy 2 R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) azaphenyl glycine N'-methyl amide obtained in Example 1, Example 10 By a method similar to that of 0, the title compound (yield 19) was obtained as a white solid.

^Χ Η- Η (DHS0-d _e ) 5ppm. 300MHz ： 10.79 (s, 1H), 10.23 (s, 1H),

8.94 (br s, 1H), 7.86 (s, 4H), 7.55 (br s.1H), 7.40-7.20 (m, 4H),

7.07 (t.J = 7.1 Hz, 1H). 4.02 (dd.J = 13.7. 11.0 Hz, 1H).

3.80-3.60 (m. 1H), 2.74 (d. J = 4.2 Hz. 3H), 2.80-2.55 (m, 2H).

1.80-1.65 (m, lfl), 1.50-1.30 (m, 1H), 1.30-1.20 (m. 1H).

0.90 (d, J = 6.4 Hz, 3H), 0.81 (d.J = 6.4 Hz, 3H);

^{1 3 C-NMR (DMS0-} d 6), 75 MHz:...... 171.64 168.79 167.49, 155.99 142.66, 134.42 131.69, 128.14, 124.17, 123.08 122.60 44.24, 41.77, 40.03,

36.21.26.99, 25.06, 23.32, 21.58;

MS [SIMS (+)] m / z 496 (MH ⁺ ).

Example 1 1 7

 N- [4— (Ν'—hydroxyamino) 1 2 R—isobutyl-3 (R or S) monophthalimidomethylsuccinyl] other (0—benzyl) tyrosine N '' — methylamide

Example 8 Ν— (4-hydroxy 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) other (0—benzyl) tyrosine N ′ obtained in 2 The title compound was obtained as a white solid (yield 23) in the same manner as in Example 100 using monomethylamide.

 Ή-NMR (DMSO-de) <5 pm. 300HHz: 10.59 (br s, 1H), 10.03 (s. 1H),

8.81 (s, 1H), 7.84 (s.4H), 7.40-7.29 (m, 5H).

 7.15 (d.J = 8.6 Hz, 2H), 6.92 (d.J = 8.6 Hz.2H), 5.04-5.02 (m.2H).

4.90 (br s, lfl), 4.00 (br s. 1H), 3.64 (m. 2H).

 2.69 (d, J = 6.7 Hz, 3H), 2.61-2.57 (m, 1H), 2.51-2.45 (m, 1H),

 1.68 (m. 1H). 1.27 (m. 1H), 1.14-1.11 (m, lfl),

 0.79 (d, J = 6.4 Hz.3H) .0.73 (d, J = 6.4 Hz, 3H);

¹³ (: -Lease (DMSO-de). 75 MHz: 169.06. 159.84, 159.15, 138.81, 136.01,

133.29, 131.14.130.09.129.45, 129.23, 128.30.124.68, 116.04.70.79.

52.00, 46,02, 28.66. 26.75, 25.20. 23.07;

MS [SIMS (+)] m / z 616 (MH ⁺ ).

Example 1 1 8

 N- [4- (Ν'-hydroxyamino) -1 2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl] other (2-pyridyl) alanine N ''-methylamido

 Example 8 Using 実 施-(4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) aza (2-pyridyl) alanine Ν, -methylamide obtained in Example 3, By a method similar to that in Example 100, the title compound (yield: 32 mg) was obtained as a pale and color solid.

 lH-NM (DMSO-de) 5ppm. 300MHz ： 10.79 and 10.62 (s. 1H total. 17:83). 10.13 and 10.12 (br s. IB total), 8.85 (br s, 1H).

 8.45 (d, J = 4.6 Hz. 1H). 7.90-7.71 (m. 5H). 7.37 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.1, 5.3 Hz. 1H). 5.98 (br s, 1H), 4.35 (br s, 1H),

3.98 (t. J = 11.5 Hz. 1H), 2.71 (d. J = 4.4 Hz. 3H).

2.64-2.58 (m, 1H). 1.67 (m, 1H), 1.23-1.10 (m, 2H), 0.74 (d, J = 6.4 Hz. 3H), 0.65 (d. J = 6.4 Hz. 3H). [The otamer peak was observed.]

Example 1 1 9

 N- [4-(Ν'-hydroxyamino) 1-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl] aza-1 (2-ditrophenyl) alanine Ν ''-methylamide

 Using Ν- (4-hydroxy-2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) other (2-nitrophenyl) aranan N'-methylamide obtained in Example 8, The title compound (yield: 52%) was obtained as a pale yellow solid in the same manner as in Example 100.

 ^ -NiiR (DMSO-de) 5ppm. 300MHz: 10.62 (br s, 1H), 10.23 (s, 1H),

8.87 (s. 1H). 7.98 (dd, J = 8.1. 0.9 Hz, 1H), 7.84 (s, 4H),

7.76 (dd. J = 8.7. 1.3 Hz. 1H), 7.65 (d, J = 6.7 Hz. 1H),

7.52 (dd. J-8.3. 1.3 Hz. 1H), 5.15 (d, J = 16.7 Hz. 1H).

4.60 (d, J = 15.4 Hz, 1H). 3.96 (apparent t. J = 13.3 Hz. 1H).

3.59 (d, J = 11.0 Hz, 1H), 2.71 (d.J = 4.3 Hz. 3H).

2.62-2.58 (m. 1H), 2.9-2.40 (m. 1H). 1.64 (J = 8. Hz. 1H).

1.23-1.13 (m, 2H). 0.72 (d.J = 5.9 Hz, 3H),

0.63 (d, J = 5.9 Hz, 3H);

MS [SIMS (+)] ni / z 555 (MH ⁺ ).

Example 1 2 0

 N- [4- (Ν'-hydroxyamino) 1-2R-isobutyl-13 (R or S) -phthalimid-methylsuccinyl] aza- (2-aminoamino) alanine Ν ''-methylamide

Example 11 Ν— [4- (Ν'-hydroxyamino) -1-2 R-isobutyl-3 (R or S) —phthalimid-methylsuccinyl] other obtained in 19 (2-nitrophenyl) alanan N '' —Methyl amide, the same as in Example 11 By the method, the title compound was obtained as a pale and color solid (yield 10).

^ -NR (D S0-d ₅ ) <ppm. 300MHz, 60 ° C: 10.50 (br s. 1H). 9.91 (s. 1H), 8.60 (s. 1H). 7.82 (s. 4H), 7.07 ( br s. 1H),

6.96 (apparent ΐ, J = 11.0 Hz, 1H), 6.82 (d.J = 6.3 Hz, 1H),

6.59 (d, J = 7.9 Hz, 1H). 6.43 (apparent t, J = 7.5 Hz, 1H).

5.12 (br s, 1H), 4.78 (d. J = 15.4 Hz. 1H), 4.09 (br s, 1H).

4.01 (dd. J = 13.7, 11 Hz. 1H). 3.66 (d, J = 15.4 Hz. 1H),

2.71 (d, J = 4.0 Hz. 3H) .1, 74 (m. 1H), 1.49 (m. 1H).

1.27-1.23 (m.1H) .0.86 (d.J = 6.4 Hz, 3H),

0.84 (d. J = 6.4 Hz. 3H);

¹³ C-NMR (DMSO-de). 125 MHz: 168.11. 147.81, 135.01, 132.36. 131.45.

129.15.123.68.120.71, 115.87.115.03.49.23, 45.05.41.97, 36.67, 27.67.25.86.24.30, 22.27;

MS [SIMS (+)] m / z 525 (MH ⁺ ).

Example 1 2 1

 N- [4-CN'-Hydroxyamino) 1 2 R-Isobutyl 1 3 (R or S) 1-fluoromethylsuccinyl] aza- (1-naphthyl) alanine N ''-Methylamide

 Example 8 Using N- (4-hydroxy 2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) other (1-naphthyl) alanine N'-methylamide obtained in Example 5, The title compound (yield 44 mg) was obtained as a white solid in the same manner as in 00.

 ^-MR (DMSO-ds) 5 pm. 300MHz: 10.95 (s, 1H), 9.92 (s. 1H).

8.80 (s. 1H). 8.22 (d.J = 7.9 Hz, 1H). 7.95-7.80 (m. 2H).

 7.84 (s, 4H), 7.60-7.25 (m.4H), 5.70-5.45 (m.1H), 4.65-4.40 (a.1H), 4.05-3.90 Cm.1H) .3.75-3.55 (m.1H) 2.77 (d, J-4.3 Hz. 3H),

2.65-2.55 (m, 1H), 2.50-2.35 (m, 1H). 1.80-1.65 (m, 1H). 1.50-1.30 (m. 1H). 1.20—1.05 (m, 1H), 0.81 (d, J = 6.4 Hz. 3H),

0.72 (d. J = 6.4 Hz. 3H);

¹³ C-concealed CDMSO-ds), 75 MHz: 171.25, 168.52.167.26.158.02.134.20, 133.32, 132.98, 131.52, 131.49, 128.27.127.92, 127.56.125.97,

125.53, 125.00, 123.93, 122.86.48.34.44.12.41.25, 39.83.35.94.

26.92. 24.95, 23.36, 21.37.

Example 1 2 2

 N— [4- (Ν'-hydroxyamino)-1 2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl] aza- (2-naphthyl) alanine Ν, '-methyl amide

 Example 10 Using 10- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) other (2-naphthyl) aranan N'-methylamide obtained in Example 6, By a method similar to that of 0, the title compound (yield: 42 mg) was obtained as a white solid.

 lH-NMR (DMSO-de) <5ppm, 300MHz: 10.58 (br s, 1H). 10.07 (br s, 1H), 8.82 (br s, 1H). 7.95-7.70 (m. 7H). 7.69 (s, 1H), 7.50-7.35 (m, 3H), 7.32 (br s. 1H). 5.20-4.90 (m. 1H). 4.55-4.20 Cm. 1H).

4.10-3.80 (m. 1H), 3.75-3.50 (m, 1H), 2.74 (d. J = 4.3 Hz. 3H).

2.65-2.50 (m. 1H), 2.50-2.35 (m, 1H). 1.75-1.55 (m. 1H),

1.30-1.00 (in. 2H), 0.66 (d, J = 5.4 Hz. 3H), 0.57 (br s. 3H);

^{1 3 C-NMR (DMSO-} de), 75 MHz:.... 171.40, 168.54, 167.34, 158.28 135.35, 134.33 132.77 132.33, 131.63, 127.72, 127.46 126.84, 126.57.

125.94, 125.61, 122.99, 51.09, 44.35, 41.56, 39.82.36.26, 27.05.

25.01.23.48, 21.15;

MS [SIMS (+)] m / z 560 (MH ⁺ ).

 Example 1 2 3

N- [4-(Ν '-hydroxyamino) 1 2 R-isobutyl 1 3-(R or S) -Phthalimid-methylsuccinyl] aza-one (4-biphenyl) alanine N '' -methyl amide

 Example 8 Using N- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) aza-1 (4-biphenyl) alanan N'-methylamide obtained in Example 7 The title compound (yield: 25 0) was obtained as a white solid in the same manner as in Example 100.

 Ή-NMR (DMSO-de) 5ppm, 300MHz: 10.60 (br s. 1H), 10.13 (s. 1H).

8.82 (br s. Lfl), 7.83 (s. 4H), 7.70-7.50 (m, 4H). 7.50-7.20 Cm. 5H).

5.10-4.85 (m. 1H). 4.30-4.10 (m. 1H), 4.10-3.90 (m, 1H),

3.75-3.50 (m, 1H), 2.72 (d. J = 4.2 Hz. 3B). 2.70-2.55 (m. 1H).

2.55-2.40 (m.1H). 1.80-1.60 (m, 1H). 1.40-1.20 (m.1H).

1.20-1.05 (m. 1H), 0.78 (d. J = 6.3 Hz, 3H), 0.73 (d, J = 6.3 Hz. 3H); ^{I 3} C-MR (DMSO-de). 75 MHz: 171.34. 168.45 , 167.26.158.11, 139.84.

138.77. 137.09, 134.21, 131.52.128, 79, 128.64, 127.17.126.39,

126.26, 122.88, 50.72.44.25, 41.8, 39.75. 36.22.26.91.25.00,

23.43, 2—1.29.

Example 1 2 4

 N— [4- (Ν'-hydroxyamino) 1-2 R-isobutyl-13 (R or S) 1-phthalimidomethylsuccinyl] azahomophenylanilanine N '' — methylamide

 Example 10 Using 100- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomopheniralanine N'-methylamide obtained in Example 8 The title compound (yield: 30 mg) was obtained as a white solid in the same manner as in.

 ! H-NMR (DMSO-de) δ ppm. 300MHz: 10.67 (s, 1H). 10.23 (s, 1H),

8.89 (s, 1H). 7.85 (s, 4H), 7.30-7.10 (m.5H), 7.09 (br s, 1H),

4.03 (dd, J = 13.6, 10.6 Hz, 1H), 3.95-3.75 (m. 1H). 3.66 (apparent d. J = 13.6 Hz, 1H), 3.35-3.20 (m. 1H),

2.80-2.55 (m. 4H), 2.66 (d.J = 3.9 Hz. 3H). 1.90-1.70 (m. 1H),

1.65-1.45 (m, 1H). 1.30-1.15 (m, 1H), 0.97 (d, J = 6.4 Hz. 3H).

0.92 (d.J-6.4 Hz, 3H);

¹³ C-NMR (腳_{-d B), 75 MHz:.} ....... 171.64 168.59 167.45 157.91, 139.20, 134.39, 131.67, 128.50, 128.43 126.13 123.05 48.66, 44.51 41.83, 40.00, 36.38, 33.65 26.92, 25.55.23.54, 21.54;

MS [SIMS (+)] m / z 524 (MH ⁺ ).

Example 1 2 5

 N— [4-(Ν'—hydroxyamino) 1 2 R—isobutyl 1 3 (R or S) -phthalimidomethylsuccinyl] azaphosphinylalanine N '' —phenylamine

 Example 8 Using Ν- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomopheniralanine N'-phenylamide obtained in Example 9 and Example 100, In a similar manner, the title compound (yield: 35 mg) was obtained as a white solid.

^ -NMR (DMS0-d ₆ ) δρριη, 500ΪΗζ: 10.79 (br s, 1H). 10.51 (s, 1H), 9.28 (br s, 1H), 8.95 (br s. 1H), 7.89-7.80 (in, 6H).

7.31-7.20 (m. 7fl). 6.97 (t.J = 7.4 Hz, 1H),

 4.09 (dd, J = 14.11 Hz. 1H). 4.06-4.00 (m, 1H), 3.80—3.75 Cm. 1H), 3,28—3.22 (m, 1H), 2.83-2.78 (m, 2H) , 2.70-2.66 (m, 2H),

1.93-1.89 (m.1H) .1.62-1.59 (m.1H) .1.35-1.31 (m.1H),

1.02 (d, J = 6.5 Hz. 3H), 0.95 (d. J = 6.5 Hz, 3H);

1 ³ CN «B (DMS0-d _e ). 125 MHz: 171.73. 168.93, 167.38. 154.71, 139.94, 138.88. 134.25, 131.59, 128.37, 128.34. 128.21, 126.09. 122.94,

 121.85.119.39, 48.49, 44.57.41.63.39.74.35.75, 33.30, 25.50.

23.27, 21.55; MS [SIMS (+)] m / z 586 (MH ⁺ ).

Example 1 2 6

 N— [4- (Ν'-hydroxyamino)-2 R-isobutyl-1 3 (: R or S) -phthalimidomethylsuccinyl] other (3-phenylpropyl) glycine

 Using Ν- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) other (3-phenylpropyl) glycine N'-methylamide obtained in Example 90, The title compound (yield: 38 mg) was obtained as a white solid in the same manner as in Example 100.

lH-N ¥ R (DMS0-d ₆ ) ρ ρπι, 300ΪΗζ: 10.65 (br s, 1H), 10.13 (s. 1H).

8.88 (br s. 1H). 7.85 (s. 4H), 7.30-7.00 Cm. 5H),

4.00 (dd, J = 13.7. 11.2 Hz. 1H). 3.80-3.45 Cm, 2H),

3.30-3.05 (m. 1H), 2.70-2.60 (m. 1H), 2.67 (d, J = 4.3 Hz, 3H),

2.60-2.50 (m, 3H). 1.85-1.60 (m, 3H). 1.50-1.35 (m. 1H),

1.25-1.10 (m, 1H). 0.88 (d, J = 6.5 Hz, 3H),

0.85 (d.J = 6.5 Hz, 3B);

¹³ C-NMR (DMSO-de). 75 MHz: 171.36. 168.48. 167.38, 157.98. 141.83.

134.22, 131.53, 128.11.128.07.125.49, 122.88.46.52, 44.33.41.64, 39.88, 36.16, 32.31.29.19, 26.78.25.19, 23.38.21.27.

Example 1 2 7

 N- [4-(N, 1-hydroxyamino) 1 2 R—Isoptyl-3 (R or S) —phthalimidomethylsuccinyl] azacyclohexylalanine N '' —methylamide

Example 9 Using N- (4-hydroxy-2-R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azacyclohexylalanine N'-methylamide obtained in Example 1 The title compound (yield 7¾) was obtained as a white solid by the same method as in the above. 'HNR (DMSO-de) ^ pm. 300MHz, 60 ° C: 10.50 (br s, 1H). 9.91 (s, IE), 8.64 (s, 1H). 7.85-7.82 (m. 4H), 6.75 ( br s, 1H).

4.01 (dd, J = 14.0. 10.6 Hz. 1H), 3.65 (d, J = 13.9 Hz. 1H),

3.49-3.38 (ra.1H), 2.97 -2.93 (m, lfl), 2.65 (d, J = 4.4 Hz, 3H),

2.61-2.51 (m.2H) .1.81-1.72 (m.1H), 1.66-1.46 (m, 7H).

1.27-1.09 (m. 4H), 0.91 (d. J = 6.5 Hz. 3H), 0.87 (d, J = 6.5 Hz, 3H); MS [SIliS (+)] m / z 516 (MH ⁺ ).

Example 1 2 8

 N- [4— (Ν'—hydroxyamino) -1 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl] azaneopentylglycine Ν · '—methyl amide

 Example 9 Using 1- (4-hydroxy2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azaneopentylglycine N'-methylamide obtained in Example 2, The title compound (44 0! Yield) was obtained as a white solid in the same manner as in 00.

Ή-NMR (DMS0-d ₆ ) 5ppm, 300 «Hz ： 10.66 (br s, 1H). 10.20 (s, 1H),

8.89 (br s.1H), 7.85 (s.4H) .7.33 (br s, 1H), 4.05-3.90 (m, 1H).

3.80-3.60 (m, 2H), 2.67 (d, J = 4.0 Hz, 3H), 2, 65—2.50 (m. 3H).

1.90-1.75 (m, 1H). 1.60-1.40 (m. 1H). 1.30-1.15 (m. 1H),

0.95-0.80 (m. 15H);

¹³ C-NMR (DMS0-d _e ). 75 MHz: 170.51, 168.81, 167.30, 158.86, 134.21, 131.57.122.89.59.07.44.29, 41.11.40.31.35.99.32.35.27.64.

26.89, 25.04, 23.40.21.45.

Example 1 2 9

N- [4- (Ν'-hydroxyamino) -12 R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl] azaglycine N ''-phenylamide Ν— (obtained in Example 93) 4-hydroxy-2 R-isobutyl-3 (R or Using S) -phthalimidomethylsuccinyl) azaglycine N'-phenylamide, the title compound (yield 21) was obtained as a white solid in the same manner as in Example 100.

 'H-NMR (DMSO-de) δ ppm. 300MHz: 10.54 (br s, 1H). 9.98 (s, 1H).

8.88 (s. 1H), 8.77 (s, 1H), 8.17 (s. 1H). 7.84 (s. 4H).

7.60-7.45 (m, 2H), 7.30-7.15 (m.2H), 6.95 (t, J-7.4 Hz. 1H).

4.02 (dd, J = 13.5, 11.1 Hz, 1H), 3.62 (dd, J = 13.5, 3.3 Hz, 1H).

2.80-2.70 (m. 1H), 2.70-2.55 (m, 1H), 1.70-1.50 (m. 2H),

1.20-1.00 (m. 1H), 0.90 (d. J = 6.4 Hz. 3H), 0.85 (d. J = 6.4 Hz. 3H); ¹³ C-NMR (DMS0-d ₆ ). 75 MHz: 172.50, 167.76 , 167.21. 155.34. 139.55.

134.22.131.47.128.48.122.91,121.73,118.41,4.22,42.09.39.38.37.31,24.89.23.66.21.42;

MS [SIMS (ten)] m / z 482 (ΪΗ ⁺ ).

Example 1 3 0

 N— [4- (Ν'-hydroxyamino)-1 2 R-isobutylsuccinyl] azaphenylalanine N ', monomethylamide

 Using the Ν- (4-hydroxy 2 R-isobutylsuccinyl) azazinylalanine N′-methylamide obtained in Example 3 as a white solid by the same method as in Example 100 The title compound (19% in yield) was obtained.

 ^-MR (DMSO-de) 5 pm, 300 MHz: 10.57 (s, 1H), 10.15 (s. 1H).

10.01 (s.1H) .9.21 (s.1H), 8.84 (s.1H), 7.40-7.15 (m, 5H),

6.94 (br s. 1H). 4.92 (br s. 1H), 4.14 (br s. 1H).

2.61 (d.J = 4.3 Hz.3H), 2.50-2.35 (m, 1H),

 2.29 (dd. J = 14.5, 10.7 Hz, 1H). 2.03 (dd. J = 14.5, 3.6 Hz. 1H), 1.32 (m, 1H), 1.18 (m, 1H). 0.97 (m, 1H), 0.72 (d, J = 6.4 Hz, 3H), 0.68 (d, J = 6.4 Hz, 3H);

¹³ C-NMR (DMSO-de), 75 MHz: 173.26. 168.03. 158.14. 138.02, 127.94, 126.77.50.90.41. 6.37.88, 35.12.26.84.24.83.23.23, 21.44;

MS [SIMS (+)] m / z 351 (MD.

Example 1 3 1

 N—Benzyru N,-[4- ('' '—Hydroxyamino) 1-2R-isobutylsuccinyl] —Ν—Methylaminocarbonylmethylhydrazine

Using Ν-benzyl-1-N '-(4-hydroxy-2R-isobutylsuccinyl) obtained in Example 9, Ν-methylaminocarbonylmethylhydrazine, in the same manner as in Example 100, The title compound (22% in yield) was obtained as a white solid. ^ -NR (DMS0-d ₆ ) <5ppm. 300MHz: 10.37 (s, 1H), 9.33 (s, 1H).

8.69 (s, 1H), 8.20-8.18 (m. 1H). 7.37-7.23 (m. 5H),

3.94 (d, J = 13 Hz, 1H), 3.88 (d, J = 13 Hz.1H). 3.30-3.27 (m.2H), 2.58 (d.J = 4.6 Hz.3H). 2.47-2.39 (m , 1H), 1.85-1.70 (m.2H).

1.28-1.15 (m. 1H) .1.00—0.80 (m, 2H) .0.66 (d, J = 6.6 Hz, 6H);

^{1 3 C-NMR (DiiSO-} de), 125 MHz:..... 173.46 169.25, 166.95, 136.83, 129.02, 127.93, 127.22 61.33 59.90, 40.99 38.30 35.65, 25.15, 24.99,

23.46. 21.45;

 MS [S1HS (+)] m / z 365 (ΪΗ +).

Example 1 3 2

 N- [4— (Ν'—hydroxyamino) 1 2 R—isobutyl-3 (R or S) 1-phenylthiomethylsuccinyl] azaphenylalalanine N '' —methylamide '

 Using〗 — (4—hydroxy-2R—isobutyl-3 (R or S) —phenylthiomethylsuccinyl) azafuenilalanine N′—methylamide obtained in Example 13 In a similar manner to the above, the title compound was obtained as a white solid (yield 44 mg).

Ή-NMR (DMS0-d ₆ ) δ p, 300 MHz: 10.75 (s. 1H). 10.06 (s, 1H),

9.02 (s. 1H), 7.35-7.10 (in.10H), 5.00-4.70 (m, 1H), 4.40-4.10 (m, 1H), 3.25-3.10 (m.1H), 3.10-2.90 (m, 1H), 2.50-2.30 (m.2H),

1.70-1.50 (m, 1H). 1.30-1.05 (m. 1H) .1.00-0.85 (m. 1H).

0.74 (d, J = 6.5 Hz. 3H). 0.64 (d, J-6.5 Hz, 3H);

¹³ C-NMR (DMS0-d _e ). 75 MHz: 171.50, 168.52, 157.89, 137.68, 136.15, 128.91, 127.99, 127.80, 127.73, 126.86. 125.54. 50.90. 45.61. 23.59. 21.08;

MS [SIMS (+)] m / z 473 (MH ⁺ ).

Example 1 3 3

 N— [4- (Ν'-hydroxyamino) 1-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl] azafeniralanyl-1-L-alanine methyl ester

 Example 100 Using Ν- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) azaazafenylalanyl-l-alanine methyl ester obtained in Example 6 The title compound (yield: 61 mg) was obtained as a white solid by the same method as in the above.

 ιΗ- 赚 (DMSO-de) 5ppm. 500MHz ： 10.55 (br s. 1H). 10.30 (s, 1H),

8.72 (s.1H) .7.86-7.82 (m.4H), 7.68-7.55 (m.1H), 7.32-7.23 (m.5H) .5.02-4.94 (m.1H) .4.24-4.22 (m.1H ) .4.13-4.05 (m. 1H),

 4.01-3.95 (m, 1H), 3.65-3.59 (m, 1H), 3.63 (s.3H) .2.58-2.50 (in, 2H), 1.72-1.69 (m, 1H), 1.43 (d, J = 6.8 Hz, 1H). 1.28-1.23 (m. 1H).

 1.13-1.10 (m, 1H) .0.79 (d.J = 6.5 Hz, 3H) .0.72-0.71 (m, 3H);

^{1 3 C-NMR (DMSO-} de) 75 MHz:. 173.86, 171.24, 171.18, 167.25, 157.01.

137.57, 134.23, 131.53, 128.00.127.92, 126.89, 122.91.51.55, 50.92.49.24.44.42, 41.25.39.69.36.28.25.00, 23.46, 21.22, 16.91;

MS [SIMS (+)] m / z 582 (MH ⁺ ).

Example 1 3 4

N- [4-(N, hydroxyamino) 1 2 R—Isoptyl-3 — (R or S) P

—Phthalimid methylsuccinyl]

 Example 13 N— [4- (Ν′-hydroxyamino) 1-2R—isobutyl-13 (R or S) —phthalimidomethylsuccinyl] azaphenylamine 2-ru L-alanine methyl obtained in 33 The ester (39.0 mg. 0.07 mmol) was suspended in water (3 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at room temperature for 14 hours. Water (50 ml) was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (35 mg, yield 94X) as a white solid.

Ή-NMR (MeOH-d ₄ ) ^ ppm, 3001ίΗζ: 7.76-7.67 (in, 4Η). 7.23-7.13 (m, 5Η).

4.98-4.90 (m. 1H). 4.25 (q.J = 7.3 Hz, 1H), 4.32-4.24 (m. 1H),

3.96-3.88 (m, 1H), 3.68-3.56 (m, 1H), 2.59-2.55 (m.

 2.48-2.44 (m.1H), 1.43 (d.J = 7.3 Hz.3H), 1.18-1.05 (m.2H).

 0.72 (d, J = 6.3 Hz. 3H). 0.63 (d. J = 4.9 Hz, 3H);

¹³ C-NMR (DMSO-de), 75 MHz: 174.86, 171.54, 170.33, 167.27, 156.98.

 137.74.134.33,131.60.128.08,127.98.126.96,123.01,50.88.49.17.

44.52.41.51, 39.73, 36.57.25.09, 23.65, 21.21.17.35;

 MS [SIMS (+)] m / z 568 (MH +).

 The compounds of Examples 135 to 147 shown below were synthesized according to the method of Example 100.

Example 1 3 5

 N- [4 -— (Ν'-hydroxyamino) 1 2 R-isobutyl-3 (R or S) 1-phthalimid-methylsuccinyl] azaphenylalanyl L-aranan benzyl ester

7- (4-Hydroxy-2R-isobutyl-3 [R or S] -phthalimidomethylsuccinyl) azaazaurinarururu L-alanine benzyl ester obtained in Example 5 as a white solid The title compound (22% in yield) was obtained. 'H-NMR (MeOH-d ₄ ) 5 ppm. 300MHz: 7.86-7.79 (m. 4H), 7.39-7.30 (m. 10H),

5.24-5.11 (m, 2H), 5.20-5.07 (m. 1H). 4.47 (q. J = 7.3 Hz, 1H), CT / JP99 / 00439

4.6-4.37 (m.1H), 4.08-3.99 (m, 1H), 3.83-3.70 (m.1H),

 2.69-2.63 (m, 1H), 2.59-2.55 (m, 1H), 1.80-1.72 (m.1H),

 1.57 (d. J = 7.3 Hz, 3H), 1.37-1.18 (m, 2H), 0.84 (d. J = 6.1 Hz, 3H),

0.75 (d, J = 6.1 Hz, 3H);

¹³ C-NMR (DMSO-de), 125 MHz: 173.41. 171. 0. 168.44. 167.33. 57.23.

137.69, 136.18.134.32.131.62.128.40, 128.08, 128.00, 127.89,

127.60, 126.97.122.99, 65.59, 50.98, 49.59.44.53, 41.28, 39.83.

36.25. 25.10, 23.53, 21.30, 16.92;

US [SIMS (+)] m / z 658 (MH ⁺ ).

Example 1 3 6

 N— [4- (Ν'-hydroxyamino) -1 2 R—isobutyl-13 (R or S) 1-phthalimidomethylsuccinyl] azaphenylara2luglycine benzyl ester

 Example 7 The title compound (yield) was obtained as a white solid using Ν— (4-hydroxy 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) azapheniralanyl-glycine benzyl ester obtained in Example 7. Rate of 20¾).

_{^ -NMR (DMS0-d e)} 5 pm 300MHz GOV:.. 10.30 (. Br s 1H).

9.95 (br s.1H) .8.0 (br s, 1H), 7.80 (s.4R) .7.33-7.18 (m.11H), 5.11 (s, 2H) .4.84 (d.J-15.2. Hz, 1H), 4.38 (d.J = 15.2 Hz, 1H).

3.98-3.90 (m. 3H), 3.58 (m, IK), 1.63 (m, 1H). 1.36-1.18 (m. 2H),

0.85 (d. J = 6.9 Hz, 3H). 0.75 (d, J = 6.9 Hz, 3H);

MS [SIMS (+)] m / z 644 (MET).

Example 1 3 7

 N- [4-(Ν '—Hyd α-amino) 1 2 R—Isobutyl 1 3 (R or S) 1-phthalimid-methylsuccinyl] azafenilalanine N' '—Methylami K

Example 7 N— [4-hydroxy 2 R—isobutyl—3 (R The title compound (17% yield) was obtained as a white solid using S) -phthalimidomethylsuccinyl] azafuranalanine N'-methylamide.

 ^ -NM (MSO-de) (5 pm, 300 MHz. QOV: 10.47 (br s, 1H), 9.92 (s, 1H). 8.60 (br s, 1H), 7.82 (s, 4H). 7.30-7.18 ( m, 5H).

 4.87 (d, J = 14.8 Hz, 1H), 4.27 (d, J = 14.8 Hz, 1H).

3.87 (dd. J = 13.9, 10.6 Hz, 1H). 3.60 (m, 1H),

 2.71 (d.J-4.4 Hz. 3H), 2.63 (m. 1H), 2.51 Cm, 1H), 1.63 (m, lfl).

1.20 (m, 1H). 1.16 (m, 1H), 0.78 (d, J = 6. Hz. 3H),

0.73 (d, J-6.4 Hz, 3H);

¹³ C-NMR (DMSO-de). 125 MHz: 171.38, 168.53, 167.35, 158.16. 138.00.

134.31.131.62.128.05.128.00, 126.88.122.97.50.99, 44.34, 41.45.

36.44.36.42, 26.96.25.07, 23.47.21.34;

MS [SIMS (+)] m / z 510 (MH ⁺ ).

Example 1 3 8

 N— [4- (Ν′—hydroxyamino) 1-2R—isobutyl—3 (R or S) —phthalimidomethylsuccinyl] azaphenylalanine benzyl ester 7— (4-hydroxy-) obtained in Example 72 2R-Isoptyl-3 (R or S) -phthalimidomethylsuccinyl) azaphenyl-2-alanine benzyl ester was used to obtain the title compound (60% yield) as a white solid.

^ -NMR (DMS0-d ₆ ) 5ppm. 300MHz, QOV: 10.21 (brs, 1H),

8.25 (br s, 1H). 7.79 (s. 4H), 7.28-7.07 (m, 10H),

 5.07 (q, J = 12.4 Hz, 2H) .4.71 (d, J = 15.0 Hz, 1H),

 4.58 (d, J = 15.0 Hz. 1H), 3.73 (m. 1H). 3.27 (m. 1H), 2.70 (m. Lfl), 2.52 (m, 1H), 1.50 (in. 1H). 1.33 (m .1H), 0.97 (m, 1H),

0.70 (d. J = 6.9 Hz, 3H). 0.68 (d, J = 6.9 Hz. 3H).

MS [SIMS (+)] m / z 587 (MH ⁺ ).

Example 1 3 9 N-Benzyl-1-N '— [4- (Ν''-Hydroxyamino) -1 2 R-Isopthyl-3 (R or S) —Phthalimidomethylsuccinyl] —Ν— (ρ-Methoxybenzenesulfonyl) hydrazine

 7-benzyl-N '-(4-hydroxy-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) mono- (ρ-methoxybenzenesulfonyl) obtained in Example 7 The title compound was obtained as a white solid using hydrazine (yield 74¾).

^J H-NMR (DMS0-d ₆ ) 5 pm. 500 «Hz. 60V 10.14 (s, 1H), 9.92 (s, 1H), 8.34 (br s, IK), 7.85 (d. J = 8.8 Hz, 2H ), 7.81 (s, 4H).

7.32-7.30 (m, 2H), 7.12 (d, J = 8.8 Hz, 2H). 7.20-7.08 (m. 3H),

4.54 (d, J = 13 Hz, 1H) .4.44 (d.J = 13 Hz.1H), 3.86 (s, 3H),

3.67-3.58 (m. 1H), 2.82-2.69 (m, 1H), 2.61-2.55 (m. 1H),

2.44-2.40 (m.1H), 1.38-1.34 (m, 1H). 1.10-1.05 (m, 1H),

0.86-0.82 (m, 1H) .0.68-0.66 (m. 6H);

¹³ C-Leave (DMS0-d ₆ ) 125 MHz, 60: 172.01.167.16, 163.46, 135.57,

134.42, 131.89.130.81, 128.81.128.16.127.51.123.10, 114.56.55.97, 53.92, 44.47.42.72.39.98, 37.91.24.82, 24.05, 21.36;

MS [SIMS (+)] m / z 623 (MH ⁺ ).

Example 1 4 0

 N- [4- (Ν'-hydroxyamino) -1 2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl] azafeniralanine N ''-phenylamino '

 As a white solid, —- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) azafuenylalanine N'-phenylamide obtained in Example 7 was used. The title compound (65% yield) was obtained.

^ -NM (DMSO-de) 5p _P m. 500MHz: 10.70 (s. 1H). 10.37 (s. 1H).

9.34 (s, 1H), 8.89 (s. 1H). 7.88-7.83 (m. 6H), 7.34-7.26 (m. 7H), 7.01-6.80 (m.1H), 5.13-5.07 (m, 1H) .4.20-4.03 (m, 2H),

 3.79-3.73 (m. 1H), 2.62-2.60 (m, 1H). 2.56-2.54 (in. 1H).

 1.80-1.75 (m, 1H), 1.37-1,32 (m, 1H). 1.24-1.20 (m, 110,

 0.82 (d.J = 6.4 Hz.3H), 0.77 (d.J = 5.1 Hz, 3H);

¹³ CN (DMS0-d _e ). 125 MHz: 171.60. 167.47. 155.15. 140.02. 137.51.

 134.35, 131.68, 128.34.128.17.127.11, 123.03, 122.05, 119.55, 51.08.

44.51, 41.38, 39.83, 35.80, 25.13, 23.36, 21.53;

 MS [SIMS (+)] m / z 572 (MH10).

Example 1 4 1

 N- [4- (Ν'-hydroxyamino)-1 2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl] azaphenylalanine Ν, '-(ρ-fluorophenyl) amide

 The Ν- (ρ-hydroxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) azaphenylalanine N '-(ρ-fluorofunyl) amide obtained in Example 80 was used. The title compound was obtained as a white solid (yield: 65%).

 ^ -NME (D SO-de) δ pm, 300MHz: 10.74 (br s, 1H). 10.39 (s. 1H).

9.43 (br s, 1H), 8.92 (s, 1H), 7.95-7.75 (m, 6H). 7.40-7.20 (m.5H).

7.10 (t, J = 8.9 Hz, 2H), 5.10 (br d. J = 14.2 Hz, 1H).

4.25-4.00 (m. 2fl). 3.76 (br d, J = 14.2 Hz. 1H). 2.70-2.50 (m. 2H), 1.90-1.70 (m. 1H), 1.45-1.15 (m. 2H), 0.83 (d. J = 6.4 Hz. 3H),

0.77 (d, J = 6.4 Hz, 3H);

¹³ C-SAT CDMSO-de). 75 MHz: 171.46, 169.03, 167.38,

 157.43 (d.J-238.3 Hz) .155.14.137.35, 136.32, 134.25.131.57,

 128.08.127.03, 122.94, 121.06 (d.J-6.9 Hz),

 114.67 (d, J = 21.7 Hz), 51.02, 44.38. 41.24, 39.73, 35.69.25.05.

23.25, 21.44; MS [SIMS (+)] m / z 590 (MH ⁺ ).

Example 1 4 2

 N '—Benzyl-N— [4- (Ν' '—Hydroxyamino) 1 2 R-isobutyl-3 (R or S) —Phthalimidomethylsuccinyl] 1 N' —Bivaloylhydrazine

 Example 9 N'-benzyl-Ν- (4-hydroxy-2R-isobutyl-13 (R or S) -phthalimid-methylsuccinyl) -N'-bivaloylhydrazine obtained in 4 was used as a white solid. The title compound (yield 46) was obtained.

'H-NMR (DMS0-d _e ) c5 pm. 500 MHz. 80: 10.29 (br s, 2H),

8.36 (br s. 1H). 7.82 (br s, 4H). 7.23-7.15 (m, 5H),

4.96 (d.J = 15 Hz, 1H). 4.48 (d.J = 15 Hz, 1H),

 3.83 (dd, J = 13, 10 Hz.1H), 3.40-3.32 (m, 1H), 2.85-2.65 (m.2H), 1.59-1.48 (m, 2H), 1.25-1.15 Cm.1H), 1.21 (s, 9H);

^{13 C-NMR (eOH-d} 4) 125 MHz:... 180.71 174.99 170.26, 169.05, 137.77.

135.45, 133.22, 129.63, 128.67, 128.52, 124.26.53.67, 46.64, 43.86, 41.10.40.19, 39.09.28.39.26.75.24.05, 21.68;

MS [SIMS (+)] m / z 537 (MH ⁺ ).

Example 1 4 3

 N '—Benzyl-1-N, 1-benzyl-1-N— [4- (Ν' '—Hydroxyamino) — 2 R—Isobutyl-1 3 (R or S) —Phthalimidomethylsuccinyl] hydracin

 Example 95 White solid using Ν, 1-benzoyl N'-benzyl-Ν- (4-hydroxy2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) obtained in 5) hydrazine As a result, the title compound (yield 51%) was obtained.

 'H-NMR (DMSO-de) δρρπι, 500MHz: 10.88 and 10.81 (s, 1H total),

 10.37 and 10.30 (s, 1H total), 8.63 and 8.59 (s. 1H total),

7.84 (br s, 4H), 7.52-6.95 (m. 10H), 5.48 and 5.42 (d, J = 15 Hz. 1H total).

4.19 and 4.10 (d, J = 15 Hz, 1H total).

3.79-3.72 and 3.67-3.60 (in.1H total), 3.07-3.00 (m, 1H),

2.45-2.27 (m, ZH) .1.0-1.25 (m.1H), 1.18-1.10 (m, 1H),

0.80-0.60 (m. 1H), 0.72 and 0.54 (d.J = 5.5 Hz. 3H total).

0.38 (d. J = 6.0 Hz. 3H). [Botamer peak was observed]

MS [SIMS (+)] m / z 557 (MH ⁺ ).

Example 1 4 4

 N- [4- (Ν '' '-Hydroxyamino) 1 2 R—Isoptyl-3 (R or S) —Phthalimidomethylsuccinyl] azaphenylalanine N'-[4- (4-Methylbiperazino) phenyl ] Amide dihydrochloride

 9— (4-Hydroxy—2R—isobutyl-3 (R or S) —phthalimidmethylsuccinyl) azapheniralanine N ′-[4- (4-methylbiperazino) obtained in Example 9 A yellow solid (yield 61%) was obtained using [phenyl] amide, and the title compound was obtained as a pale purple solid by further treating with dioxane 4HCl.

_{^ - MR (DMS0-d 6} ) 5ppm, 500MHz: 10.70 (s, 1H), 10.34 (. S 1H),

10.17 (s.1H), 9.21 (br s, 1H), 7.88-7.84 (m, 4H), 7.72-7.70 (m, 2H) .7.34-7.26 (m.5H), 6.93 (d, J = 9.1 Hz 2H), -5.10-5.06 (m. 1H),

4.18-4.05 (m, 2H), 3.79-3.73 (m. 1H) .3.75-3.73 (m, 2H).

3.51-3.8 (m.2H), 3.18-3.13 (m.2H), 3.00-2.95 (m, 2H), 2.84 (s, 3H), 2.63-2.52 (m, 2H), 1.79-1.73 (m , 1H), 1.35-1.30 (m.IK).

.. 1.22-1.16 (. M 1H) , 0.82 (d, J = 6.5 Hz, 3H), 0.76 (. D, J = 5.6 Hz 3H); 1 3 C- (DMSO-de) 125 MHz: 167.45 144.78, 137.61, 134.35.131.67, 128.14, 127.07, 123.02, 120.75.116.47.52.33, 46.46, 46.31.44.50, 42.02, 41.38, 39.84.36.43.25.12.23.34.21.54;

MS [SIMS (+)] m / z 670 (MH ⁺ ). Example 1 4 5

 N— [4-(N * —hydroxyamino) -1 R—Isoptyl-3 (R or S) —phthalimidmethylsuccinyl] azafeniralalanine N ''-(3-pyridylmethyl) amide hydrochloride

 N- (4-Hydroxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) azafuerilalanine N '-(3-pyridylmethyl) amide obtained in Example 9 was used to give a white color. After a solid (46% yield) was obtained, the title compound was obtained as a white solid by further treating with 4 N dioxane hydrochloride.

'HNR (DMS0-d _e ) (5ppm. 500MHz: 10.77 Cbr s. 1H). 10.41 (s. 1H),

8.90 (s.1H). 8.82 (dd.J = 17, 5.4 Hz, 1H), 8.65-8.61 (m, 1H).

8.25 (br s, 1H). 8.04-8.01 (m. 1H), 7.83 (br s, 4H).

7.33-7.24 Cm. 5H). 5.04—4.96 (m. 1H). 4.67 (d, J = 16 Hz, 1H).

4.43 (d, J = 16 Hz, 1H), 4.12-4.01 (m.2H), 3.70-3.67 (m, 1H).

2.65-2.62 (m.1H), 2.55-2.52 (m.1H) .1.75-1.71 (m, 1H).

1.31-1.29 (m.1H), 1.20-1.16 (m, 1H) .0.80 (d.J-6.5 Hz, 3H).

0.74 (d, J = 6.4 Hz. 3H);

¹³ C-NM (DMS0-d _e ), 125 MHz: 170.76. 168.73. 167.39. 157.79, 144.01.

 140.84, 140.67, 140.27. 137.55. 134.39, 131.54, 128.15, 128.05,

 127.07, 126.56, 123.03, 51.31, 44.39, 41.40.40.62, 39.84, 35.89,

 25.11. 23.35. 21. 6;

MS [SIMS (+)] m / z 587 (MH ⁺ ).

Example 1 4 6

 N'-Benzyl-N- [4- (N * '-Hydroxyamino) -1-2R-Isobutyl-l-3 (R or S) -Phthalimidomethylsuccinyl] -N'-Morpholinoacetylhydrazine hydrochloride

Example 9 N'-benzyl-N- (4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) obtained in 8) -N'-morpholino Using acetylhydrazine, a white solid was obtained (yield: 5500), which was further treated with 4N dioxane hydrochloride to obtain the title compound as a white solid.

Ή-NMR (DMS0-d ₅ ) 5ppm, 500MHz, 81V: 10.63 (s, 1H),

7.85-7.76 (m.4H), 7.31-7.13 (m.5H), 4.87-4.80 (m, 1H),

4.65-4.57 (m, 1H) .4.23-4.00 (m.2H), 3.89-3.87 (m, 4H),

 3.54- 3.51 (m, 2H). 3.25-3.19 (m. 4H), 2.83-2.75 (m, 1H).

2.63-2.59 (m, 1H), 1.59-1.54 (m. 1H), 1.39-1.35 (m. 1H),

1.28-1.23 (m, 1H), 0.84-0.79 On, 6H);

¹³ C-NMR (DHSO-de). 125 MHz: 172.73, 172.28, 167.44, 167.17. 135.17, 134.44. 131.58, 128.36, 128.30, 127.69.123.06, 62.94.55.61, 52.11, 51.14, 44.13. . 24.91, 23.60, 21.23;

MS [SIMS (+)] m / z 547 (Mfl ⁺ ).

Example 1 4 7

 Ν '1-benzyl-N'-(4-benzylpiperazino) acetyl-N- [4- (N ''-hydroxyamino)-1R-isobutyl-l3 (R or S) -phthalimid-methylsuccinyl] Hydrazine dihydrochloride

 Example 9 N, —benzyl-N ′-(4-benzylpiperazino) a cetyl-1N— (4-hydroxy-1 2R—isobutyl-3 (R or S) —phthalimidomethyl obtained in 9 A white solid (40% yield) was obtained using succinyl) hydrazine, which was further treated with 4N dioxane hydrochloride to give the title compound as a white solid.

 ^-MR (DMSO-de) 5 ppm, 300MHz, 80: 7.89-7.78 (m, 4H).

 7.55- 7.53 (m. 2fl) .7.42-7.36 (m. 3H). 7.28-7.22 (m. 5H),

4.78-4.60 (m, 2H). 4.17 (s, 2H). 3.94-3.20 (m, 12H),

 2.75-2.69 (m, 1H). 2.60-2.55 (m. 1R), 1.55-1.50 (m. 1H).

1.36-1.30 (m, 1H), 1.20-1.15 (m, 1H), 0.81-0.77 (m. 6H);

^{1 3 C-NMR (MeOH-} d4), 125 MHz:.. 174.90, 171.27 169.48 168.11, 135.51. 133.24, 132.67.131.43, 130.42.129.94, 129.82.129.30, 124.22.61.74, 54.25, 52.12, 50.11, 46.85, 45.87.43.62, 41.34.37.11, 26.46, 23.32.22.17;

MS [SIMS (+)] m / z 669 (MH ⁺ ).

Compounds of Examples 148 to 201 shown in the following table were synthesized in the same manner as in Examples 1 to 147.

table

S ¹ = -CH _z NPht

Table 2

 1 = -CflzNPht

¹ >> 2,3-Diastereomer of Example 137 Table 3

2,3-Diastereomer of Example 170 Table 4

"Example 176, 2,3-Diastereomer

Table 6

Example R ¹ R ^{3 4}

 No.

193-(CH ₂ ) ₃ Ph -CH ₂ Ph ANJ ⁰ -HC1

194-(CH ₂ ) ₃ Ph -CH ₂ Ph

^195- (CH _z ) ₃ Ph -CH ₂ Ph ^〜0-Hci

196-(CH ₂ ) ₃ Ph -CH ₂ Ph

197 -CCH ₂ ) ₃ Ph-CH ₂ Ph -C0CH ₂ NMe ₂ -HCl

198-(CH ₂ ) ₃ Ph -CH ₂ Ph -C0Ca ₂ CH ₂ NH ₂ -HCl

199-(CH ₂ ) ₃ Ph -CH ₂ Ph -C0CH ₂ H ₂ -HC1

200-(CH ₂ ) ₃ Ph -CH ₂ Ph -C0CH ₂ CH ₂ NMe ₂ -HCl

201-(CH ₂ ) ₃ Ph-CH ₂ Ph -CONKCH _z CH ₂ NMe ₂ -HCl The meaning of each symbol in the table is as follows.

CHzNPht: Futarui Mi Domechiru, Ph: phenyl, obtain cyclo - Hex: cyclohexyl Et: Echiru, Me: methyl, Bu ': tert-butyl _{isopropyl, CH 2 Ph - 0H):} .. 4 over hydroxycarboxylic benzyl, 3-Pyr: 3-pyridyl

Example 1 4 8

 N- [4 -— (N * -hydroxyamino) 1-2 R—isobutyl-13 (R or S) phthalimidomethylsuccinyl] azaphenylalanine N '' — 2-morpholinoethylamid hydrochloride

 ^-M (DMSO-de) (5 pm. 500MHz: 10.90 (brs, 1H). 10.25 (s. 1H),

9.95 (br s, 1H). 8.97 (br s, 1H). 7.87-7.83 (m, 4H), 7.64-7.60 (m.1H) .7.33-7.24 (m, 5H) .5.01-4.95 (m, 1H) ), 4.16-4.10 (m. 1H),

4.07-3.97 (m. 3H), 3.76-3.65 (m. 5H), 3.55-3.47 (m. 4H).

3.24-3.18 (m, 2H) .2.65-2.63 (m.1H), 2.49-2.46 (m.1H).

1.72-1.68 (m.1H). 1.29-1.25 (m, 1H), 1.20-1.15 (m, 1H).

0.80 (d, J-6.5 Hz. 3H), 0.74 (d. J = 6.5 Hz, 3H);

^{..... 1 3 C} - Flame (DMSO-de), 125MHz: 172.10, 169.50 168.24 158.29 138.19, 135.14, 132.26, 128.81, 127.76 123.76, 63.98, 56.32 52.13, 51.91, 44.99, 42.17, 40.52, 36.53, 35.47 . 25.77, 24.01, 22.20;

MS [ESI (+)] m / z 609 (1IH +).

Example 1 4 9

 Ν '1-benzyl-1-N'-dicyclohexylaminoaminoacetyl-N- [4- (Ν' '-hydroxyamino) 1 2R-isobutyl-3 (R or S) phthalimidimemethylsuccinyl] hydrazine hydrochloride

^ -NME (MeOH-d ₄ ) 5 ppm. 500MHz: 7.90-7.84 (m. 4H), 7.40-7.32 (m, 5H). 5.16 (d, J-14.0 Hz. 1H). A.63-4.59 ( m, 1H), 4.49 (d.J = 14.0 Hz.1H) .4.31-4.25 (m.2H), 3.88 (d, J = 13.0 Hz, 1H), 3.67-3.60 (m, 2H),

2.76-2.74 (m.1H), 2.59-2.55 (m, 1H), 2.15-1.96 (m, 8H), / JP99 / 00439

1.76-1.45 (πι.15H) .0.94-0.87 (m.6H);

¹³ C-NMR (MeOH—d ₄ ), 125 MHz: 174.68, 171.24. 170.05. 169.28. 136.11, 135.48. 133.31, 129.87.129.82, 129.32.124.21.64.44.53.11, 51.96.

46.07, 43.76, 41.54.37.45.29.24.26.50, 26.10.23.53.22.09.

MS [ESI (+)] m / z 674 (MH +).

Example 15

 4-N '-[N- (4- (Ν' '-hydroxyamino) 1-2R-isobutyl-3 (R or S) phthalimidomethylsuccinyl) azaphenylaralanyl] aminophenoxyacetate

 • H-NMR (DMSO-de) <5ppm, 500MHz: 10.69 (br s. 1H). 10.34 (s, 1H),

9.26 (br s, 1H), 8.88 (s. 1H), 7.88-7.83 (m. 4H), 7.72-7.70 (m. 2H),

7.32-7.26 (m. 5H), 6.85 (d. J = 9.1 Hz. 2H). 5.13-5.09 (m. 1H).

4.73 (s, 2H), 4.17 (q, J = 7.1 Hz. 2H), 4.15—4.08 (m, 2H).

3.79-3.75 (m. 1H) .2.65-2.60 (m, 1H), 2.54-2.50 (m, 1H),

1.80-1.76 (m. Lfl), 1.35-1.30 (m. 1H) .1.24-1.20 (m. 1H),

1.22 (t, J = 7.1 Hz, 3H), 0.82 (d, J = 6.5 Hz. 3H),

0.76 (d. J = 6.2 Hz. 3H).

Example 1 5 1

 4—Ν · —CN- (4- (Ν ''-hydroxyamino) -12R-isobutyl-13 (R or S) phthalimidomethylsuccinyl) azafurinylalanyl] aminofuronoxyacetic acid

 'H-NMR (MSO-de) δ pp. 500MHz: 12.90 (br s. 1H), 10.70 (s. IB), 10.34 (s. 1H), 9.25 (br s, 1H). 8.88 (s. 1H) 7.88-7.83 (in, 4H).

7.72-7.70 (m.2H), 7.34-7.24 (m, 5H), 6.83 (d, J = 9.0 Hz, 2H),

5.14-5.10 (m.1H), 4.63 (s, 2H), 4.16-4.10 (m, 2H), 3.79-3.75 (m, 1H) .2.62-2.60 (m.IB), 2.55-2.53 (m, 1H ), 1.80-1.77 (m. 1H).

1.35-1.32 (m.1H) .1.25-1.23 (m, 1H) .0.82 (d, J = 6.5 Hz.3H), 0.76 (d. J = 5.9 Hz. 3H);

¹³ C-NMR (DMSO-de), 125 MHz: 171.45. 170.31. 169.01, 167.37. 155.19, 152.91, 137.51. 134.24, 133.51. 131.58, 128.06. 128.05, 126.97. 122.94. 41.26.39.74.35.74, 25.04, 23.27.21.42;

 MS [ESI (+)] m / z 646 (MH +).

Example 1 5 2

 N'-Benzyl-N- [4- (Ν ''-Hydroxyamino) -1-2R-isobutyl-3 (R or S) phthalimid-methylsuccinyl] -N '-(2-Methylbenzoyl) hydrazine

^ -NMR (MeOH-d ₄ ) 5ppm. 500MHz: 7.93-7.81 (m, 4H). 7.50-6.84 (m. 9H), 5.69-5.59 (m, IK), 4.65-4.56 (m. 1H), 4.28 (d, J = 14.0 Hz, 1H).

3.87-3.70 (m. 1H), 3.12-3.05 (m. 2H), 2.66-2.61 (m. 1H),

2.48-2.45 (m. 3H), 2.34-2.29 (m. 1H), 2.60-2.54, 2.48-2.42 (m. Each 1H), 1.33-1.25 (m. 1H), 0.99-0.82 (m, 1H), 0.87-0.72. 0.54-0.40 (m, each 6H); ¹³ C-NMR (MeOH-d ₄ ), 125 MHz: 175.54. 174.24, 169.98, 168.81, 137.25.

136.40.135.51.133.09.131.79, 130.57, 129.89, 129.78.129.09, 128.05, 127.63, 126.56.

US [ESI (+)] m / z 571 (MH +).

Example 1 5 3

 N- [4-(Ν'-hydroxyamino) — 2 R-isobutyl- 1 3 (R or S) phthalimid-methylsuccinyl] azaphenylalanine N '' — 4-— (morpholinomethyl) phenylamide hydrochloride

¹ HNR (DMSO-de) 5 pm, 500MHz: 10.76 (s, 1H), 10.69 (br s, 1H).

10.43 (s. 1H). 9.55 (s, 1H), 8.93 (br s, 1H). 7.98-7.95 (m, 2H),

7.87-7.84 (m. 4H), 7.49 (d. J-8.6 Hz, 2H). 7.34—7.25 (m, 5H), 5.08 (d.J = 15.5 Hz, 1H), 4.28 (d.J = 3.8 Hz.2H),

 4.18 (d.J-15.5 Hz. 1H) .4.09-4.04 (m, 1H), 3.96—3.93 (m, 2H),

 3.88-3.71 (m, 3H), 3.26-3.21 (m. 2H). 3.10—3.05 (m. 2H),

 2.63-2.60 (m, 1H), 2.58-2.54 (m, 1H). 1.80-1.76 (m, 1H).

 1.37- 1.33 (m. 1H), 1.27-1.23 (m. 1H), 0.82 (d, J = 6.5 Hz, 3H),

0.78 (d.J = 6.5 Hz, 3H);

¹³ C-NMS (D SO-de), 125 «Hz: 171.59, 169.14, 167.47, 155.10, 141.33.

137.34, 134.38, 131.67.128.17.127.15, 123.00, 122.29, 119.48.63.11, 58.90, 51.23, 50.49.44.53, 41.39, 39.83, 35.69, 25.13, 23.28, 21.59; MS [SIMS (+)] m / z 671 ( (ΪΗ +).

Example 1 5 4

 N- [4- (Ν'-hydroxyamino) 1-2R-isobutyl-13 (R or S) phthalimidomethylsuccinyl] azaphenylalanine N '' — 4_ (2-morpholinoethoxy) phenylamide hydrochloride

'H-NMR (DMS0-d e) 5ppm, 500MHz:.. 10.72 (br s, 1H), 10.37 (. Br s 2H) 9.27 (br s, 1H) 8.86 (s, 1H), 7.88-7.83 (m , 4H). 7.79-7.77 (m. 2H).

7.34-7.26 (m. 5H), 6.93 (d. J = 9.0 Hz. 2H), 5.10-5.07 (m, 1H).

 4.38- 4.36 (m. 2H). 4.20-4.15 (m. 1H). 4.10-4.05 (m, 1H).

3.79-3.74 (m. IE). 3.51-3.39 (m, 4H) .3.07-3.03 Cm, 2H).

2.63-2.61 (m.IB), 2.56-2.54 (m, 1H), 1.80-1.75 (m.5H),

1.42-1.31 (m, 1H), 1.25-1.21 (m, 1H). 0.82 (d. J = 6.5 Hz, 3H),

0.76 (d, J = 6.5 Hz, 3H).

¹³ C-NMR (DMSO-de) .125 MHz: 171.54, 169.06, 167.42.155.25, 152.74, 137.57, 134.32, 133.97, 131.65, 128.10, 127.03.122.98.121.09.114.55, 62.52.54.82, 52.64. 41.38, 39.84.35.77.25.10, 23.31.22.35.21.52;

MS [ESI (-)] m / z 699 (MH-). Example 1 5 5

 N- [4-(Ν'-hydroxyamino) 1 2 R-isobutyl-3 (R or S) fluoromethyl succinyl] -aza [4- (3-dimethylaminopropoxy :)] phenyl Luranine N ''-phenylamide hydrochloride

 -赚 (DMSO-de) ^ ρρπι, 500MHz. 87: 10.46 (br s, 2H), 10.02 (s, 1H), 8.91 (br s, 1H), 7.82-7.80 (m. 4H), 7.74 (d , J = 7.9 Hz, 2H),

7.25-7.21 (m. 4H), 6.97-6.94 (m. 1H). 6.87 (d, J = 7.9 Hz, 2H),

4.85 (d. J = 15.0 Hz, 1H), 4.35 (d. J = 15.0 Hz. 1H). 4.08-4.03 (m, 3H). 3.74-3.72 (m, 1H), 3.19-3.16 (m. 2H) , 2.76 (s, 6H). 2.72-2.70 (m. 1H). 2.60-2.59 (in, 1H). 2.15-2.11 (m. 2H), 1.73-1.68 (m, 1H).

1.45-1.40 (m.1H) .1.34-1.29 (m, 1H) .0.84 (d, J = 3.2 Hz, 3H).

0.83 (d.J = 3.2 Hz, 3H);

¹³ C-NMR (DMS0-d ₆ ), 125 MHz: 171.50. 169.06, 167.38, 157.43, 155.03, 140.01. 134.29, 131.60, 129.53, 128.25, 122.95. .41.36, 39.83.35.68.25.04.23.83, 23.31, 21.57;

 MS [ESI (+)] m / z 673 (MH +).

Example 1 5 6

 N '1 [4-1 (3-Dimethylaminopropoxy) benzyl]-N-[4-(N' '-Hydroxyamino) 1 2 R-Isobutyl-3 (R or S) Phthalimidometyl Succinyl]-N'- Pivaloyl hydrazine hydrochloride

'H-NMR (DMS0-d ₆ ) 5 ppm, 500 MHz. 87 ° C: 10.19 (br s. 1H). 10.14 (s. 1H), 8.30 (br s, 1H). 7.82-7.81 (m. 4H) 7.17 (d. J = 8.7 Hz. 2H).

6.80 (d, J = 8.7 Hz, 2H). 4.86 (d.J-15.0 Hz, 1H),

4.44 (d, J = 15.0 Hz.1H). 3.99-3.96 (m, 2H), 3.90-3.84 (m, 1H),

3.39-3.33 (m, 1H), 3.13 (t.J = 7.8 Hz.2H) .2.76-2.74 (m.1H).

2.74 (s, 6H), 2.69-2.65 (m, 1H). 2.09-2.06 (m. 2H), 1.59-1.5 (m, 2H). 1.27-1.22 (m. 1H). 1.20 (s. 9H). 0.82 (d.J-6.4 Hz. 6H);

¹³ C-NMR (DMSO-ds) .125 MHz, 87: 172.20, 166.60, 156.90, 153.84,

 133.63, 131.26, 128.42, 122.33, 114.02, 64.48, 53.98, 51.59, 41.92.

 39.83, 37.24, 34.90, 27.27, 24.61, 23.49, 22.72.21.12;

 MS [ESI (+)] m / z 638 (MH +).

Example 1 5 7

 N '—Acetyl— N— [4- (Ν' '—Hydroxyamino)-1 2 R-isobutyl — 3 (R or S) phthalimidomethylsuccinyl] — N' —Phenethylhydrazine

'fl-NMR (DMS0-d ₆ ) <5 ppm, 500 MHz. 87: 7.81 (m, 4H), 7.23-7.13 (m, 5H), 4.03 (dd. J = 13.0, 10.0 Hz, 1H). 3.69- 3.64 (m. 2H). 3.57-3.51 (m. 1H). 2.85-2.82 (m, 3H), 2.72-2.67 (m, 1H), 1.94 (s, 3H), 1.68-1.63 (m, 1H). 1.57-1.52 (m. 1H), 1.23-1.18 (m, 1H), 0.93 (d. J = 6.5 Hz. 3H).

0.88 (d.J = 6.5 Hz. 3H);

^1S C_ 赚 (DMS0-d ₆ ), 125MHz. 87: 171.60, 166.64, 138.52. 133.62,

131.31. 127.89, 127.67. 125.47. 47.96. 44.16, 42.11, 39.83, 37.37,

32.62.24.92, 23.04.20.79, 19.87;,

MS [ESI (+)] m / z 509 (MH +).

Example 1 5 8

 N- [4- (Ν ''-hydroxyamino) 1-2 R-isobutyl-3 (R or S) phthalimid-methylsuccinyl] — Ν, 1-morpholinoacetyl — N '— phenethylhydrazine hydrochloride

^ -NM (D «S0-d _e ) (5 pm.500MHz.87 ° C: 10.83 (br s, 1H). 7.81 (m, 4H), 7.27-7.16 (m, 5H), 4.15-3.96 (in , 3H), 3.85-3.74 Cm.5H),

3.65-3.62 (m, 2H), 3.18-3.14 (m, 5H), 2.90-2.87 (m, 2fl),

 2.79-2.75 (m.1H) .1.73-1.68 (m, 1H) .1.63-1.58 (m, 1H).

1.38-1.33 (m. 1H), 0.96 (d.J = 6.5 Hz, 3H), 0.91 (d, J = 6.5 Hz. 3H); MS [ESI (+)] m / z 594 (MH +).

Example 1 5 9

 N— [4— (Ν'—hydroxyamino) — 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl] azahomophenylanilanine N '“—tert-butylamyl

_{Ή-NMR (DMSO- d 6)} <ρρπι (300MHz: 10.53 (s, 1H), 10.47 (s, 1H).

8.72 (s.1H), 7.9-7.8 (m.4H), 7.3-7.1 (m, 5H).

 4.01 (dd, J = 13.4, 10.3 Hz, 1H). 4.0-3.65 (m. 1H). 3.65-3.45 Cm. 1H).

3.4- 3.2 (m. 1H), 2.85-2.55 (m. 4H) .1.85-1.65 (m, 1H), 1.6-1.4 (m, 1H), 1.27 (s. 9H), 1.25-1.1 (m, 1H) ) .0.95 (d, J = 6.5 Hz, 3H),

 0.89 (d. J = 6.5 Hz. 3H);

^{13 C-NMR (DMS0-d} e) 125 MHz:........ 171.61 167.85, 167.24 156.11, 139.22, 134.33 131.56, 128.42 128.29, 125.99, 123.00 49.92 48.01, 44.60, 41.89, 39.99 36.81, 33.64, 28.98, 25.48, 23.68, 21.28;

MS [ESI (+)] m / z 566 (MH +).

Example 16

 N— [4-(Ν'—hydroxyamino) 1 2 R—Isoptyl-3 (R or S) -phthalimidomethylsuccinyl] azahomophenylalananine N '' — benzylamide

lH-NSiR (DMSO- _ds ) δ ppm. 300ΜΗζ: 10.63 (s. 1H), 10.31 (s. 1H).

8.84 (s. 1H). 7.84 (s, 4H), 7.35-7.1 (m. 10H). 4.4—4.2 (m, 2H).

4.03 (dd. J-13.7. 10.3 Hz, 1H), 4.0-3.75 (m. 1H), 3.7-3.5 (m, IE),

3.5- 3.25 (m, IB), 2.8-2.6 (m, 4H), 1.9-1.7 (m, 1H), 1.65-1.45 (m.1H) .1.35-1.15 (m, 1H), 0.95 (d, J = 6.3 Hz. 3H), 0.89 (d. J = 6.3 Hz. 3H); ^{I 3} C-NME (DMSO-ds). 75 MHz: 171.79, 168.42, 167.34, 157.21, 140.40,

139.12, 134.34, 131.62.128.47.128.36, 127.99.127.14.126.33, 126.09, 123.00, 48.48.44.62.43.34.39.97.36.44, 33.61, 25.49, 23.56, 21.44; MS [ESI (+)] m / z 600 (MH +).

Example 16 1

 N- [4-(N * -hydroxyamino) 1 2 R-isobutyl-3 (R or S) 1-phthalimidomethylsuccinyl] azahomophenylanilano cyclohexylamide

■ fl-NMR (DMS0-d ₆ ) (5ppm, 300MHz: 10.57 (s, 1H). 10.22 (s. 1H),

8.77 (s, 1H), 7.9-7.8 (m, 4H). 7.3-7.1 (m. 5H).

4.03 (dd, J = 13.6. 10.4 Hz. 1H). 4.0-3.75 (m, 1H), 3.7-3.55 (m, 1H). 3.4-3.1 (m. 2H), 2.8-2.55 (m. 4H), 1.9-1.6 (m, 5H), 1.6-1.45 Cm. 2H). 1.45-1.1 (m. 6H). 0.97 (d. J = 6.5 Hz. 3H). 0.91 (d, J = 6.5 Hz. 3H); ¹³ C-NMR (DMS0-d ₆ ). 75 MHz: 171.46. 168.46. 167.35. 156.49, 139.23.

134.35, 131.63, 128.46.128.36.126.06, 123.02, 49.10, 48.35.44.75, 41.80.40.15.36.54, 33.66, 32.77.32.66, 25.52.25.19.24.98, 23.63.21.41;

 MS [ESI (+)] m / z 592 (MH +).

Example 1 6 2

 N— [4- (Ν'-hydroxyamino) 1-2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl] azahomophenylanilanamide

Ή-N (DMS0-d ₆ ) <5 ppm. 300MHz: 10.60 (br s, 1H), 10.26 (s, 1H).

8.86 (s, 1H). 7.9-7.8 (m, 4H). 7.3-7.1 (m. 5H). 6.33 (br s, 2H).

4.02 (dd, J = 13.7, 10.1 Hz, 1H). 3.95--3.75 (m, 1H), 3.75--3.6 (m, 1H), 3.-3.15 (m.1H), 2.8-2.55 (m.4H) , 1.85-1.7 (m, 1H), 1.65-1.45 (m, 1H) .1.3-1.15 (m, 1H) .0.97 (d, J = 6.5 Hz, 3H) .0.91 (d.J = 6.5 Hz.3H ..); 1 ³ C- thigh _{(DMS0-d 8) 125MHz:} 171.76, 168.14, 167.37, 158.25 139.15.

134.32. 131.65.128.45, 128.35, 126.06, 122.99, 48.28, 44.60, 41.74, 39.84.36.59, 33.60.25.41.23.57, 21.48;

MS [ESI (+)] m / z 510 (MH +). Example 1 6 3

 N- [4- (Ν'-hydroxyamino) 1-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl] azaphenylalanine N ''-methylamide (Example 13 —Diastereomer)

'Β-note (DMS0-d ₆ ) <ρρπι, 300MHz: 10.68 (br s, 1H), 10.13 (br s, 1H), 9.27 (br s. 1H). 7.91-7.81 (m, 4H). 7.30- 7.21 (m, 5H),

6.44 (apparent d. J = 4.0 Hz. 1H). 4.93 (br d. J = 14.3 Hz. 1H),

4.11 (br d, J = 14.3 Hz. IB). 3.76 (dd. J = 13.5, 9.2 Hz. 1R).

 Two

3.45 (d.J-12.7 Hz, 1H) .2.61 (d.J5 = 3.7 Hz.3H), 2.41 (m.2H).

1.52-1.38 (m, 2H), 1.14-1.11 (m.1H), 0.75 (d, J = 6.3 Hz. 3H).

0.67 (d, J = 6.3 Hz. 3H);

¹³ C-Awake (DMSO-de). 75 MHz: 172.90, 169.21, 168.13, 158.82. 138.82,

135.12, 132.51, 128.78, 128.66, 127.59, 123.85, 51.57, 45.95, 42.26, 38.81, 37.22.27.60.26.03, 24.82.21.72;

MS [SIMS (+)] m / z 510 (MH ⁺ ).

Example 1 6 4

 N- [4-(Ν '-hydroxyamino) 1 2 R-isoptyl-3 (R or S) 1-phthalimid-methylsuccinyl] azachicin Ν "-methylamide

'H-NMR (DMS0-d ₆ ) δ ppa, 300 MHz: 10.57 (br s, 1H). 9.96 (br s, 1H).

9.21 (br s, 1H). 8.77 (br s. 1H). 7.86—7.82 (m. 4H).

7.01 (d. J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.83 (br s, 1H).

3.97 (m, 2H), 3.67 (m. 1H), 2.68 (d, J = 4.3 Hz, 3H), 2.61-2.58 (m. 1H), 2.50-2.47 (m. 1H). 1.67 (m. 1H) 1.30 (m, lfl). 1.12 (m. 1H).

0.81 (d. J = 6.5 Hz, 3B). 0.75 (d, J = 6.5 Hz. 3H);

1 ³ (: -...讀_{(DMS0-d 6), 75MHz} : 171.34, 168.55 167.32 156.39 134.25.

131.61, 129.40.127.96.122.93.114.76.50.31, 44.31.41.43.39.79.

36.21, 26.90.25.05, 23.48, 21.39. Example 1 6 5

 N— [4-(Ν '—hydroxyamino) 1 2 R—isobutyl 1 3 (R or S) phthalimid methyl succinyl] azapheniralanine' '_ 4 — (4-methylbiperazine-1 1-ylmethyl) phenylamino De dihydrochloride

'H-NME (DMS0-d _e ) 5ppm, 500MHz: 11.94 (br s, 1H). 10.77 (s, 1H).

10.47 (s. 1H), 9.53 (s, 1H), 8.96 (br s, 1H), 7.95 (d, J = 7.Hz, 2H), 7.88-7.83 (m. 4H), 7.53 (d, J = 7.4 Hz. 2H), 7.36-7.24 (m, 5H),

5.09 (d. J = 14.5 Hz. 1H). 4.35 (br s, 1H). 4.19-4.07 Cm. 2H),

3.43 (m. 8H). 2.79 (s, 3H), 2.64-2.55 (m, 2H), 1.79 (m, 1H).

1.33-1.24 (m. 2H), 0.82 (d. J = 6.1 Hz. 3H). 0.76 (d. J = 6.1 Hz. 3H); MS [ESI (+)] m / z 684 (MH ⁺ ).

Example 1 6 6

 N- [4-(Ν'-hydroxyamino) 1 2 R-isobutyl 13 (R or S) phthalimid methyl succinyl] azapheniralanine N '' — (2-dimethylamino) ethylamido hydrochloride

lH-NMR (DMS0-d ₆ ) δ ppm, 500 MHz, 87: 7.81 (s, 4H), 7.32-7.20 (m.5H). 4.88 (d. J = 15.0 Hz, 1H). 4.30 (d. J = 15.0 Hz, IB),

4.09 (dd, J = 15.0, 11.0 Hz, 1H), 3.74 (dd.J = 15.0, 3.1 Hz. 1H),

3.61-3.52 (m, 2H). 3.35-3.29 (m. 2H), 2.88 (s, 6H) .2.75-2.70 (m, lfl) .2.55-2.50 (m, 1H) .1.71-1.66 (m. 1H ), 1.38-1.27 (m. 2H),

0.80 (d. J = 6.5 Hz. 3H). 0.78 (d, J = 6.5 Hz. 3H);

1 ³ CN R (DMS0-d ₆ ). 75 MHz: 171.35, 168.98. 167.49. 157.57. 137.49.

134.38, 131.56, 128.06, 128.03.127.00, 123.01, 56.29.51.13, 44.25.

42.70, 42.51. 41.40, 40.00, 35.77, 35.43. 25.03, 23.23. 21.47;

MS [ESI (+)] m / z 567 (MH +).

Example 1 6 7

N- [3S—Hydroxy_4— (Ν'-Hydroxyamino) 1 2R—Isopuchi Rusuccinyl] azapheniralanine N ''-methylamide

lH-NMR (MeOH-d ₄ ) <5ppm. 300MHz: 7.4-4.2 (m. 5H). 5.1-4.9 (m. 1H), 4.45-4.25 (m, 1H), 3.91 (d, J = 8.9 Hz. 1H) .2.73 (s, 3H),

2.65-2.55 Cm, lH), 1.65-1.5 (m.1H) .1.3-1.1 (m.1H) .1.05-0.9 (m.1H), 0.82 (d.J = 6.5 Hz, 3H), 0.71 (d , J = 6.5 Hz. 3H);

1 C-NMR (MeOH-d ₄ ). 75 MHz: 175.17, 170.88. 160.39, 138.16, 129.85,

129.49, 128.63, 73.65. 52.36. 47.57. 37.35. 27.31, 26.95, 24.02. 21.67; MS [SIMS (+)] m / z 367 (MH +).

Example 1 6 8

 N— [4— (Ν'-hydroxyamino) 1 2 R—Isoptyl-3 (R or S) -methylsuccinyl] azafeniralanine N '' — methylamide

'H-NMR (DMS0-d ₆ ) <5 ppin, 300MHz: 10.61 (s, 1H). 9.99 (s. Lfl),

8.85 (s. 1H), 7.35-7.15 (m, 5H), 6.47 (br s, 1H), 5.0-4.5 (m, 1H),

4.5—4.0 (m, 1H), 2.64, (d, J = 4.4 Hz, 3H), 2.5-2.25 (m, 1H),

2.25-2.1 Cm.1H) .1.6-2.45 Cm, 1H), 1.3-1.05 (m.1H), 1.05-0.8 (m, 1H), 0.95 (d.J = 6.0 Hz, 3H) .0.75 (d, J = 6.5 Hz. 3H).

0.67 (d, J = 6.5 Hz. 3H);

¹³ C-NMR (D ¥ S0-d ₆ ), 75MHz: 172.24, 171.43, 158.08. 137.98, 128.15,

127.89.126.97.50.85,43.03.40.16,40.05.27.03.25.26,23.86.21.21.14.73;

 MS [SIMS (+)] m / z 365 (MH +).

Example 1 6 9

 N- [4 — ('— Hydroxyamino) 1 2 R—Isobutyl 13 (R or S) —Methylsuccinyl] azaphenylalanine phenylamide

 Ή-NMR (D SO-de) 5 ppm, 300MHz: 10.75 (s. 1H), 10.20 (s, 1H).

9.12 (br s. 1H). 8.93 (s. 1H) .7.8-7.65 (m, 2H). 7. -7.2 (m, 7H).

6.97 (t.J = 7.3 Hz, 1H) .5.25-4.9 (m.1H), 4.3-3.95 (m.1H) .- 2.55-2.4 (m. 1H), 2.35—2.2 (m, 1H), 1.7—1.55 (m. 1H), 1.35-1.15 (m. 1H). 1.03 (br d, J-4.5 Hz. 3H). 1.0 -0.85 (m. 1H). 0.78 (d, J = 6.5 Hz, 3H). 0.73 (br d. J = 6.5 Hz, 3H);

¹³ C-NMR (DMSO-de). 75 MHz: 171.90. 155.15, 139.90, 137.54, 128.55,

128.25, 128.12, 127.18, 122.15, 118.97, 51.00, 42.31, 40.13, 39.91, 25.34, 23.74, 21.38, 13.42;

MS [SIMS (+)] m / z 427 (MH +).

Example 1 7 0

 N-C4-(Ν '-hydroxyamino) 1 2 R-isobutyl 13 (; or S) -methylsuccinyl] azahomophenylalanine N' '-methylamide

 'H-NMR (DMSO-de) <5 pm. 300MHz: 10.65 (s. 1H), 10.10 (s, 1H).

8.90 (s. 1H). 7.35-7.05 (m, 5H), 6.42 (br s, 1H), 3.85-3.6 (m. 1H),

3.4- 3.2 (m, 1H) .2.8-2.6 (m, 2H) .2.6-2.45 (m.1H),

 2.59 (d.J = 4.5 Hz.3H) .2.3--2.2 (m, 1H), 2.3-2.15 (m.1H),

1.7-1.5 (m, 1H). 1.5—1.35 (m. 1H), 1.04 (d, J = 6.9 Hz, 3H).

1.05—0.95 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H). 0.86 (d, J = 6.5 Hz, 3H); ¹³ C-thigh (DMSO-de). 75 MHz: 172.40, 171.41, 157.68 . 139.09. 128.43.

128.39, 126.10, 48.63. 43.25, 40.20, 40.12, 33.55, 26.89. 25.56, 23.82, 21.38, 14.76;

 MS [ESI (-)] m / z 377 (H-)

Example 1 7 1

 N- [4- (N'-hydroxyamino) 1-2R-isobutyl-13 (R or S) -methylsuccinyl] azahomophenylalanine N ''-methylamide (Example 3, 180,2,3-diastereomer )

^ -NMR (DMS0-d ₆ ) d pm. 300 MHz: 10.72 (s, 1H), 10.23 (s, 1H),

8.86 (s. 1H). 7.35-7.05. (M. 5H). 6.24 (br d. J = 4.4 Hz, 1H),

3.95-3.7 (m. 1H), 3.25-3.0 (m, 1H) .2.75-2.6 (m. 2H), 2.58 (d. J-4.4 Hz. 3H). 2.5-2.35 (m. 1H), 2.3-2.15 (m. 1H),

1.6—1.4 (m. 2H), 1.35—1.2 (m, 1H), 1.11 (d, J = 6.9 Hz. 3H).

 0.99 (d, J = 6.4 Hz. 3H). 0.90 (d, J = 6.4 Hz. 3H);

¹³ C-NMR (DMSO-de), 75 MHz: 173.24, 172.23. 157.63. 139.19. 128.42.

 128.40, 126.07. 48.50, 44.55, 40.09. 39.26, 33.60. 26.74, 25.77. 24.05,

21.23, 17.00;

 MS [ESI (-)] m / z 377 (M-H-).

Example 1 7 2

 N— [4- (Ν'-hydroxyamino) 1-2 R-isobutyl-13 (R or S) -methylsuccinyl] azahomophenylanilanine N ''-phenylamide

 'H-NMR (DMSO-de) 5 ppm. 300ίίΗζ: 10.81 (br s. 1H). 10.32 (s, 1H),

9.00 (s, 1H), 7.75-7.5 (m. 2H). 7.35-7.1 (m. 7H).

6.95 (t, J = 7. Hz, 1H), 4.1-3.8 (m, 1H), 3.4-3.15 Cm. 1H).

2.9-2.65 (m, 2H), 2.65-2.5 (m.1H), 2.35-2.2 (m.1H), 1.8-1.6 (m, 1H) .1.6-1.4 (m.1H), 1.1-0.95 (m , 1H), 1.09 (d, J = 7.0 Hz. 3H),

0.97 (d, J = 6.5 Hz. 3H). 0.89 (d. J = 6.5 Hz. 3H);

l ³ C-NMR (DMSO-de). 75 MHz: 172.18. 171.88, 154.79, 139.95, 138.99,

128.47.126.20, 121.96, 118.87, 48.51, 42.60, 40.33, 40.00, 33.36,

25.68, 23.69. 21.48, 13.51;

MS [ESI (-)] m / z 439 (-H-).

Example 1 Ί 3

 N— [4— (Ν'—hydroxyamino) 1 2 R—Isoptyl-3 (R or S) methylsuccinyl] azahomophenylalanine N ″ — 4— (4-Methylbiperazine—1-ylmethyl) phenylamide 2HCl salt

-NMR (D S0-d _e ) 5 ppra. 500MHz. 87 ° C: 10.65 (br s. 1H), 10.19 (s, 1H). 8.97 (br s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz. 2H), 7.30-7.15 (m, 5H), 4.11 (s, 2H), 3.87 (m, 1H), 3.27 Cm. 8H), 2.75 (s.3H), 1.76-1.66 (m.1H), 1.57-1.48 (m, 1H),

 1.09 (d. J = 7.0 Hz, 3H). 0.95 (d. J-6.6 Hz. 3H), 0.88 (m, 3H);

¹³ C-NMR (DMSO-ds), 125 MHz: 155.41, 139.60, 132.00, 129.10, 126.84,

126.08, 119.30, 66.99, 40.41, 40.13, 33.94, 26.33.24.28, 22.16;

MS [ESI (+)] m / z 553 (MH ⁺ ).

Example 1 7 4

 N- [3 (R or S) -aryl-1 41- (Ν'-hydroxyamino) 1-2R-isobutylsuccinyl] azapheniralanine N ''-methylamide

'Η-ΝΜΕ (D S0-d _e ) (5ppm. 300MHz ： 10.61 (s. 1H). 10.00 (s. 1H),

8.87 (br s.IB), 7.35-7.15 (m.5H) .6.55 (br s.1H). 5.65-5.45 (m, 1H) .5.0-4.8 (m, 2H) .4.9-4.6 (m.1H) ), 4.4-4.1 (m. 1H),

2.64 (d.J = 3.7 Hz, 3H), 2.45—2.3 (m.IB). 2.25—1.95 (m, 3H),

 1.6- 1.45 (m, 1H), 1.3-1.1 (m, IB), 1.0-0.85 (m, 1H).

0.76 (d. J = 6.5 Hz, 3H). 0.67 (d, J = 6.5 Hz, 3H);

l ³ C_Awake (DMS0-d _e ). 75 MHz: 171.98, 169.59, 158.01, 137.91. 135.98, 128.11.127.87, 126.95, 116.34.50.81, 45.79, 42.76, 39.97, 32.75.

26.99, 25.23, 23.83, 21.16;

KS [ESI (-)] m / z 389 («-Η-).

Example 1 7 5

 N- [3 (R or S) —aryl-1 4— (Ν'-hydroxyamino) 1-2R isobutylsuccinyl] azahomophenylalanine N '' — methylamide

¹ H-NM (DMSO-de) 5 ppm. 300 MHz: 10.67 (s, 1H), 10.12 (s. 1H).

8.94 (s, 1H), 7.3-7.1 (m.5H) .6.50 (br s.1H), 5.7-5.5 (m.1H),

5.0-4.85 (m, 2H) .3.85-3.6 (m.1H), 4.4-4.2 (m, 1H), 2.8-2.65 (m, 2H) .2.60 (d, J = 3.7 Hz, 3H) .2.6- 2.45 (m, 1H), 2.4-2.1 (m. 3H),

 1.7—1.55 (m, 1H), 1.55-1.4 (m, 1H). 1.1-1.0 (m. 1H).

0.93 (d, J = 6.5 Hz. 3H), 0.87 (d, J = 6.5 Hz. 3H); ¹³ C-NMR (DMSO-de). 75 MHz: 172.19, 169.60, 157.66, 139.07. 135.99,

128.44. 128.41, 126.13, 116.40, 48.68. 45.90. 43.04, 40.10, 33.56,

32.81, 26.89, 25.56, 23.83, 21.35;

MS [ESI (-)] m / z 403 (M-H-).

Example 1 7 6

 N- [4- (Ν'-hydroxyamino) 1-2 R-isobutyl-13 (R or S)-(3,4,4-trimethyl-2,5-dioxo-1-1-imidazolidinyl) methylsuccinyl] azafufenylalanine N '' —Methylamide

 Ή-NMR (DMSO-ds) ^ ppm. 3001ίΗζ: 10.62 (br s. 1H), 10.03 (s, 1H),

8.86 (s, 1H), 7.30-7.21 (m, 5H) .7.23-7.05 (m.1H). 4.96-4.87 (m.1H). 4.20-4.10 (m.1H). 3.80-3.73 (m, 1H 3.26-3.21 (m.1H). 2.76 (s.3H). 2.66 (d.J = 4.5 Hz, 3H), 2.58—2.55 (m.1H). 2.43—2.40 (m, 1H),

1.63-1.57 (in.1H), 1.27-1.24 (m.1H) .1.25 (s.6H), 1.06-1.00 (m, 1H) .0.75 (d, J = 6.6 Hz, 3fl), 0.68 (d, J = 6.6 Hz, 3H);

^{1 3 C-NMR (DMSO-} de), 75MHz:. 175.94, 171.38, 168.37 158.15, 154.14,

137.97, 128.02, 127.96.126.86.60.41, 50.97.43.75, 41.41.39.75,

36.81.26.94.25.01.24.16.23.47, 21.44.21.40, 21.32;

US [ESI (-)] m / z 503 (MH-).

Example 1 Ί 7

 N— [4— (Ν'—hydroxyamino) 1 2 R—isobutyl 1 3 (R or S) 1 (3,4,4—trimethyl-2,5-dioxo-1 1—imidazolidinyl) methylsuccinyl] azazirylalanine N ''-Methylamide (Example 1, 76-2,3-Diastereomer)

^! H-NMR (DMSO-de) δ ppm, 300MHz. 80: 10.49 (br s. 1H), 9.76 (s, 1H), 8.50 (br s, 1H). 7.3-7.1 (m. 5H), 6.29 ( br d, J = 4.4 Hz.1H).

4.82 (d. J = 15.2 Hz. 1H), 4.24 (d. J = 15.2 Hz. 1H),

3.62 (dd.J = 13.7, 8.8 Hz.1H), 3.5-3.35 (m, 1H), 2.77 (s, 3K), 2.64 (d, J = 4.4 Hz. 3H). 2.6-2.5 (m. 1H). 2.45-2.3 (m, 1H).

 1.65-1.4 (m. 1H) .1.45-1.1 (m. 2H), 1.27 (s. 6H),

 0.74 (d. J = 6.4 Hz, 3H), 0.70 (d, J = 6.4 Hz, 3H);

¹³ C-NMR (D SO-ds). 75 MHz: 175.85, 171.97, 168.32. 158.01. 154.10.

 138.01, 128.00, 127.90, 126.81, 60.62, 50.74, 44.61, 41.70. 39.41.

 38.73, 26.84.25.24, 24.21, 23.94, 21.45, 21.42, 20.91;

 MS [ESI (+)] m / z 505 (MH +).

Example 1 7 8

 N— [4-(Ν '—hydroxyamino) — 2 R—isobutyl-13 (R or S) 1- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) methylsuccinyl] azahomo Phenylalanine N ''-methylamide

 Ή-ΝΜβ (DMSO-ds) <5ppm, 300MHz: 10.69 (s, 1H). 10.17 (s, 1H),

8.95 (br s. 1H) .7.3-7.05 (m, 5fl), 7.00 (br s, 1H), 3.85-3.7 (m. 1H). 3.83 (dd, J = 13.5. 10.8 Hz. 1H). 3.5- 3.15 (m, 2H), 2.8-2.55 (m, 4H), 2.77 (s, 3H), 2.62 (d, J = 3.6 Hz, 3H), 1.8-1.65 (m, 1H),

1.6-1.4 (m. 1H), 1.27 (s, 6H), 1.3-1.1 (m. 1H).

0.94 (d. J = 6.5 Hz. 3H), 0.88 (d, J = 6.5 Hz. 3H);

l ³ C-NMR (DMS0-d ₆ ), 75 MHz: 176.00, 171.58, 168.31, 157.81. 154.17.

139.15, 128. 4. 128.38, 126.09. 60.46, 48.65, 43.85, 41.70. 39.86.

36.88. 33.59, 26.86. 25.45. 24.20, 23.52, 21.48;

MS [ESI (-)] m / z 517 (-H-).

Example 1 7 9

 N— [4— (Ν′—hydroxyamino) 1 2 R—isobutyl 13 (R or S) 1 (3,4,4-trimethyl-2,5-dioxo-1 1-imidazolidinyl) methylsuccinyl] azazirylalanine N '' — phenylamide

 'H-MR (DMSO-ds) 5 ppm, 300MHz: 10.72 (s. 1H). 10.32 (s, 1H).

9.23 (br s, IB), 8.94 (s, 1H) .7.9-7.7 (m. 2H), 7.35-7.15 (m. 7H). 6.97 (t, J = 7.4 Hz, 1H), 5.09 (d.J = 14.6 Hz. 1H).

 4.14 (d, J = 14.6 Hz. 1H). 4.0-3.8 (m. 1H), 3.6-3.4 (m, 1H).

 2.78 (s.3H) .2.65-2.45 (m.2H), 1.75-1.6 (m, 1H), 1.4-1.05 (m, 2H).

1.28 (s, 6H), 0.79 (d, J = 6.5 Hz. 3H). 0.73 (d, J = 6.5 Hz. 3H);

¹³ C-NMR (DMS0-d ₆ ), 75 MHz: 176.07, 171.57. 169.00, 155.11, 154.19,

139.93.137.48, 128.32, 128.14, 127.09.122.04, 119.58.60.48.51.01,

43.95, 41.36, 39.82, 36.32, 25.08, 24.21, 23.38.21.52.21.46;

 MS [ESI (-)] m / z 565 (M-Η-)

Example 1 8 0

 Ν · —benzyl-N— [4 -— (Ν '' —hydroxyamino) -1 2 R—isobutyl — 3 (R or S) — (3,4,4-trimethyl-2,5-dioxo-1 1-imidazolidinyl) Methylsuccinyl] — N '— Bivaloylhydrazine

^ -NMR (DMS0-d _e ) (5 ppm.300Mflz, 60: 10.37 (s.1H). 10.31 (s.1H) .8.51 (br s.1H) .7.3-7.1 (m.5H), 5.15 -4.9 (m, 1H), 4.5-4.25 (m.1H), 3.59 (dd.J = 13.0, 10,2 Hz, 1H) .3.2-3.0 (m.1H), 2.76 (s, 3H).

2.7-2.55 (m, 2H), 1.6-1. (M. 2H), 1.25 (s. 6H), 1.20 (s, 9H),

1.15-1.0 (m, 1H). 0.79 (d. J = 6.6 Hz, 3H). 0.76 (d, J = 6.6 Hz, 3H); ¹³ C-NMR (DMSO-d ₆ ), 125 MHz: 177.74, 175.65, 172.54.166.88, 153.88.

137.14.128.13.127.11, 126.85.60.38, 51.33, 44.26, 41.62.39.27.

38.34.38.02.27.60, 25.02.24.18, 23.72.21.3, 21.39, 21.16;

MS [ESI (-)] m / z 530 (-H-).

Example 18 1

 N—Benzyru N ′ — [4-(Ν ′ '—Hydroxyamino) -1 2 R—isobutyl-3 (R or S)-(3,4,4-trimethyl-2,5-dioxo-1 1-imidazolidinyl ) Methyl succinyl] mono-phenylacetylhydrazine

• H-NMR (DMS0-d _e ) 5 pm. 300MHz, 80 ° C: 10.51 (br s. 1H),

10.28 (br s, 1H), 8.42 (br s. 1H), 7.3-7.15 (m, 10H), 4.9-4.5 (m, 2E). 3.76 (s, 1H), 3.75-3.55 (m.1H) .3.15-3.0 (m, 1H), 2.75 (s, 3H).

 2.75-2.6 (m. 1H), 2.6-2.5 (m. 1H), 1.6-1.45 (m. 1H), 1.45-1.3 (m, lfl),

1.25 (s, 6H), 1.15-1.0 (m, 1H), 0.77 (d, J-6.4 Hz.3H),

 0.75 (d, J = 6.4 Hz. 3H);

¹³ C-NMR (DMS0-d ₆ ), 75 MHz: 176.59, 172.96, 167.76. 154.81, 137.57.

136.21, 130.46, 129.22, 129.06, 128.84, 128.19, 127.39, 61.34.50.94.44.91.42.87.40.26, 38.93.38.46, 26.41, 25.16.24.94, 22.38.21.73; US [ESI (+)] ffl / z 566 ( MH +).

Example 1 8 2

 N- [4- (Ν'-hydroxyamino) -12 R-isobutyl-13 (R or S) 1-1 (3,4,4-trimethyl-1,2,5-dioxo-1-imidazolidinyl) methylsuccinyl] azafazi Lulanin N '' -isopropylamide

Ή-NMR (DMS0-d ₆ ) 5 ppm. 300MHz, 80: 10.35 (br s, 1H), 9.77 (s, 1H), 8.39 (br s. 1H), 7.3-7.1 (m. 5H), 6.30 ( br s, 1H),

 4.79 (d.J = 15.4 Hz, 1H), 4.35 (d, J = 15.4 Hz, 1H), 3.85-3.65 (m, 2H).

3.4-3.25 (m. 1H). 2.76 (s, 3H), 2.65—2.5 (m. 1H), 2.5-2.35 (m. 1H).

 1.65-1.5 Cm. 1H), 1.4-1.25 (m. 1H). 1.30 (s. 6H). 1.15-1.0 (m. 1H),

1.11 (d, J = 6.6 Hz. 3H), 1.10 (d. J = 6.6 Hz. 3H),

 0.76 (d. J = 6.6 Hz. 3H). 0.73 (d, J = 6.6 Hz, 3H);

^{13 C-NMR (DMS0-d} e) 75MHz:... 175.90, 171.32 167.99 156.82, 154.10,

 138.06, 128.07.127.93.126.87.60.1, 50.69.44.01, 41.86, 41.41.

 39.92, 36.96, 25.08.24.19, 23.63.22.70.21.46, 21.43.21.21;

 US [ESI (+)] m / z 533 (MH +).

Example 1 8 3

N- [4-(Ν '—hydroxyamino) 1 2 R-isobutyl-3 (R or S)-(3,4,4-trimethyl-2,5-dioxo- 11-midazolidinyl) methylsuccinyl] azazirylalanine N '' — 2,6-Dimethylphenylamide ^ -NME (DMSO-ds) δρριη. 300MHz. 80: 10.39 (br s. 1H). 10.06 (s, 1H). 8.53 (br s, H). 8.24 (br s. 1H). 7.3-7.15 (m .5H), 7.00 (s, 3H).

4.98 (d. J-15.3 Hz. 1H), 4.31 (d, J = 15.3 Hz, 1H),

3.87 (dd, J = 13.6, 9.9 Hz, 1H), 2.73 (s, 3H), 2.65-2.45 (m.2H),

2.23 (s, 6H), 1.75-1.6 (m, 1H), 1.5-1.3 (m, 1H), 1.3-1.1 (m, 1H),

 1.23 (s, 3H) .1.22 (s, 3H) .0.78 (d, J-6.5 Hz, 3H),

0.75 (d. J = 6.5 Hz. 3H);

¹³ C-encom (DMSO-de). 75 MHz: 175.85. 171.77. 168.73. 155.90, 154.18.

138.01. 136.52. 136.14. 128.15. 127.82, 127.39. 126.96. 125.89. 60.43. 51.17. 44.07.

 MS [ESI (+)] m / z 595 (MH +).

Example 18

 N- [4-(Ν '-hydroxyamino) 1 2 R-isobutyl 1 3 (R or S)-(3,4,4 -trimethyl-1,2,5-dioxo 1 -imidazolidinyl) methylsuccinyl] azafufenilalanine N '' —4_ (4-Methylbiperazine-1-ylmethyl) phenylamide dihydrochloride

 ^ -N (DMSO-de) ppm, 500MHz, 87: 10.63 (br s, 1H), 10.21 (s, lfl),

9.24 (br s, 1H), 7.84 (d.J = 8.3 Hz, 2H), 7.46 (d.J = 8.3 Hz.2H), 7.30-7.20 (m.5H), 4.98 (d.J = 15.2 Hz. 1H). 4.30 (d. J = 15.2 Hz, 10), 4.18 (s. 2H). 3.85 (dd. J = 13.8. 3.5 Hz. 1H). 3.48-3.41 (m. 8H).

2.78 (s, 3H), 2.77 (s. 3H), 1.66 (m, 1H), 1.28 (s, 6H).

 0.78 (d, J = 6.8 Hz, 3H). 0.76 (m. 3H);

¹³ C-NM (DMS0-d ₆ ), 125 MHz: 175.48, 170.90.157.17.154.45.153.58, 136.72, 127.54, 126.53.124.83, 118.91.59.89.50.00.43.36, 40.13, 24.47, 22.74, 20.96.

MS [ESI (+)] m / z 679 (MH ⁺ ). Example 1 8 5

 N— [4— (Ν′—hydroxyamino) -1 2 R—isobutyl — 3 (R or S) 1- (3,4,4-trimethyl-2,5-dioxo-1 1-imidazolidinyl) methylsuccinyl] azafudinylalanine Ν '· —1, 1—Dimethyl 2-Hydroxy Shetylamide

lH-NMR (DMS0-d ₆ ) <5 ppm, 500 MHz, 87: 7.26-7.16 (m.5H), 5.96 (s, 1H), 4.69 (d.J = 15.0 Hz.1H), 4.45 (d, J = 15.0 Hz, 1H),

3.66 (dd, J = 14, 0, 10.0 Hz. 1H), 3.42 (d, J = 11.0 Hz. 1H).

3.36 (d, J-11.0 Hz, 1H), 3.29-3.27 (m, 1H), 2.76 (s, 3H),

2.66-2.60 (ID. LH). 2.48-2.43 (m. 1H), 1.56-1.51 (m. 1H),

1.35-1.30 Cm. 1H). 1.26 (s. 6H). 1.23 (s. 3H). 1.22 (s, 3H).

1.13-1.08 (m. 1H). 0.76 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 6.6 Hz. 3H); ¹³ C-NMR (DMS0-d ₆ ). 125 MHz: 175.78, 171.62, 156.74. 154.02. 137.99, 127.95, 127.83, 126.82, 68.58, 60.35, 53.88, 50.08, 43.88. 41.67, 40.00, 37.1, 27.05.

MS [ESI (+)] m / z 563 (MH +).

Example 1 8 6

 N- [4-(Ν ''-hydroxyamino) 1 2 R-isobutyl-3 (R or S) 1 (3,4,4-trimethyl-1,2,5-dioxo-11-imidazolidinyl) methylsuccinyl] — N '— (4-Hydroxybenzyl) -N' —Bivaloylhydrazine

^ -NMR (DMS0-d _e ) 5 pm. 300 MHz. 70 ^: 10.32 (br s. 1H), 10.16 (s. 1H). 8.97 (s, 1H). 8.44 (br s, 1H), 6.98 (d , J = 8.4 Hz.2H), 6.64 (d.J = 8.4 Hz.2H), 5.05-4.75 (m, 1H), 4.35-4.15 (m, 1H), 3.8-3.55 (m.2H), 3.15-3.05 (m. 1H), 2.76 (s, 3H), 2.7-2.55 (m. 1H), 1.6-1.4 (m. 2H).

1.26 (s. 6H). 1.19 (s, 9H), 1.15-1.0 (m, 1H). 0.79 (d. J = 6.0 Hz, 3H). 0.77 (d. J = 6.0 Hz, 3H); MS [ESI (+)] m / z 548 (MH +).

Example 1 8 7

 N- [4- (Ν'-hydroxyamino) 1 2 R-isobutyl 13 (R or S) 1- (3-phenylpropyl) succinyl] azahomophenylanilanine N ''-methylamide

'H-NMR (DMS0-d _e ) 5 pm, 300MHz: 10.67 (s, 1H), 10.08 (s, 1H),

8.92 (s.IB), 7.30-7.13 (m, 10H), 6.0-6.30 (m.1H) .3.74-3.67 (m, 1H).

3.28-3.23 (in, 1H), 2.72-2.68 (m.2H), 2.58 (d, J = 4.5 Hz.3H).

2.58-2.56 (m, 1H), 2.55-2.51 (m. Lfl). 2.47-2.42 (m. 1H).

 2.17-2.13 On, lfl), 1.62-1.57 (m.2H) .1.47-1.36 (m, 4H),

 1.03—0.96 (m. 1H). 0.91 (d. J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H);

¹³ C-NMR (DliSO-de), 75 MHz: 172.40, 170.12, 157.63, 141.96, 139.09,

 128.41, 128.35.128.18, 128.16, 126.08, 125.62, 48.52.46.04.43.23,

40.20, 35.02, 33.48, 29.27, 28.18, 26.84. 25.51, 23.81, 21.31;

 MS [ESI (-)] m / z 481 (MH-).

Example 1 8 8

 N— [4- (Ν'-hydroxyamino) 1 2 R—isobutyl 13 (R or S) — (3-phenylpropyl) succinyl] azaphenylalanine N '' — methyl amide

 Ή-ΝΜΒ (D S0-de) <5 pm, 300MHz. 60: 10.48 (s, 1H), 9.82 (s. 1H), 8.65 (s. 1H). 7.35-7.1 (m. 10H), 6.17 (br s, 1H),

 4.70 (d, J = 15.0 Hz, 1H) .4.41 (d.J = 15.0 Hz, 1H),

 2.64 (d, J = 4.2 Hz.3H) .2.6-2.3 (m, 3H), 2.2-2.05 (m.1H),

1.6-1.2 (m, 6H), 1.0-0.85 (m, 1H), 0.76 (d. J-6.5 Hz, 3H),

0.70 (d.J = 6.5 Hz, 3H);

_{^{13 C-NME (DMSO- d 6}} ) 75Hflz:... 172.22 170.04, 157.93, 142.02 137.95.

128.21, 128.12, 127.77.126.92, 125.64.50.66.45.94.42.96.40.10, 34.94, 29.28.28.06, 26.98, 25.23, 23.87.21.11;

MS [ESI (-)] m / z 467 (M-fl-).

Example 18 9

 Ν '1-benzyl-N- [4- (N', 1-hydroxyamino)-1 2 R-isobutyl- 3 (R or S)-(3-phenylpropyl) succinyl]-N'-Vivaloy-l-hydrazine

'H-NMR (DMS0-d ₆ ) 5p m, 500ΪΗζ. 87: 10.25 (br s, 1H), 10.10 (s. 1H), 8.39 (br s. 1H), 7.29-7.07 (m. 10H), 4.79 (d. J = 15.0 Hz. 1H).

4.39 (d, J = 15.0 Hz, 1H) .2.54-2.50 (m, 2H), 2.40-2.35 (m.1H).

2.28-2.20 (m.1H) .1.49-1.42 (m.5H) .1.34-1.29 (m.1H), 1.19 (s.9H) .1.11-1.05 (m, lfl), 0.78 (d.J = 6.5 Hz, 3H), 0.75 (d, J = 6.5 Hz, 3H); MS [ESI (+)] m / z 496 (ΪΗ +).

Example 19

 N- [4 -— (N, -hydroxyamino) 1-2R—isobutyl —3 (R or S) -1- (3-phenylpropyl) succinyl] azaphenylalanine N '' — phenylamide

'H-NMR (DMS0-d e) 5 pm 300MHz:.... 10.73 (br s, 1H) 10.18 (br s, 1H) 9.14 (br s, 1H) 8.92 (s, 1H), 7.66 (br s , 2H), 7.34-6.96 (m, 13H), 5.15-5.06 (m, 1H) .4.16-4.07 (m.1H). 2.48-2.45 (m.2H),

2.39-2.35 (m. 1H). 2.15-2.12 (m. 1H), 1.64-1.21 (m, 6H),

0.95-0.90 (m. 1H). 0.78-0.71 (m, 6H);

MS [ESI (+)] m / z 531 (H +).

Example 19 1

 N- [4- (Ν ''-Hydroxyamino) 1 2 R—Isobutyl 1 3 (R or S) 1 (3-Phenylpropyl) succinyl] — N ′ —Morpholinacetyl N ′ — Phenetyl hydrazine hydrochloride

Ή-ΝΜΕ (DMS0-d _e ) 5ppm. 500MHz, 87te: 10.69 (s. 1H), 10.33 (br s, 1H). 7.29-7.10 (m, 10H). 3.95-3.88 (m, 2H). 3.83-3.81 (m. 4H).

 3.69-3.64 (m, 2H). 3.15-3.08 (m, 4H). 2.84 (t, J-9.0 Hz, 2H).

 2.65-2.50 (m. 3H). 2.36-2.28 (m. 1H), 1.72-1.0 (m, 6H),

 1.18-1.13 (m. 1H) .0.92 (d.J = 6.5 Hz.3H), 0.87 (d, J = 6.5 Hz, 3H);

MS [ESI (+)] m / z 553 (MH +).

Example 1 9 2

 N— [4- (Ν'-Hydroxyamino) 1-2R-isobutyl-13 (R or S) -1- (3-phenylpropyl) succinyl] azaphenylalanine N '' — (3-pyridylmethyl) amide Hydrochloride

Ή-NMR (DMS0-d _e ) δρρπι. 300MHz. 70: 10.59 (br s, 1Η), 10.06 (s, 1H), 8.75 (s, 1H). 8.70 (d, J = 5.5 Hz. 1H). 8.35 (d. J = 7.9 Hz. 1H),

7.85 (dd.J = 7.9.5.5 Hz.1H) .7.3 (br s, 1H), 7.35-7.15 (m.7H), 7.15-7.0 (m, 3H) .4.77 (d.J = 15.3 Hz .1H) .4.55-4.35 (m, 2H),

4.37 (d.J = 15.3 Hz, 1H), 2.55-2.3 (m. 3H). 2.25-2.1 (m. 1H).

1.6-1.1 (m. 6H). 1.0-0.9 (m, 1H). 0.73 (d, J = 6.5 Hz, 3H),

0.70 (d, J = 6.5 Hz, 3H);

¹ C-NM (DKS0-d _e ), 125 MHz: 172.19, 170.40.157.70, 143.30, 141.95.

140.86, 140.65, 140.16, 137.55.128.11.127.82, 126.97, 126.35, 125.56, 51.14, 45.93, 42.75.40.58, 39.90.34.81.29.24.27.00.25.18.23.65.21.26;

 MS [ESI (+)] m / z 546 (MH +).

Example 1 9 3

 N— [4— (Ν'—hydroxyamino) 1 2 R—Isoptyl-3 (R or S) — (3—phenylpropyl) succinyl] azafunerilalanine N '' — 2—morpholinoethyla Mid hydrochloride

^ -NMR (DMSO-de) δ ppm. 300MHz. 70: 10.72 (brs, 2H), 9.90 (s, 1H), 7.3-7.15 (m, 7H), 7.15-7.05 (m. 3H), 7.02 ( br s, 1H), 4.75 (d, J = 15.5 Hz, 1H), 4.37 (d. J = 15.5 Hz, 1H). 4.0—3.75 (m. 4H). 3.6-3.0 (m. 8H). 2.6-2.35 (m, 3H) , 2.25-2.15 (m.1H), 1.7-1.1 (m.6H), 1.05-0.9 Cm, 1H), 0.75 (d.J = 6.5 Hz.3H), 0.70 (d, J = 6.5 Hz, 3H) ; ¹³ C-NMR (DMSO-de). 75 MHz: 171.81, 170.55. 157. 3. 142.09. 137.52,

128.22, 128.09, 127.85, 126.98, 125.65, 63.16, 55.55. 51.30, 51.14.

50.98. 45.82, 42.84, 39.92, 34.88, 34.72. 29.47, 25.16, 23.70, 21.35; MS [ESI (+)] m / z 568 (MH +).

Example 1 9 4

 N— [4-(Ν'—hydroxyamino) 1 2 R—Isoptyl-3 (R or S) 1 (3-phenylpropyl) succinyl] azaphenylalanine Ν '· —4 1 (4-methylbiperazine-1 1-ylmethyl) phenylami De dihydrochloride

 ^ -NMR (DMSO-ds) <5 pm. 300 MHz. 87: 10.60 (br s, 1H), 10.08 (s, 1H). 9.04 (s, 1H). 7.70 (d. J = 8.4 Hz. 2H) 7.46 (d, J = 8.4 Hz, 2H),

7.29-7.08 (m, 10H), 4.88 (d, J = 15.2 Hz, 1H),

4.30 (d, J = 15.2 Hz. 1H), 4.13 (s. 2H), 3.56-3.36 (m, 8H),

2.75 (s, 3H). 2.41 (m. 1H), 2.21 (m. 1H). 1.64—1.36 (m. 5H).

1.27-1.24 (m, 1H), 1.04-0.95 (m, 1H). 0.77 (d. J = 6.6 Hz. 3H).

0.74 (d, J = 6.6 Hz, 3H);

¹³ C-NMR (SO-de). 75 MHz: 171.68, 170.80, 155.04. 141.96, 137.35,

131.64, 128.19, 128.13, 127.99, 127.05.125.60, 118.75.66.31.50.94.45.88, 39.95, 34.89, 29.49.25.27, 23.57, 21.33;

MS [ESI (+)] / z 643 (ΪΗ ⁺ ).

Example 1 95

 Ν'-benzyl-N- [4- (Ν ''-hydroxyamino) 1-2R-isobutyl-3 (R or S)-(3-phenylpropyl) succinyl] -N'-morpholinoacetylhydrazine hydrochloride

^ -NMR (DMS0-d ₆ ) δ ppm, 500MHz, 87 ^: 7.32-7.11 (m. 10H), 4.70-4.59 (m, 2H). 4.04-3.99 (m. 2H). 3.86-3.85 (m. 4H).

3.20-3.19 (m, 4H), 2.55-2.43 (m. 3H). 2.29-2.23 (m. 1H).

1.53-1.39 (m.4H), 1.32-1.29 (m, 2H) .1.09-1.03 (m, 1H).

0.79 (d, J = 6.6 Hz, 3H), 0.77 (d, J = 6.6 Hz, 3H);

MS [ESI (+)] m / z 539 (MH +).

Example 1 9 6

 N '—Benzyl-1-N_ [4— (Ν' '-hydroxyamino) -1-2R-isobutyl-3 (R or S) — (3-phenylphenyl) succinyl] —N' — (4-methylbibe Razin-1-yl) acetyl hydrazine dihydrochloride

 ^-MR (DMSO-de) <5 pm. 500MHz, 87: 7.31-7.11 (m. 10H).

4.67-4.56 (m, 2H), 3.61 (br s, 2H). 3.29-3.25 (m, 4H).

3.11-3.08 (m, 4H), 2.72 (s, 3H) .2.56-2.38 (m, 3H). 2.29-2.23 (m, 1H) .1.52-1.25 (m.6H) .1.07-1.02 (m, 1H ), 0.78 (d, J = 6.6 Hz, 3H).

0.76 (d.J = 6.6 Hz, 3H);

liS [ESI (+)] m / z 552 (MHO.

Example 1 9 7

 Ν'-benzyl-N '-(dimethylaminoacetyl) -N- [4- (Ν' '-hydroxyamino) 1-2R-isobutyl-3 (R or S)-(3-phenylpropyl) succinyl] hydrazine hydrochloride

 ιΗ-note (DMSO-ds) 5ppm.500MHz.87: 7.33-7.11 (m.10H).

4.66 (br s, 2H). 4.10 (br s. 2H), 2.85 (s, 6H), 2.55-2.40 (m. 3H).

2.29-2.23 (m.1H) .1.54-1.25 (m, 6fl) .1.09-1.04 (m.1H).

0.79 (d. J = 6.5 Hz. 3H). 0.77 (d, J = 6.5 Hz, 3H);

) (S [ESI (+)] m / z 497 (MH +).

Example 1 9 8

N '-(3-aminopropionyl) i N'-benzyl i N-[4-(Ν ''-hydroxyamino) 1 2 R-isoptyl-3 (R or S)-(3-phenylpro Pill) succinyl] hydrazine hydrochloride

'H-NMR (DMS0- _ds ) 5 ppm, 300MHz. 70: 10.60 (brs, 1H).

8.01 (br s, 3H), 7.35-7.1 (m.10H) .3.05-2.9 (m, 2H), 2.85-2.6 (m.2H), 2.6-2.3 (m.3H), 2.25-2.1 (m. 1H), 1.6-1.1 (m. 6H) .1.05-0.9 (m, 1H) .0.78 (d, J = 6.1 Hz, 6H);

MS [ESI (+)] m / z 483 (MH +).

Example 1 9 9

 Ν '—aminoacetyl-Ν-benzyl-Ν- [4- (Ν' '-hydroxyamino) -1-2R-isobutyl-l-3 (R or S) — (3-phenylphenyl succinyl) hydrazine Hydrochloride

 Ή-Ν Ε (DMSO-de) <5 pm. 300MHz. 70: 10.79 (s. 1H). 10.45 (br s. 1H), 8.29 (br s, 3H). 7.35-7.0 (m, 10H), 3.8 —3.55 (m. 2H), 2.6—2.3 (m, 3H), 2.25-2.1 Cm. LH), 1.55-1.1 (m, 6H), 1.1-0.95 (m, 1H),

0.79 (d, J = 5.4 Hz, 6H);

MS [ESI (+)] m / z 469 (MH +).

Example 2 0 0

 Ν '1-benzyl-N'-(3-dimethylaminopropionyl) 1 N- [4- (N ''-hydroxyamino) 1 2 R-isobutyl-3 (R or S)-(3-phenylpropyl) succinyl ] Hydrazine hydrochloride

'H-NMS (DMS0-d ₆ ) 5 ppm. 300 MHz. 70 and 10.43 (br s. 1H).

7.35-7.05 (m, 10H). 2.69 (t, J = 7.2 Hz. 2H) .2.6-2.3 (m, 5H).

2.3-1.2 (m. 1H), 2.25 (s. 6H) .1.55-1.1 (m. 6H), 1.05-0.9 Cm, 1H).

0.78 (d, J-6.5 Hz, 6H);

MS [ESI (+)] m / z 511 (H +).

Example 2 0 1

N- [4 -— (N'—hydroxyamino) 1 2 R—isobutyl 13 (R or S)-(3-phenylpropyl) succinyl] azaphenylalanine — 2-di Methylaminoethylamide hydrochloride

 'H-NME (DMSO-ds) <5ppm. 500MHz, 87 ^: 7.28-6.97 (m, 10H),

4.77 (d.J = 15.0 Hz.1H), 4.37 (d.J = 15.0 Hz, 1H) .3.56-3.40 (m.2H), 3.23-3.19 (m, 2H), 2.80 (s, 6H) .2.58 -2.54 (m. 1H), 2.45-2.40 (m. 2H). 2.28-2.21 (m, 1H), 1.65-1.38 (m, 5H), 1.27-1.22 (m. 1H).

1.05-1.00 (m, 1H), 0.76 (d. J = 6.6 Hz. 3H), 0.72 (d. J = 6.6 Hz, 3H); ¹³ C-NME (DMSO-de). 125 MHz: 171.65, 170.67, 157 6, 142.01, 137.46.

128.23, 128.16, 128.03.127.83, 126.93, 125.59, 56.30.50.90.45.80.

42.72, 42.43. 39.83, 35.35, 34.84. 30.88, 29.34. 25.11. 23.58. 21.31; KS [ESI (+)] m / z 526 (MH +).

Experimental Example 1 (in vitro TNFα inhibitory activity)

 The inhibitory effect of the example compounds of the present invention on the release of TNF from THP-1 cells, which are monocyte-cultured cells, was examined [Reference: Nature 370, 218-220 (1994)]. First, THP-1 cells were suspended in lxlO ^ cellsZml in an RPMI164 medium containing 10% FCS (Fetal Cow Serum), and dispensed in 1001 portions. Subsequently, 2 μg / m 1 LPS was prepared in RPMI 1640 medium containing 10% FCS, and each compound (dissolved in DMSO) was diluted 500-fold.

100 μl of the diluted solution of these compounds was added to the cell suspension previously dispensed, and the mixture was reacted for 3 hours under the condition of 5% CO ₂ . After completion of the reaction, the culture supernatant was collected by centrifugation, and the amount of TNFα in the culture supernatant was quantified by ELISA (Enzyme Linked Immunosorbent Assay). The inhibitory effect of each compound on the inhibition of TNFα release was calculated from the ratio of the amount of free TNF in the compound addition group at each concentration to the amount of free TNFa in the group without compound addition. Table 7 shows the results.

4 3 Table 7: In vitro TNFa inhibitory activity of the example compounds

The above experimental results show that the azapeptide hydroxamic acid derivative of the present invention inhibits TN Fa production.

Experimental Example 2 (Solubility)

The solubility of the example compounds of the present invention in physiological saline (0.9% aqueous sodium chloride solution) at 25 ° C. was measured. Table 8 shows the results. Table 8: Solubility of example compounds Example No. Solubility

 Physiological saline, mg / mL

145 10

 146> 20

 147 10

 148> 20

 156> 20

 158> 20

 166 10

 173> 30

 184> 20

 185> 40

 191 5-10

 194> 30

 196> 40

 197> 40

 198> 20

199> 20

201 10 Formulation Example 1

 Tablets containing the following components were produced by a conventional method. Ingredients per tablet

Compound of the present invention (I) 10 mg

Lactose 1 2 5 mg

Cornstarch 7 5 mg

Tanolek 4 mg

Magnesium stearate l mg

Total weight 2 15 mg

Formulation Example 2

 Capsules containing the following ingredients were prepared by a conventional method. <Ingredient> 10 mg of the compound of the present invention (I) per capsule

Lactose 1 6 5 mg

Cornstarch 20 mg

Talc 5 mg

Weight of one capsule 200 m e

Formulation Example 3

It was prepared by a conventional method钦晉containing the following ingredients _(component dose

0.2 g of the compound of the present invention (I)

97.8 g of white cellulose

Liquid paraffin 2 g

 1 0 0 g

Formulation Example 4

An injection containing the following components was produced by a conventional method. Ingredient dose 0.2 g of the compound of the present invention (I)

0.9 g of sodium chloride

Distilled water for injection

Total weight 100 g

Formulation Example 5

An eye drop containing the following components was produced by a conventional method ₍

Ingredient dose

0.1 g of the compound (I) of the present invention

0.3 g of sodium chloride

Appropriate amount of sterilized purified water

 100 g The azapeptide hydroxamic acid derivative and the pharmacologically acceptable salt thereof of the present invention have a TNFα production inhibitory action, and include, for example, sepsis, MOF, rheumatoid arthritis, Crohn's disease, It is useful for the prevention and treatment of diseases such as cachexia, myasthenia gravis, systemic lupus erythematosus, asthma, type I diabetes, psoriasis, other autoimmune diseases, and inflammatory diseases. This application is based on Japanese Patent Application No. 256664 filed in Japan. The contents of which are incorporated in full herein.

Claims

The scope of the claims

 1. Formula (I):

[In the formula, X represents hydrogen or a protecting group for a hydroxyl group, and R ¹ represents hydrogen, a hydroxyl group, amino, mercapto, alkoxy, optionally substituted alkyl, alkenyl, optionally substituted aryl, or — ( CH ₂ ) k —A (k is an integer of any one of 1 to 4, and A is (a) linked by an N atom, and (b) as a further hetero atom at a position not adjacent to the bonded N atom. At least selected from N, 0 and S

One or more atoms, (c) with respect to one or both C atoms adjacent to the bonding N atom, which are substituted by oxo, and (d) benzocondensed or one or more other Represents a force substituted by lower alkyl or oxo with respect to the C atom of, and / or a 5- or 6-membered N-heterocycle optionally substituted by lower alkyl or phenyl with respect to another N atom.] R ² represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl, R ^s represents hydrogen, an optionally substituted alkyl, an optionally substituted aryl, An optionally substituted heteroaryl or

R ¹¹

 -(C ONH) m-(CH) n-Y

(Wherein, R ¹¹ represents hydrogen or alkyl which may be substituted, Y one C0 ₂ R ^l2, one CONR ¹² R ¹² 'or - COR ¹² {R ¹² and R ^12' have been the same or different Each represents hydrogen, optionally substituted alkyl or optionally substituted aryl, wherein R ¹² and R ¹² ′ together with the adjacent nitrogen atom are optionally substituted hetero. May form a cycle}, m represents 0 or 1, n represents an integer of 0 to 4), and R represents Optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, — S 0 ₂ R ¹² , —CO— (CH ₂ ) q — NR ¹² R ¹² '

{q represents 1 or 2, R ¹² and R ¹² ′ are as defined above), -C ONH-Z-R ¹³ (Z represents an alkylene having 2 to 4 carbon atoms, R ¹³ represents a hydroxyl group, amino or NR ¹² R ¹² '[R ¹² and R ¹² ' are as defined above]] or

R ¹¹

 I

 One (C ONH) m-(CH) n-Y

(Wherein, ¹¹ , Y, m and η are the same as defined above), and R ³ and R * together with an adjacent nitrogen atom form a heterocycle which may be substituted Or a pharmacologically acceptable salt thereof.

2.R ¹ is hydrogen, hydroxyl, amino, mercapto, alkoxy, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylthioalkyl, substituted Arylthioalkyl, phthalimidalkyl which may be substituted, alkenyl, aryl which may be substituted, or — (CH ₂ ) k-A (where k is an integer of 1 to 4 , A

 (vii) (viii)

(In the formula, R ⁸ and R ^fl each represent hydrogen or together form another bond to form a double bond, R ¹⁰ represents hydrogen, lower alkyl or phenyl, and X ′ represents —C 0- , One CH _2- , -CH (R ¹⁹ ) one, — C (R ¹⁹ ) one, one NH-,-N (R ^{, 9} ) — or — 0—, and Y ′ is — 0—, — NH- or —N (R ¹⁹ ) represents one group, and R ¹⁹ represents a lower alkyl group.], And R ² represents hydrogen, an optionally substituted alkyl, Represents an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl or an optionally substituted aryl, wherein R ³ is Hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, substituted Even if the good Teroarirua alkyl, optionally substituted cycloalkyl, optionally substituted Shikuroa Alkylalkyl, optionally substituted aryl, optionally substituted heteroaryl or

R ¹¹

 I

 ― (CONH) m-(CH) n -Y

(Wherein, R represents hydrogen, alkyl optionally substituted, optionally substituted § reel alkyl, an alkyl thio alkyl optionally substituted, Upsilon is ^{_{- C 0 2 R 12, -}} CONR 12 R ¹² ′ or one COR ¹² (R ¹² and R ¹² ′ may be the same or different and each is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted A good heteroalkyl, an optionally substituted cycloalkyl or an optionally substituted aryl, wherein R ¹² and R ′ ² ′ may be substituted together with an adjacent nitrogen atom; M represents 0 or 1, n represents an integer of 0 to 4), and R ⁴ represents an optionally substituted group. Alkyl, optionally substituted To reelalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted Teroaryl, — S 0 ₂ R ¹² , one CO— (CH _Z ) g -NR ¹² R ¹² ′ (q represents 1 or 2, R ¹² and R ¹² ′ are as defined above), —C 0NH—Z — R ¹³

{Z represents an alkylene having 2 to 4 carbon atoms, R ¹³ represents a hydroxyl group, amino or —NR ¹² R ¹² ′ (R ¹² and R ¹² ′ are as defined above)) or

R ^M

 I

 One (C ONH) m One (CH) n — Y

(Wherein, R ", Y, m and η are the same as defined above), and R ³ and R ⁴ together with an adjacent nitrogen atom represent a heterocycle which may be substituted. The azapeptide hydroxamic acid derivative according to claim 1, which may be formed, or a pharmaceutically acceptable salt thereof.

3. The method of claim ¹ , wherein R ¹ is hydrogen or optionally substituted alkyl. Zapeptide hydroxamic acid derivatives or pharmacologically acceptable salts thereof.

4. The azapeptide hydroxamic acid derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is an optionally substituted alkyl.

5. The azapeptide type hydroxamic acid derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein R ² is isobutyl.

6. The azapeptide hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R and R ⁴ are combined with an adjacent nitrogen atom to form an optionally substituted heterocycle.

 7. The azapeptide hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according to claim 6, wherein the optionally substituted heterocycle is 2-oxoquinazolinyl or morpholino.

8. formula ^{(II): 1 4 0 (} II)

[Wherein R ¹⁴ represents hydrogen, optionally substituted alkyl or optionally substituted aryl,

Represents a single bond or a double bond, and R ¹⁵ is

Is a single bond, hydrogen, hydroxyl, amino, mercapto, alkoxy, optionally substituted alkyl, alkenyl, optionally substituted aryl,-(CH ₂ ) k-A (k is any of 1-4 A is: (a) linked by an N atom; (b) as a further heteroatom at a position not adjacent to the bonded N atom, (C) at least one of the C atoms adjacent to the bonded N atom is substituted by oxo, and (d) a benzocondensation Or a 5- or 6-membered N-, which is substituted on one or more other C atoms by lower alkyl or oxo, and which is substituted on lower or another N atom by lower alkyl or phenyl. Represents a heterocycle] or —COOR ¹⁶ (R ¹⁶ represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl), or

Is a double bond, represents CH ₂ , R ² represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl, R ³ represents hydrogen, an optionally substituted alkyl, Optionally substituted aryl, optionally substituted heteroaryl or

R ¹¹

 ― (C ONH) m-(C H) n — Y

(Wherein, R ¹¹ represents hydrogen or alkyl which may be substituted, Y one _{^{C0 2 R 12, -CONR l2 R}} 12 ' or - COR ¹² {R ¹² and R ^12' is identical other different Each represents hydrogen, optionally substituted alkyl or optionally substituted aryl, wherein R ¹² and R ¹² ′ are optionally substituted together with an adjacent nitrogen atom. M may represent 0 or 1, n represents an integer of 0 to 4), and represents an optionally substituted alkyl, substituted Optionally substituted heteroaryl, optionally substituted heteroaryl, — S 0 ₂ R ¹² , one CO— (CH ₂ ) q one NR ¹² R ¹² ′

{q represents 1 or 2, R ¹² and R ¹² ′ are as defined above), -CONH-Z-R ¹³ (Z represents an alkylene having 2 to 4 carbon atoms, and R ¹³ represents a hydroxyl group, amino or NR ¹² R ¹² '[R ¹² and R ¹² ' are as defined above]] or R ¹¹

 -(CONH) m — (CH) n-Y

(Wherein, R ", Y, m and n are as defined above), and R ³ and R ⁴ together with an adjacent nitrogen atom represent a heterocycle which may be substituted. May be formed].

 9. A pharmaceutical composition comprising the azapeptide hydroxamic acid derivative according to claim 1 or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

10. The pharmaceutical composition according to claim 9, which is a TN Fa production inhibitor.