WO1998015525A1 - Hydroxamic acids - Google Patents

Hydroxamic acids

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Publication number
WO1998015525A1
WO1998015525A1 PCT/JP1997/003542 JP9703542W WO9815525A1 WO 1998015525 A1 WO1998015525 A1 WO 1998015525A1 JP 9703542 W JP9703542 W JP 9703542W WO 9815525 A1 WO9815525 A1 WO 9815525A1
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group
2h
amino
1h
ch
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PCT/JP1997/003542
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French (fr)
Japanese (ja)
Inventor
Fumio Samizo
Yumiko Kamikawa
Akira Sasaki
Yasuyuki Ueki
Hitoshi Hochigai
Kiyoko Kogita
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Sumitomo Pharmaceuticals Co., Ltd.
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36Oxygen or sulfur atoms
    • C07D207/402,5-Pyrrolidine-diones
    • C07D207/4162,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00Thiocarboxylic acids
    • C07C327/38Amides of thiocarboxylic acids
    • C07C327/48Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/08Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54Radicals substituted by carbon atoms having three bonds to heteroatoms, with at the most one to halogen, e.g. ester or nitrile radicals
    • C07D213/56Amides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D275/00Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated

Abstract

Hydroxamic acid derivatives represented by the following general formula and useful as a matrix metalloprotease inhibitor: R-X-B-N(R1)-A-CO-NHOH, wherein R is an optionally substituted cyclic hydrocarbon group or the like; X is optionally substituted alkylene or the like; B is carbonyl or the like; R1 is hydrogen or optionally substituted lower alkyl in the case wherein B is carbonyl or sulfonyl, and R1 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkanoyl or the like in the case wherein B is methylene; and A is methylene substituted with one or two optionally substituted lower alkyl groups.

Description

Akira fine manual hydroxamic acid technology field

The present invention relates to hydroxamic acid derivatives useful and matrix meth port protease Ichize inhibitor as matrix meth port protease Ichize inhibitor. BACKGROUND

Constituting the connective tissue, collagen, extracellular matrix represented by Puroteodarikan is metabolized Te cowpea to a group of proteolytic enzymes termed matrix Protea Ichize. The matrix meth port Protea Ichize is Collagenase one peptidase (Matricaria Kkusumeta port Protea Ichize one 1, MMP- 1), Zerachina one peptidase A (matrix meth port Protea Ichize one 2, MMP- 2), stromelysin (matrix meth mouth Protea Ichize one 3, MMP- 3), Zerachina one peptidase B (matrix meth port proteinase § one peptidase one 9, MMP- 9), Collagenase one zero one 3 (matrix meth port Protea one See 1 3, MMP- 1 3) such as, currently it is known one six. Extracellular Matoritsu box, the normal, the synthesis of these matrices meth port Protea Ichize, by endogenous inhibitors at levels of secreted or extracellularly (e.g., TIMP (Tissue Inhibitor of matrix metal lo protease)) It is strictly controlled. There are many reports about the relevance of the disease symptoms destruction Protea Ichize increased activity and connective tissue occurs when this balance is lost is.

For example, destruction of articular cartilage is characterized, osteoarthritis, the rheumatoid arthritis patient's joint, the matrix meth port proteases, particularly stromelysin, Collagenase -.. Ze is detected at high levels (Arthr Rheum, 33 , 388-397 (1990);. SM Krane, etc., "Modulation of matrix synthesis and degradation m joint inflammation, The Control of Tissue Damage", AB Glauert (Editor), Elsevier Sci.Publ, Amsterdam, 1988, Ch.14, ... pp 179-195; Clin Chim Acta, 185, 73 - 80 (1989);... Arthr Rheum, 27, 305-312 (1984);. J.Clin Invest, 84, 678 - 685 (1989) ).

Cancer cells invade the tissue, metastasis to to form secondary tumors, since the step of degrading the basement membrane is essential, Zerachina one Ze A, expression of matrix meta port protease B and the like, enzymes activity, cancer cell invasion, are associated with metastatic potential (FEBS J., 5, 2145-2154 (1991); Trends Genet, 6, 121-125 (1990);.. cancer Res, 46, 1- 7 (1986); Cell, 64, 327-336 (1990); Cancer and Metastasis Rev., 9, 305-319 (1990)).

In fibroblast cells removed from tissue that develop gingivitis, Collagenase one Ze, stromelysin are confirmed to be activated (J. Periodontal Res., 16, 417-424 (1981)). Further, those enzymes levels are found associated with severe gingivitis (J. Periodontal Res., 22, 81-88 (1987)).

Collagenase one zero one 3 (matrix metalloproteinase - 1 3, MMP- 1 3) is expressed in human chondrocytes has developed rheumatoid Ryu one gusset patient synovial, osteoarthritis (J. Clin .. Invest, 97, 2011-2019 (1996); J.Rheumatol, 23, 509 - 595 (1996);.. J.Biol.Chem, 271, 23577-23581 (1996); J.Clin Invest,.. 97, 761- 768 (1996)). Further, ΜΜΡ- 1 3 type II collagen is the major extracellular matrix structure Ingredient cartilage matrix, has strong decomposition activity against Agurikan, cartilage deformity arthropathy, associated with rheumatoid arthritis has been pointed out (. J.Biol.Chem, 271, 1544-1550 (1996); FEBS Lett "380, 17 - 20 (1996)).

Thus, the matrix meth port protease Ichize inhibitors, osteoarthritis, joint diseases such as rheumatoid arthritis, cancer cell metastasis, a therapeutic agent such as gingivitis, can use as a prophylactic agent.

Matrix meth port Protea Ichize is addition to the destruction of the extracellular matrix as described above, conversion of latent forms of tumor necrosis factor to a mature form (Nature, 370, 555- 557 (1994)), serine protease one degradation of alpha 1-antitrypsin is a peptidase inhibitors (FEBS Lett, 279, 191-194 (1991).), the matrix meth port protease mutually by that activation (Biochemistry, 29, 10261-10670 (1990); J . Biol. Chem., 267, are involved in the 21712- 21719 (1992)).

Thus, the matrix meth port protease Ichize inhibitors, it can use as anti-inflammatory agents.

The WO 95/35275, there is described a useful hydrate Rokisamu acid derivatives as matrix meth port protease Ichize inhibitor. However, no description about the result of inhibition tests of the hydroxamic acid derivatives, also does not describe or inhibit any matrix meth Rob port tare Ichize. Disclosure of the Invention

An object of the present invention is to provide novel compounds useful as matrix meth port protease Ichize inhibitor, and a novel matrix meth port protease Ichize inhibitor.

The present inventors have, MMP- 3, MMP- 1 3 like matrix meth port Protea one peptidase intensive research as a result the compound having an inhibitory activity for the, found to have an inhibitory action superior hydroxamic acid derivatives, the invention has been completed.

That is, the present invention is,

Equation 1:

RXBN (R 1) -A-CO -NHOH

In the formula, R may be substituted hydrocarbon cyclic group, optionally substituted heterocyclic group, Yo Le substituted, vinyl group substituted with a cyclic hydrocarbon group, optionally substituted Moyore represents a vinyl group or modified amino group substituted by a heterocyclic group.

X is an alkylene group which may be substituted,

Formula: - (CH 2) m - Y - (CH 2) n -

(In the formula, Y is an integer of oxygen atom or a sulfur atom, or substituted with a lower alkyl group represents an imino group which may. M and n are each independently 0-1 5, and, m and the sum of n is an integer from 1 to 20. However, when n is 0, B is a carbonyl group or a sulfonyl group. (CH 2) m and (CH 2) n is by independent replacement group represented by may be substituted with a group.), or

Formula: - (CH 2) p - Z - (CH 2) q - ( wherein, Z is a sulfinyl group, a sulfonyl group, a carbonyl group, One NL 1 - C (= NL 1 ) one NL 1 - One NL 2 - CONL 2 -, -O- CONL 2 -, - C ON L 3 one or a S0 2 NL 3 -. represents a wherein, L 1 is independently a hydrogen atom, lower alkyl group, a lower Arukanoiru group , Aroiru group, a lower alkylsulfonyl group or § Li - represents a Rusuruhoniru group, L 2 represents a hydrogen atom or a lower alkyl group independently, L 3 represents a hydrogen atom or an optionally substituted lower alkyl group. p represents an integer of 0 to 1 to 5, q is an integer of from 1 to 1 to 5, and the sum of p and q are integers 1 to 20. (CH 2) p and (CH 2) q represents a group represented by but it may also be substituted with a substituent independently.).

B represents a carbonyl group, a methylene group or a sulfonyl Le group.

R 1, when B is a carbonyl group or a sulfonyl group, a hydrogen atom or a substitution which may be a lower alkyl group, when B is a methylene group, a hydrogen atom, a lower alkyl which may be substituted group, optionally substituted lower Arukanoiru group, or represents an optionally substituted lower alkyl sulfonyl Le group.

A represents an optionally substituted lower alkyl group 1 also or two substituted methylene group. ]

In about Matrix meth port protease Ichize inhibitor containing a hydroxamic acid derivative or a pharmaceutically acceptable salt thereof represented. In addition, the present invention is,

Equation 2:

RX 1 -BN (R 1) -A 1 -CO-NHOH

Wherein, R, R 1 and B are as defined above. A 1 and X 1 are as follows.

(1) A 1 represents a methylene emissions group substituted with one or two lower alkyl group which may be substituted.

X 1 is an optionally substituted alkylene group with carbon number 3-20,

Formula: - (CH 2) ml -Y- (CH 2) nl -

(Wherein, Y has the same meaning as defined above. M 1 and eta 1 each independently represent an integer from 0 1 to 5, and the sum of m 1 and eta 1 is an integer of 3-20. ( CH 2) ml and (CH 2) nl may be substituted with a substituent independently. However, if n 1 is 0, B is represented by a carbonyl group or a sulfonyl group.) group or,

Formula: - (CH 2) p: -Z- (CH 2) ql -

(Wherein, Z has the same definition as above. P 1 represents an integer from 0 to 1 5, 1 represents an integer from 3 1 5 and an integer of total 3 to 20 p 1 and q 1 it is. represents a (CH 2) pl and (CH 2) ql may be substituted with a substituent independently.) a group represented by.

Or,

(2) A 1 is,

Formula: R 2 - (CH 2) i - Z 1 - (CH 2) j -CH =

{Wherein, R 2 is optionally substituted hydrocarbon cyclic group, substituted by a heterocyclic group which may, be substituted by optionally substituted hydrocarbon cyclic group vinyl group, it may be substituted It represents a vinyl group or modified amino group substituted with not good heterocyclic group. Z 1 is one CONL 2 -, - S 0 2 NL 2 - or - 0- CONL 2 - a represents (L 2 are as defined before follow.). i represents an integer of 1 to 7, j represents 1, 2, 3, 5 or 6. (CH 2); and (CH 2) "includes but it may also be substituted with a substituent independently. If it represents a substituted methylene group represented by},

X 1 is a substituted carbon atoms which may be 1 or 2 alkylene groups,

Formula: -. (CH 2) m2 -Y- (CH 2) n 2 - ( wherein, Y has the same meaning as defined above m 2 and eta 2 are each independently an integer from 0 to 2, and, total m 2 and eta 2 is 1 or 2. However, if eta 2 is 0, beta is a carbonyl group or a sulfonyl group. (CH 2) m 2 and (CH 2) n 2 are independently and which may be substituted with a substituent.) in the depicted Ru group or,

Formula: - (CH 2) p 2 - Z- (CH 2) q 2 _

(Wherein, Z is the same as defined above. P 2 represents an integer of 0 to 1 5, q 2 is 1 or represents a 2. (CH 2) p 2 and (CH 2) q 2 are independently may be substituted with a substituent Te.) may represent a group represented by. ]

In about hydroxamic acid derivative or a pharmaceutically acceptable salt thereof. The hydrocarbon cyclic group include aliphatic hydrocarbon cyclic group and an aromatic hydrocarbon cyclic group (§ reel group).

Examples of the aliphatic hydrocarbon cyclic group, for example, include aliphatic hydrocarbon cyclic group of saturated or 5 carbon atoms of the unsaturated 8, specifically, cyclopentyl, Shikuropen thenyl, cyclohexane cyclohexyl, cyclohexylene cyclohexenyl, cycloheptyl, and the like cyclohexylene. The Ariru groups include, for example, Ariru group 6-1 0 carbon atoms, specifically, phenyl, naphthyl and the like.

The heterocyclic groups include aliphatic heterocyclic group and an aromatic heterocyclic group. The aliphatic heterocyclic group, for example, 1 to 4 nitrogen atoms, oxygen atoms or monocyclic or bicyclic Z and ring-constituting atoms containing sulfur atom is 5-1 0 saturated or unsaturated It includes aliphatic heterocyclic groups. Specifically, piperidyl, piperazinyl piperazinyl, piperidinyl, morpholinyl such as an oxygen atom, a nitrogen atom, 1 arbitrarily chosen from the group of sulfur atoms to 6-membered saturated heterocyclic ring monocyclic ring containing two heteroatom Shikimoto, Okisoraniru, pyrrolidinyl, oxygen atom such as Birazorijiniru, nitrogen atom, 5-membered saturated heterocyclic group monocyclic ring containing sulfur atom 1 to hetero atoms two of the arbitrarily chosen from the group of, isoindolyl, Indoriniru, 2 H, 3 H- base emission zone [d] isothiazoloxy - rules 2 I le group, 5 H, 6 H, 7 H- pyro port [3, 4- b] pyridine - such as 6-I le radical oxygen atom, a nitrogen atom, 9-membered saturated heterocyclic group having 2 ring containing two heteroatoms to 1 arbitrarily chosen from the group of sulfur atoms, chromanyl, oxygen atom such as Inkuromaniru, nitrogen atom, sulfur atom It 1 was arbitrarily selected from a group of two To 2 1 0-membered saturated heterocyclic group ring containing TeroHara child, Imidazoriniru, pin port Riniru, oxygen atom, such as pyrazol nil, nitrogen atom, 1 arbitrarily chosen from the group of sulfur atoms to two heteroatoms 5-membered unsaturated heterocyclic group monocyclic ring containing atoms, oxygen atoms such Biraniru, ChissoHara child, 1 was arbitrarily selected from the group of sulfur atoms to 6-membered monocyclic ring containing two heteroatom and unsaturated heterocyclic groups.

The aromatic heterocyclic group, for example from 1 to 5 nitrogen atoms, monocyclic ring oxygen atoms and / or ring-constituting atoms is 5-1 4 containing a sulfur atom, a bicyclic or tricyclic Kaoru incense It includes family heterocyclic group. Specifically, pyridyl, pyridazinyl, oxygen atom such Piraji two Le, nitrogen atom, 6-membered heterocyclic group monocyclic ring containing 1 to hetero atoms two of the arbitrarily chosen from the group of sulfur atoms, imidazolyl, furyl, 2 - Okiso - 1, 3-Jiokisoreniru, thienyl, oxygen atom pyrrolyl, nitrogen atom, 1 arbitrarily chosen from the group of sulfur atoms to 5-membered monocyclic ring containing three heteroatom heterocyclic group, quinolyl, isoquinolyl, indolyl, benzimidazolyl, oxygen atom, such as benzofuryl, nitrogen atom, to 9 to 2 ring containing TeroHara terminal 3 of the to 1 selected arbitrarily from the group of sulfur atoms 1 0-membered heterocyclic group, an oxygen atom, a nitrogen atom, such as anthraquinolyl, 1 2 or 3 rings and 1 4 membered heterocyclic group is exemplified comprising 1 to 3 heteroatom selected arbitrarily from the group of sulfur atoms It is. The position of substitution in the vinyl group substituted with a hydrocarbon cyclic vinyl group substituted with a group and heterocyclic group may be any position of the vinyl group, but preferably include 2-position of the vinyl group, particularly preferred examples include trans position a 2-position of the vinyl group. The substituent of the substituted hydrocarbon ring group and a substituted heterocyclic group include, for example, the following groups, to 1 are arbitrarily chosen three groups may be substituted.

Group: a lower alkyl group, a carboxyl group, lower alkoxycarbonyl group, one CO one NHOH, amino group, lower alkyl-substituted amino group (which may be 1 or 2 lower alkyl groups are substituted), tri-lower alkyl ammonium Nio group, power Rubamoiru group, lower alkyl-substituted force Rubamoiru group, guaiacolsulfonate Niji Roh carbonyl group, a lower Arukanoiruami amino group, a lower alkylsulfonyl § amino group, a lower alkoxycarbonyl § amino group, § Li one Le sulfonyl § amino group, amino lower alkyl group, Shiano lower alkyl group, lower alkanoyloxy Noi Le amino-lower alkyl group, lower alkylsulfonyl § amino lower § alkyl group, a lower alkoxycarbonyl § amino-lower alkyl group, § Li one Rusuruhoni Ruamino lower alkyl group, lower alkylamino-lower alkyl group, Guanijino group, a substituted grayed Nijino group (as this substituent, such as a lower alkyl group, a lower Arukanoi group, Aroiru group, a lower alkylsulfonyl group, § Li one Rusuruhoniru groups include et al is, 1 to 3 may be substituted), Guanijino lower alkyl group, a substituted Guani Gino lower alkyl group, a ureido group, (as this substituent, for example, a lower alkyl group, and 1 to 3 may be substituted) substituents Ulei de group, a lower alkylthio O group , lower alkylsulfonyl group, a nitro group, Shiano group, a halogen atom, Amiji amino group, substituted amidino group (as this substituent, such as a lower alkyl group, lower alk force Noiru group, Aroiru group, a lower alkylsulfonyl group, § Li one Rusuruhoniru group ani Gerare be 1 to 3 is substituted), a thiol group, a hydroxyl group, Okiso group, scan Le Ho, lower alkoxy, lower alkanoyloxy Noi Ruo alkoxy group, Aroiruokishi group, human Dorokishi lower alkyl group, lower alkanoyloxy Noi Ruo alkoxy-lower alkyl group, Aroiruo alkoxy-lower alkyl group, cyclic hydrocarbon group, a heterocyclic group, a substituted been hydrocarbon cyclic group {the substituent, such as a lower alkyl group, a carboxyl group, a lower alkoxy carbonyl group, - CO _ NHOH, amino group, 1 or 2 lower alkyl-substituted amino group (the lower alkyl group is substituted and may be), a tri-lower alkyl ammonium Nio group, forces Rubamoiru group, lower alkyl-substituted force Rubamoiru group, guaiacolsulfonate Niji Roh carbonyl group, a lower alkanoyloxy Noi Rua amino group, a lower alkylsulfonyl § amino group, a lower alkoxy carbonyl § amino group , § Li one Le sulfonyl § amino group, amino lower alkyl group, lower Kyua Kanoiruamino lower alkyl group, lower alkylsulfonylamino lower alk kill group, a lower alkoxycarbonyl § amino-lower alkyl group, § Li one Rusuruhoniru Amino-lower alkyl group, lower alkylamino-lower alkyl group, Guanijino group, substitution Guanijinino group (the substituent as the base, for example, a lower alkyl group, a lower Arukanoi group, Aroiru group, a lower alkylsulfonyl group, it includes § Li one Rusuruhoniru group is, 1 may be three substituents), Guanijino lower alkyl group, a substituted Guaniji-lower-alkyl group, Ulei de group, a lower alkylthio group, a lower alkylsulfonyl group, a nitro group, Shiano group, a halogen atom, an amidino group, the substituent amidino group (the substituent, such as a lower alkyl group, a lower Arukanoiru group, Aroiru group, a lower § Alkylsulfonyl group, and § Li one Rusuruhoniru group, 1 to 3 may be substituted), a thiol group, a hydroxyl group, a sulfo group, a formyl group, a lower alkoxy group, lower alkanoyloxy Noi Ruo alkoxy group, Aroiruokishi group , hydroxy-lower alkyl group, lower grade alk Noi Ruo alkoxy-lower alkyl group, Aroiruokishi lower alkyl group include et al is, 1 may be three substituents}, as the substituted heterocyclic group (the substituent group, the same thing can be mentioned as the substituents of the "hydrocarbon cyclic group which is substituted", three one-stone may be substituted). The preferred have group in the substituent of the substituted hydrocarbon ring group and a substituted heterocyclic group for R, for example, the following groups.

Group: carboxyl group, lower alkoxycarbonyl group, an amino group, Amino lower § alkyl group, Shiano lower alkyl group, lower alkoxycarbonyl § amino lower alkyl group, Guanijino lower alkyl group, a nitro group, Shiano group, amidino group, lower alk kill group, a hydroxyl group, Okiso group, a lower alkoxy group, a halogen atom, a lower Arukirua amino-lower alkyl group, lower alkanoyloxy Noi Rua amino group.

More preferred groups, for example, the following groups. Group: carboxyl group, main butoxycarbonyl group, an amino group, aminomethyl group, § Minopuropiru group, Shianoechiru group, Guanijinomechiru group, a nitro group, Shiano group, amidino group, a hydroxyl group, Okiso group, main butoxy group, a propyl group, a fluorine atom , EnsoHara child, t - butoxycarbonylamino ethyl group. The modifying group in the modified Amino group, the protecting group (for example commonly used, "Protect ive Groups in Organ ic Synthes is, TW Greene, PGM Wuts, A Wi ley-Intersc ience Publ i cat i on, New york;. "basic peptide synthesis and experimental" Nobuo Izumiya et al., specific modifying group can be used ones) such as described in Maruzen, for example, benzyl O alkoxycarbonyl group, t - butyl O butoxycarbonyl urethane-type modifying group such as a group, Ami de type modifying group such as Asechiru, cyclic imide type modifying group phthaloyl etc., Ariru type modifying group such as Ariru, benzylic modifying group such as benzyl, t - Petit Le dimethylsilyl group as, for example, it includes an alkylene group having a carbon number of 1-2 0 straight or branched chain, specifically a silyl-type modifying group, and the like. alkylene groups etc., methylene, ethylene, trimethylene Tetramethylene styrene, pentamethylene, to Kisamechiren, nonamethylene, 3 Mechirunonamechi Ren, decamethylene, Undekamechiren, dodecamethylene, eicosapentaenoic methylene, and the like. Substituents of the substituted alkylene group, and (CH 2) alkylene represented by m, etc. the location substituent chains, include groups exemplified below, for example, to 1 are arbitrarily selected three groups may be substituted.

Group: a lower alkyl group, a carboxyl group, lower alkoxycarbonyl group, -CO - NHOH, amino group, forces Rubamoiru group, lower alkyl-substituted force Rubamoiru group, grayed § Niji Bruno carbonyl group, a lower alkanoyloxy Noi Rua amino group, a lower alkylsulfonyl § amino group, a lower alkoxycarbonyl § amino group, § Li one Le sulfonyl § amino group, § amino lower alkyl group, lower alkanoyloxy Noi Rua amino-lower alkyl group, a lower Arukirusu Ruhoniruamino lower alkyl group, lower alkoxycarbonyl-lower alkyl group, § reel sulfonyl § amino-lower alkyl group, lower alkylamino lower alkyl group, Guanijino group, the substituent Guanijino group (the substituent, for example, lower alkyl groups, lower Arukanoiru group, Aroiru group, a lower alkylsulfonyl group, Ariru sul Include alkenyl groups, may be 1 or 3 substituents), Guanijino lower alk kill group, a substituted Guanijino lower alkyl group, a ureido group, a lower alkylthio group, lower alkyl sulfonyl group, a nitro group, Shiano group, a halogen atom as the amidino group, substitution amidino group (the substituent, such as a lower alkyl group, a lower Arukanoiru group, Aroiru group, a lower alkylsulfonyl group, and § Li one Rusuruhoniru group, even if three substituents from 1 good), a thiol group, a hydroxyl group, a lower alkoxy group, a lower § Rukanoiruokishi group, Aroiruokishi group, hydroxy-lower alkyl group, lower alk Kanoiruokishi lower alkyl group, Aroiruokishi lower alkyl group, a lower alkyl Amino-lower alkyl group, - CO- substituted with NHOH lower alkyl group, Guani

The lower alkyl group is, for example, an alkyl Le group having 1 to 7 carbon atoms straight or branched chain, specifically, methyl, Echiru, propyl, 1 Mechiruechiru, butyl, 1 one-methylpropyl, 2 - methylpropyl, pentyl, hexyl, heptene chill and the like to.

Substituted lower alkyl group in R 1, substituent Arukanoiru group and substituted alkyl sulfates Honiru substituent groups, and examples of the substituent of the substituted lower alkyl group in the L 3, for example, include the following groups, to 1 are arbitrarily selected 3 number of groups may be substituted. Group: carboxyl group, lower alkoxycarbonyl group, One CO- NHOH, amino group, lower alkyl-substituted amino group (1 or 2 lower alkyl groups but it may also be substituted), a tri-lower alkyl ammonium Nio group, force Rubamoiru group, lower alkyl-substituted Cal Bamoiru group, guaiacolsulfonate Niji Roh carbonyl group, a lower alkanoyloxy Noi Rua amino group, lower alkyl sulfonyl § amino group, a lower alkoxycarbonyl § amino group, Guanijino group, substitution guaiacolsulfonate two Gino group (the substituent the, for example, lower alkyl group, a lower Arukanoiru group, a lower alkylsulfonyl group, a lower alkylsulfinyl group includes, 1 may be three substituents) Ulei de group, a lower alkylthio group, a lower alkyl sulfonyl group, nitro group, Shiano group, a halogen atom, an amidino group, a substituted amidino group (As this substituent, for example, a lower alkyl group, a lower Arukanoiru group, a sulfo group, and a lower alkylsulfonyl group, 1 may be three substituents), Chio group, a hydroxyl group, a lower alkoxy group, a lower alkanol Iruokishi group. The methylene group substituted with a lower alkyl group 1 or 2 represented by A 1 A or Formula 2 Formula 1, specifically, Echiriden, propylidene, 2-Mechirupuro Piriden, butylidene, pentylidene, isopropylidene , 1 one Mechirupuropiri den, 1-methylstyrene butylidene, 1-methylstyrene cyclopentylidene, to xylidine, Okuchi alkylidene, 2-methyl-Petit alkylidene, 3-methyl-Petit isopropylidene and the like.

Examples of the substituent in the substituted lower alkyl group in A 1 of A or Formula 2 Formula 1, include groups exemplified below, for example, to 1 are arbitrarily selected three groups may be substituted.

Group: a lower alkyl group, a carboxyl group, lower alkoxycarbonyl group, one CO - NHOH, amino group, forces Rubamoiru group, lower alkyl-substituted force Rubamoiru group, grayed § Niji Bruno carbonyl group, a lower alkanoyloxy Noi Rua amino group, a lower alkylsulfonyl § amino group, a lower alkoxycarbonyl § amino group, § Li one Le sulfonyl § amino group, grayed Anijino group, the substituent Guanijino group (the substituent, such as a lower alkyl group, lower grade Arukanoiru group, Aroiru group, lower alkylsulfonyl group, and § Li one Rusuruhoni group, may be 1 to 3 is substituted), a ureido group, the substituent Ulei de group (the substituent, for example, a lower alkyl group, and 1 to 3 There may be substituted), lower alkylthio group, a carboxyl lower alkylthio group, a lower § Ruki Rusuruhoniru group, a nitro group, Shiano group, a halogen atom, an amidino group, the substituent § Mijino group (the substituent, such as a lower alkyl group, a lower Arukanoiru group, § Royle group, a lower alkylsulfonyl group, § Li one Rusuruhoniru group and the like, may be three substitutions 1 stone), a thiol group, a hydroxyl group, a lower alkoxy group, carboxyl lower alkoxy, lower alkanoyloxy Noi Ruo alkoxy group, Aroiruokishi group, an optionally substituted hydrocarbon (Examples of the substituent, the same thing can be mentioned as the substituents of the "substituted hydrocarbon cyclic group" of the may be 1 to 3 is substituted) cyclic group, optionally heterocyclic substituted the cyclic group (the substituent, the same thing can be mentioned as the substituents of the "substituted carbon hydrocarbon cyclic group" of the, even 1 to 3 is substituted There), substituted with optionally substituted hydrocarbon cyclic group vinyl group, substituted with an optionally substituted heterocyclic group vinyl group, modified Amino group, a lower alkyl substitution Amino group (lower one or two alkyl groups may be substituted), a tri-lower alkyl Ruanmonio group, a lower alkylsulfinyl group, a sulfo group, a tetrazolyl group, a force carboxymethyl methyl thio group, a carboxymethyl substituted amino group (carboxymethyl group 1 or 2 There may be substituted), tri (carboxymethyl) Anmonio group, Cal Bo carboxymethyl sulfonyl group, a carboxymethyl sulfide El group of the formula: R 2 - (CH 2) i - Z 1 - (CH 2) j - { wherein, Z 1 R 2, i and j are as defined above. Groups represented by}. One NH- A- CO-, or a group represented by one NH- A 1 -CO- in Formula 2 in Formula 1, for example, include residues of α-amino acids. Specifically, § La Nin, valine, Noruparin, leucine, isoleucine, norleucine, serine, threonine, Asuparagin acid, Asuparagin, glutamic acid, glutamine, homo-glutamic acid, homoglutamine, lysine, hydroxylysine, Ol two Chin, arginine, histidine, homo-histidine, phenylene Ruaranin, Homofue two Ruara two emissions, tyrosine, Toributofan, cysteine, Mechionin, methylcarbamoyl O Nin sulfoxide, methylcarbamoyl O Nin sulfone, homocitrulline, citrulline, / 3-Mechirudarutami phosphate, / 3- methyl homoglutamine acid, O-carboxymethyl-threonine, S- force Rubokishimechiru Bae Nishiramin, ct, 9 over di § amino acid residues, such as propionic acid can be mentioned, et al are.

As the group represented by one NH- A- CO-, or a NH- A 1 -CO- in Formula 2 in Formula 1, preferably, Asuparagin acid, glutamic acid, Homodarutami phosphate, Ol two Chin, lysine, arginine, homocitrulline include residues of citrulline. Preferred examples of the group represented by A 1 in A or Formula 2 in Formula 1, in example embodiment,

Formula: R 2 - (CH 2) s - Z 1 - (CH 2) "one CH =

{Wherein, Z 1, R 2, i and j are as defined above. } Ru include groups represented by.

The substituent of the substituted cyclic hydrocarbon groups and substituted heterocyclic groups in this R 2, the substituted hydrocarbon cyclic group and Substituents of substituted heterocyclic groups, the following are particularly preferable .

Group: a lower alkyl group, a carboxyl group, lower alkoxycarbonyl group, -CO- NHOH, amino group, Amino lower alkyl group, Guanijino group, Guanijino lower § alkyl group, a lower alkylthio group, a lower alkylsulfonyl group, a nitro group, Shiano group a halogen atom, an amidino group, Chio Ichiru group, a hydroxyl group, a sulfo group, a formyl group, a lower alkoxy group, a lower alkylthio group, (which may be lower alk kill group 1 or 2 is substituted) lower alkyl-substituted amino group, tri-lower alkyl ammonium Nio group, hydrin proxy lower alkyl group and the substituted hydrocarbon cyclic group (the substituent, the same thing can be mentioned as the substituents of the "substituted hydrocarbon cyclic group" of the, may be 1 to 3 is substituted), substituted heterocyclic group (as the substituent, the The same thing can be mentioned as the substituents of the "hydrocarbon cyclic group substituted", 1 to 3 may be substituted). The lower Arukanoiru group, for example, Kisanoiru include § Rukanoiru group with carbon number 1-7 straight or branched chain, specifically, Asechiru, propionyl, Butanoiru, 2-methylpropanoyl Noi Le to, Heputanoiru group, and the like.

The Aroiru groups include, for example, § reel carbonyl group of 7-1 1 carbon atoms, specifically, Benzoiru, naphthylcarbonyl and the like.

The alkoxy group include straight-chain or alkoxy group having 1 to 7 carbon atoms in the branched may be mentioned, specifically, main butoxy, Kishiruokishi ethoxy, Purobokishi, butoxy, 2-methyl Provo carboxymethyl to, Hepuchiruokishi group etc. the.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In this specification, one NL ^ -C (= NL 1) _ NL] - phrase case, addition to the described etc. your directory structure, including isomers where the double bond has moved.

Further, in the description of symbols in this specification, -CONL 3 -, - when there the S 0 2 NL 3 Chief, in addition to that which it is joined in this order, including those bound to reverse. The pharmaceutically acceptable salts of the hydroxamic acid derivatives of the formula 1, include acid addition salts and base addition salts. The acid addition salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, inorganic salts such as phosphates, Kuen salt, oxalic acid salt, acetate, formate salt , propionate, benzoate, Torifuruoro acetate, fumarate Le, maleate, tartrate, Asuparagin salt, glutamate, methanesulfonate, and organic acid salts such as benzenesulfonic acid salts. Is the base addition salts include sodium salts, potassium salts, calcium salts, magnesium salts, inorganic base salts such as ammonium © unsalted, tri E chill ammonium Niu unsalted, triethanol ammonium Niu arm salts, Pirijiniumu salt, diisopropyl ammonium Niu organic base salts include, et al are such as unsalted. In the present invention, the salts are acceptable hydroxamic acid derivative or a pharmaceutically formula 1, include solvates such as hydrates thereof. Hydroxamic acid derivatives of the formula 1 may, for example, the manufacturing child according to the production method described below.

R 1 -N (R 3) - A - C0 2 H + H 2 N OR 4 - - R 1 - NH- A - CO - NH OR 4

3 4 5

R - X - B -Q

^ RXBN (R 1) -A- CO-NHOH

1

Wherein, R, X, B, R 1 and A are as defined above. R 3 represents a coercive Mamorumoto of Amino group, R 4 represents benzyl, t one heptyl, t one heptyl dimethylsilyl, trimethylsilyl, trityl, tetrahydropyran Vila alkenyl or benzhydryl. Q represents a hydroxyl group, a chlorine atom, a bromine atom or an iodine atom. ]

The protecting group of the Amino group represented by R 3, there may be mentioned protecting groups which are usually used, preferably, t one-butoxycarbonyl, benzyl O alkoxycarbonyl, p- two Torobe Nji Ruo butoxycarbonyl, p- main butoxy benzyl O alkoxycarbonyl include those that can be deprotected easily by hydrogenation or hydrolysis of 9 such one full O Les methylpropenylmethyl O butoxycarbonyl.

The condensation reaction of a compound of formula 3 with a compound of formula 4 can be carried out according to methods known to peptide chemistry ( "Fundamentals and Experiments of peptide synthesis" Nobuo Izumiya et al, Maruzen, etc.). For example, C terminal activation methods (acid halide method, acid azide method, mixed acid anhydride method, active E ester method, symmetric acid anhydrides, etc.), a method using a coupling reagent (N, N '- dicyanamide Black hexyl Cal positive imide method using a (DCC), etc.), N terminal activation methods (iso Shiana one method, a Hosufazo method, the phosphite method, and the like) and the like. As a method of using a coupling reagent, for example, a compound with a compound of formula 4 of the formula 3, N, N-dimethyl formamidine de (DMF) in N- (dimethylaminoethyl) Single N 'one Echirukarupoji imide hydrochloride (WSC hydrochloride) and 1-hydroxy-benzo preparative Riazo Ichiru (HOB t) the presence, in 0 ° Celsius to room temperature, a method for condensation, and the like. A compound obtained by condensation reaction, followed by, the protecting group of the Amino group represented by R 3 is thus deprotecting a conventional method, to give a compound of formula 5. As R 3 t-butoxycarbonyl, benzyl O alkoxycarbonyl, p - two Toro benzyl O propoxycarbonyl sulfonyl, p- main butoxy benzyl O butoxycarbonyl, 9-O-les methylpropenylmethyl O propoxycarbonyl case of using two Le etc. may a child deprotected by hydrogenolysis or hydrolysis.

The reaction of hydrogenolysis, for example, using a hydrogenation catalyst (e.g. a palladium catalyst or the like), in an inert organic solvent (e.g. methanol, ethanol, etc.), if necessary, acetic acid, an acid such as hydrochloric acid were added Te under a hydrogen atmosphere, can be reacted at room temperature. The reaction of hydrolysis, for example, acetic, Torifuruoro acetic acid, methanesulfonic acid, p - toluenesulfonic acid, sulfuric acid, hydrochloric acid, the presence of an acid such as hydrobromic acid, solventless or is in the water-containing organic solvent, at room temperature it can react. Condensation with a compound of formula 6 of the formula 5, Ru can be carried out as follows.

(1) If B in 6 is a carbonyl group

In Equation 6, Q is a hydroxyl group, a chlorine atom, with a compound of a bromine atom or an iodine atom, preferably reacted with a compound of formula 5. This reaction can be carried out in the same manner as the condensation reaction of the compound of formula 3 with a compound of formula 4.

(2) If the 6 B is a methylene group

In Equation 6, Q is a chlorine atom, with a compound of a bromine atom or an iodine atom, preferably reacted with a compound of formula 5. Reaction of the compound with a compound of formula 6 of the formula 5 can be reacted under the same conditions as conventional nucleophilic substitution reaction. For example, in DMF compound of a compound of formula 6 of the formula 5 in the presence of potassium carbonate, and this is reacted at room temperature.

Further, in the equation 6, wherein: B- Q (. B and Q are the same as defined above) moiety which is table with compounds representative of the formyl group in, the compound of formula 5, for "Organic Chemistry Experiment Guide 3 "(Toshio Goto et al., Kagaku Dojin) according to the method such as that described in, it is also possible to perform reductive amination reaction.

(3) In the equation 6 when B is sulfonyl group

In Equation 6, Q is a chlorine atom, with a compound of a bromine atom or an iodine atom, preferably reacted with a compound of formula 5. For example, in DMF with the compound of compound of formula 6 of the formula 5 in the presence of Toryechiruamin, at room temperature, it can be reacted. A compound obtained by condensation reaction, followed by a protective group for a hydroxyl group represented by R 4 By accordance connexion deprotected conventional method, to give a compound of formula 1. For example, hydrogenolysis, in hydrolyzed or non-aqueous solutions as possible out be deprotected by treatment with a Lewis acid. Specific reaction conditions, the same conditions or Ξ boron bromide in an aprotic solvent such as methylene chloride, boron trichloride, and the like due to trimethylsilane iodide. However, protecting groups Amino groups represented by R 3 includes a hydroxyl-protecting group represented by R 4, have the preferred for deprotection conditions to select a different protecting group. Compounds of formula 6, depending on the type of group represented by X, can be prepared as follows.

(1) When X is an alkylene group

Compounds of formula 6, or prepared according to a conventional method, or optionally, for example, bit Tihhi reaction was homologation by Horner-Emmons reaction or the like, by Rukoto to further reduce the double bond, by extending the alkylene group it can be produced.

(2) ether bond in the group represented by X, Chioe one ether bond, a sulfinyl group, if there is a sulfonyl group or Imino group

Compounds of Formula 6, in a conventional manner, by nucleophilic substitution reaction, an ether bond, by forming the Chio ether bond or an imino group, optionally further acid the Chioe one ether, can be produced. Or by reductive Amino reaction, it can also be formed Imino group.

(3) amino-de-binding or compounds when Formula 6 sulfonamide linkage thereof is present in the group represented by X, it may be prepared by condensing corresponding amine with the acid in the same manner as in the above manner it can.

Among the groups represented by (4) X, wherein: A NL '- C (= NL] ) one NL 1 - (in, have has the same meaning as defined above.) If there is a group represented by

R- (CH 2) p - NL 1 H R- (CH 2) p -NL 1 NL

8 SMe

Wherein, R, p, L 1, q, and B and Q are as defined above. Q 1 represents a protected force Rupokishiru groups, protected hydroxymethyl group or a protected mercapto group. ]

Compounds of Formula 6, for example, according to Synthesis, 1988, 456, can be prepared as described above. That, is reacted with base down zone I Louis Seo thio Xia Ne one preparative compound of Formula 7, followed by de-Benzoiru reduction, by subsequent treatment with methyl iodide to produce the compound of formula 8. The compound of formula 8, by nucleophilic substitution reaction of the compound of formula 9, with a compound of formula 1 0, further, deprotection, and optionally, by performing oxidation or Z and halogenated, it can be prepared a compound of formula 1 1.

(5) Among the groups represented by X, - the formula: - NL 2 - CO- NL 2 - or formula: - 0- C 0- NL 2 - _ ( wherein, L 2 is a as defined above when the group represented by.) present

L 2 HN - (CH 2) q - Q 1 CI 3 C - NL 2 - (CH 2) q - Q 1

12 13

O 15

R - (CH 2) p L 2 - (CH 2) q -B - Q

O 16

Wherein, R, p, L 2, q, B, Q and Q 1 are as defined above. Q 2 is an oxygen atom or a NL 2 - represents a (L 2 are as defined above.). ]

Compounds of Formula 6, for example, Angew. Chem. Int. Ed., Can be prepared as described above in accordance with 26, 894 (1997). That is, the compound of formula 1 3 by black port formylated by the action of triphosgene to the compound of formula 1 2, further reacting the the reduction compound formula 1 4, further deprotection and optionally, by performing the oxidation or and halogenation can be produced a compound of formula 1 6.

(6) when a force carbonyl group in the groups represented by X are present

Compounds of Formula 6, for example, according to a conventional method, by reacting Gurinya Lumpur reagent to the corresponding aldehyde, can be prepared by oxidizing the hydroxyl group to generate subsequently.

Compounds of formula 3 can be synthesized by using a known method or a similar method as compound of formula 6 above.

In the above reaction, the compound of formula 3, by reacting a compound of formula 4, but further described what order reacting of compound of formula 6, in a different order, the compound of Formula 6, Formula 3 reacting a compound or compounds of formula 3 in which the carboxy group is protected, followed be properly is after removal of the protecting group of a carboxy group, may be reacted with a compound of formula 4.

Incidentally, in the hydroxamic acid derivative of formula 1, if the functional group that changes the above reaction conditions is present, preferably it keeps protect them. As the protecting group, it can be used normally known ones.

Hydroxamic acid derivatives of the formula 1 according to a conventional method, it is a child in a pharmaceutically acceptable salt. Acceptable salts hydroxamic acid derivative or a pharmaceutically formula 1 is formulated in accordance with pharmaceutical formulations may be adapted to oral or parenteral (injection (intravenous, intramuscular meat, subcutaneous, intraarticular) , transdermal, ophthalmic, suppository, as possible out be administered in intranasal, etc.). When administered orally, as the formulation forms, such as tablets, capsules, pills, granules, powders, solutions, may be in the form of such syrups. When administered parenterally, the pharmaceutical forms, injectable aqueous agents or oily, ointments, creams, lotions, patches, can be in the form of such aerosols. These formulations can be prepared according to conventional methods. For example, hydro Kisamu acid derivative or excipients in a pharmaceutically acceptable salt thereof of formula 1, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending agents, such as coatings, pharmaceutical It may be formulated using known adjuvants usually used in formulation technology partial fields.

The dose of acceptable salt hydroxamic acid derivative or a pharmaceutically formula 1, the number of administration times on the patient's condition, weight, age, varies administration methods and dosage forms, usually for adults, 1 曰per, 1~ 1, 0 0 O mg, preferably be administered once to several times a 5 to 3 0 O mg. Example

The following examples are not intended to be limiting as to explain the present invention.

Examples of specific compounds of the present invention, for example, can include the following compounds. CONHOH

COONa

CONHOH

COONa

ZPS £ 0 / L6d £ / lDd

HOHNOO

Roh Z

ZPS £ 0 / L6d £ flDd

CONHOH

COONa

6Z

ZPS £ 0 / L6d £ / ΣOd

I C

Z SZ0 / L6d £ / lDd

Shed seo / arm 6df / JL: W

ZfS £ 0IL6dr / lDd

o

HOHNOO

92

ZtS £ 0 / L6d £ / lDd cn

Shed SCO / arm 6dfAi: 



SZSST / 86 OAV

41

6 O ZsAVvo ifed

Dimensions

Example 1

(4 R) - 5 - (hydroxymethyl § Mino) 5 one Okiso one 4- [(1 0-phenylene Rudeka amino pentanoic acid

(4 R) - 5- [(Benjiruokishi) Amino] one 5-Okiso one 4 one [(1 0 Hue Nirudekanoiru) Amino] base pentanoic acid Njiru (1 g, 1. 99mmo l) the main Tano Ichiru (1 0 m l), tetrahydrofuran (THF) (1 0m l), acetic acid (0. 5 m l), was dissolved in a mixed solvent of water (0. 5m 1), 1 0% - palladium Bruno carbon (20 Omg) was added, It was stirred for 7 hours under hydrogen atmosphere. The catalyst was filtered and vacuum evaporated Solvent, the residue by crystallizing the in E one ether, (4 R) - 5 one (hydroxyamino) Single 5- Okiso one 4- [(1 0 - to give 6 3 1 mg of phenylalanine dec Noi Le) § amino] pentanoic acid.

] H-NMR δ (DMSO- d 6) 10. 62 (b rs, 1H), 7. 20-7. 32 (m, 2H), 7. 05-7. 20 (m, 3H), 4. 16 (dd, 1 H, J = 8. 24Hz, 11. 56Hz), 2. 55 (t, 2H, J = 7. 59Hz), 2. 21 (m, 2H), 2. 09 (m, 2H), 1. 79 (m, 2 H), 1. 46 (m, 2H), 1. 23 (s, 1 OH) was used as the starting material (4 R) - 5- [(Benjiruokishi) Amino] - 5- O Kiso one 4- [(1 0-phenylpropyl dec Noi Le) Amino] pentanoic acid benzyl was prepared as follows.

(A) (4 R) - 5- [(Benjiruokishi) Amino] -4 one [(t-Bed

Boniru) Amino] one 5-Okisopentan acid base Njiru

(4 R) - 5- [(Benjiruokishi) Amino] one 4 one [(t chromatography Bed

Yl) Amino] - 5- Okisopentan acid (2 5 g, a 74. 1 mm o 1) was dissolved in THF (28 Om 1), N- methylmorpholine (8. 1 5m l, 74. 1 mm o 1) after addition of isobutyl chloroformate (1 0. lml, 74. l mmo l) a - added at 1 5 ° C, and stirred for 15 minutes. To 0 benzyl hydroxy § Min hydrochloride (1 1. 8 3 g, 874. l mmo l) and N- methylmorpholine (8. 1 5m 1, 74. l mmo l) was added to 1.5 hours with stirring and further stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with acetic acid Echiru, the organic layer 1 0% - Kuen acid solution, saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off The solvent was distilled off under reduced pressure, by recrystallization from hexane the residue to ether one, (4 R) - 5 - [(base Njiruokishi) Amino] _4- [(t one butoxycarbonyl ) Amino] - 5-O the Kisopentan benzyl give 27. 4 g.

^ -NMR δ (CDC 1 3) 9. 13 (b rs, 1 H), 7. 34 (b rs, 1 OH), 5, 23 (b rd, 1 H, J = 8, 58Hz), 5, 10 (s, 2H), 4, 88 (s, 2H), 4. 02 (m, 1H), 2. 45 (m, 2H), 2. 06 (m, 1 H), 1. 93 (m, 1 H), 1, 41 (s, 9H) (B) (4 R) - 5 - [(Benjiruokishi) Amino] one 5-Okiso one 4 - [(1 0 one phenylalanine dec Noi Le) Amino] pentanoic acid base Njiru

(4 R) one 5- [(Benjiruokishi) Amino] one 4 one [(t-butoxycarbonyl) yl Amino] one 5-Okisopentan acid base Njiru (2. 2 1 g, 5mmo l) the Asetonitoriru (25 m 1) was suspended in ice water cooling under methanesulfonic acid (3. 8 4 g, 40 mm 0 1) was added and stirred for one hour. Toryechiruamin (4. 04 g, 40mmo l) was added, 1 0 Fuenirudekan acid (1. 49 g, 6 mm o 1) and HO B t (8 1 0mg, 6 mm o 1) and WSC. HC 1 (1 . 1 5 g, 6 m mo 1) was added, and stirred for 30 minutes and allowed to stand overnight at room temperature. 1 N-hydrochloric acid was added, followed by extraction with acetic acid Echiru, the organic layer was washed with saturated aqueous sodium bicarbonate, washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue silica force gel strength column chromatography (stationary phase: silica gel 60, 7 0 230 mesh, 1 50 g, mobile phase: hexane Z acetate Echiru = papermaking rectification in 3 Z2), by crystallization in ether, (4 R) - 5- [(Benjiruoki Shi) Amino] _ 5 _ Okiso one 4- [(1 0-phenylpropyl dec Noi Le) Amino] the pentane benzyl 1. give 38 g.

J H - NMR δ (CDC 1 3) 9. 64 (s, 1H), 7. 33 (s, 1 OH), 7. 25 (d, 2H, J = 4. 30Hz), 7. 15 (m, 3H), 6. 43 (d, 1 H, J = 7. 92Hz), 5. 09 (s, 2H), 4. 87 (s, 2H), 4. 36 (m, 1 H), 2. 58 (t, 2H, J = 7. 26Hz), 2. 45 (m, 2H), 2. 10 (t, 2H, J = 7. 26Hz), 2. 01 (m, 2H), 1. 56 (br one t, 4H), 1. 24 (b rs, 1 OH) example 2 (4 R) Single 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- [(1 0-phenylene Rudeka Noiru) amino] sodium pentanoic acid salt

(4 R) Single 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- [(1 0-phenyl Dekanoiru) Amino] pentanoic acid (600mg, 1. 53 mm o 1) the methanol one Le (7 m 1) and added to a mixed solvent of water (2 1 m 1), in addition 5 N-hydroxide Natoriumu aqueous solution (306 ^ 1) and stirred for 15 minutes at room temperature. The residue and the solvent was distilled off under reduced pressure and recrystallized with a mixed solvent of methanol and ether, (4 R) - 5- (hydroxymethyl Amino) Single 5- Okiso one 4 one [(1 0-phenylpropyl dec Noi Le) Amino] sodium salt pentanoic acid was obtained 609 mg.

iH-NMR δ (DMSO-d 6) 9.62 (d, 1 H, J = 7.25Hz), 7.25 (m, 2H), 7.17 (m, 3H), 4.05 (dd, 1 H, J = l 4.17Hz) , 2.55 (t, 2H, J = 7.2 6Hz), 2.06 (m, 2H), 1.99 (m, 2H), 1. 73 (m, 2H), 1.55 (m, 2 H), 1.46 (m, 2H) , 1.23 (br- s, 1 OH) example 3

(4 R) Single 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- [(8-Fueniruokuta Noiru) Amino] pentanoic acid

(4 R) - 5 One [(8-full E sulfonyl O Kuta Noi Le) Amino] pentanoic acid base Njiru (3 1. 7 g, 57. 1 mm o 1) the THF (200 ml), methanol Ichiru (200 ml), acetic acid (7 . 5 m 1), was dissolved in a mixed solvent of water (7. 5 m 1), 1 0% - palladium Bruno carbon (6 g) was added, and the mixture was stirred for 5 hours under hydrogen atmosphere. The catalyst was removed by filtration, The solvent was evaporated under reduced pressure, the residue was washed with E one ether, to give the desired compound 20. 56 g.

] H-NMR δ (DMSO d 6) 10. 59 (b rs, 1H), 7. 93 (d, 1 H, J = 8. 25Hz), 7. 26 (m, 2H), 7. 18 (m , 3H), 4. 15 (dd, 1 H, J = 8. 25Hz, 14. 18Hz), 2. 55 (t, 3H, J = 7. 59Hz), 2. 18 (m, 2H), 2. 10 (m, 2H), 1. 76 (m, 2H), 1. 55 (m, 2H), 1. 46 (m, 2H), 1. 27 (b rs, 6 H) was used as the starting material ( 4 R) - 5 - [(Benjiruokishi) Amino] one 5-O Kiso one 4 one [(8-phenylene Ruokutanoiru) Amino] pentanoic acid benzyl was prepared as follows.

(4 R) - 5 - [(Benjiruokishi) Amino] -4 one [(t-butoxycarbonyl two Le) Amino] one 5-Okisopentan benzyl (3 5. 1 g, 7 9. 4 mm o 1) the Asetonitoriru (350 m 1), and the suspension under ice water cooling with methanesulfonic acid (4 1. 2m l, 6 3 5 mm o 1) was added and stirred for one hour. Toryechiruamin (88. 5m l, 635 mm o 1) was added, 8-phenylalanine octanoate (1 7. 5 g, 79. 4mm o 1) and HOB t (1 0. 72 g, 7 9. 4mmo l) and WSC · HC 1 (1 5. 3 g, 79. 4mmo 1) was added, and stirred for 30 minutes and allowed to stand overnight at room temperature. 1 N-hydrochloric acid was added, followed by extraction with acetic acid Echiru, the organic layer was washed with saturated aqueous sodium bicarbonate, washed with saturated brine and dried over anhydrous magnesium sulfate. Except desiccant by filtration, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chroma Togurafi one silica gel 60, 70-2 30 mesh, 2000 g, mobile phase: hexane / acetic acid Echiru == 3/2) in purified by crystallization from a mixture of black port Holm and E one ether, (4 R) - 5-[(Benjiruokishi) Amino] one 5 - Okiso one 4_ [(8-phenylene Ruokutanoiru) Amino] pentanoic acid benzyl 3 1. give 7 g.

J H-NMR 5 (CDC 1 3) 9. 73 (b rs, 1H), 7. 32 (b rs, 1 OH), 7. 2 4 (d, 2H, J = 5. 28Hz), 7. 16 (m, 3H), 5. 08 (b rd, 1 H, J = 7. 26 Hz), 5. 08 (s, 2H), 4. 86 (s, 2H), 4. 38 (b rd, 1 H, J = 7. 26Hz), 2. 57 (t, 2H, J = 7. 92Hz), 2. 44 (m, 2H), 2. 10 (m, 2H), 2. 01 (m, 2H) , 1. 58 (m, 4H), 1. 28 (s, 6H) example 4

(4 R) --5 - (hydroxy § Mino) Single 5- Okiso one 4- [(8-Fueniruokuta Noiru) Amino] sodium salt pentanoic acid

(4 R) one 5- (hydroxymethyl § Mino) _ 5- Okiso one 4- [(8-Fueniruo Kutanoiru) Amino] pentanoic acid (20. 39 g, 56 mm o 1) water (750 ml) and methanol ( 250 m 1) mixture is dissolved in a solvent, under ice water cooling, 5 N- water sodium hydroxide aqueous solution (1 1. 2m l) was added and stirred for 2 hours. The solvent was distilled off under reduced distillation, the residue by methanol, crystallized child in a mixed solvent of hexane ether and to the, (4R) - 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- [(8-Hue two Ruokutanoiru) Amino] sodium salt pentanoic acid to give 20. 57 g. J H- NMR δ (DMSO- d 6 ) 10. 42 (b rs, 1H), 8. 43 (d, 1 H, J = 7. 59Hz), 7. 26 (m, 2H), 7. 15 ( m, 3H), 4. 10 (dd, 1 H, J = 7. 59Hz, 14. 85Hz), 2. 55 (t, 2H, J = 7. 59Hz), 2. 08 (t, 2H, J = 7. 58H z), 1. 96 (t, 2H, J = 7. 26Hz), 1. 73 (m, 2H), 1. 52 (m, 2H), 1. 4 5 (m, 2H), 1 . 26 (b rs, 6H) example 5

(4 R) - 5- (hydroxymethyl § Mino) Single 5- Okiso one 4 one [(3-Fuenirupuropa Noiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) _ 5 Okiso _4 one [(3-phenylpropyl prop Noi Le) Amino] pentane acid Njiru (lg) from (4R) - 5- (hydroxymethyl § Mino) one 5-O key source 4 one [(3-phenylpropyl prop Noi Le) amino] pentanoic acid to give 552 mg.^ -NMR δ (DMSO- d 6) 10. 63 (b rs, 1H), 8. 04 (d, 1 H, J = 8.

25Hz), 7. 2 l (m, 5H), 4. 17 (dd, 1 H, J = 8. 24Hz, 14. 18Hz), 2. 80 (t, 2H, J = 7. 25Hz), 2. 43 (dt, 2H, J = 3. 30Hz, 7. 92Hz), 2. 1 (t, 2H, J = 7. 59Hz), 1. 78 (m, 2H)

It was used as the starting material (4 R) - 5- (benzyl O carboxymethyl § mino) _ 5-O key source 4 one [(3 _ phenylalanine prop Noi Le) Amino] benzyl pentanoate second section of Example 1 obtained cowpea in an analogous manner to that described.

] H- NMR δ (CDC 1 3) 9. 62 (d, 1H), 7. 33 (m, 15H), 6. 49 (d, 1 H, J = 7. 58Hz), 5. 08 (s, 2H), 4. 84 (s, 2H), 4. 36 (dd, 1 H, J = 7. 58Hz, 13. 84Hz), 2. 85 (t, 2H, J = 7. 59Hz), 2. 42 (m, 2H), 2.

33 (m, 2H), 1. 92 (m, 2H) Example 6

(4 R) - 5 - (hydroxymethyl § amino) Single - 5- Okiso one 4- _ [(4 one Fuenirubutano I le) Amino] pentanoic acid

(4 R) - 5 - (benzyl O carboxymethyl § mino) Single 5- Okiso one 4 one [(4-phenylene Rubutanoiru) Amino] base pentanoic acid Njiru (lg, 2 mm o 1) the THF (1 0 m 1 ), methano Ichiru (1 0 m l), acetic acid (0. 5 m l), was dissolved in a mixed solvent of water (0. 5m l), 1 0% - palladium Bruno carbon (20 Omg) was added, hydrogen Kiri囲and the mixture was stirred for 9 hours under the gas. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, the residue was purified by silica gel force column chromatography (stationary phase: silica gel 60, 70- 230 mesh Interview, 30 g, mobile phase: black port Holm Bruno methanol Bruno acetate = 1 . 0Z 1 was purified from 0.1 to 5/1/0 1), by methanol and ether, and to a mixed solvent of hexane is sintered crystallized, (4 R) - 5 - (hydroxymethyl § Mino) Single 5 - Okiso one 4 - the (4 one-phenylalanine pig Noi Le) Amino] pentanoic acid to give 1 2 Omg.

] H-NMR δ (DMSO- d 6) 10. 69 (b rs, 1H), 8. 10 (br_s, 1H), 6. 90-7. 26 (m, 5H), 4. 19 (m, 1H ), 2. 55 (m, 2H, J = 7. 92Hz), 2. 14 (b rd, 4H), 1. 78 (b rt, 4H)

Used as starting material (4 R) - 5- (the benzyl O carboxymethyl § mino) Single 5- Okiso 4- [(4-phenylpropyl pig Noi Le) Amino] benzyl pentanoate second section of Example 1 It was prepared by analogous method to that described.

NMR δ (CDC1 3) 9. 33 (s, 1H), 7. 13-7. 37 (m, 15H), 6. 30 (d, 1H, J = 7. 90Hz), 5. 09 (s, 2H ), 4. 87 (s, 2H), 4. 31 (m, 1H), 2. 60 (t, 2H, J = 7. 59Hz), 2. 26-2. 57 (m, 2H), 1. 82- 2. 20 (m, 6H) example 7 (4 R) - 5 - (hydroxymethyl § Mino) Single 5- Okiso one 4 one [(5-phenylene Rupenta Noiru) amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4- [(5-phenylene Rupentanoiru) Amino] pentane acid base Njiru (lg) from (4 R) - 5 - (hydroxyamino) an 5-O key saw 4- [(5-phenylene Rupentanoiru) amino] pentanoic acid to give 5 94m g.} H-NMR 8 (DMSO- d 6) 10. 63 (b rs, 1H), 8. 00 (d, 1 H, J = 8. 24Hz), 7. 2 l (m, 5H), 4. 15 (dd, 1 H, J = 8. 24Hz, 14. 51Hz), 2. 56 (t, 2H, J = 6. 93Hz), 2. 15 (m, 4H), 1. 79 (m, 2H), 1. 70 (b r- s, 4H)

Used as starting material (4 R) - 5 - (benzyl O carboxymethyl § mino) Single 5- Okiso 4- [(5 _ phenylene Rupentanoiru) Amino] benzyl pentanoic acid according to Section II of Example 1 It was prepared by a method analogous.

] H-NMR 8 (CDC 1 3) 9. 61 (s, 1 H), 7. 33 (b rs, 1 OH), 7. 21 (m, 5H), 6. 44 (d, 1H, J = 7. 92Hz), 5. 08 (s, 2H), 4. 86 (s, 2H), 4. 34 (dd, 1H, J = 7. 92Hz, 14. 2Hz), 2. 59 (b rs, 2H ), 2. 34 (m, 2H), 2. 12 (b rs, 2H), 1. 97 (m, 2H), 1. 59 (b rs, 4H) example 8

(4 R) one 5- (hydroxyamino) 5-Okiso one 4- [(the 6-phenyl hexa Noiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) Single 5- Okiso [(Kisanoiru to 6 phenyl) Amino] one 4-pentane acid base Njiru from (1. 1 g) (4 R) - 5- (hydroxyamino) Single 5- Okiso one 4 - [(to 6- phenyl Kisanoiru) amino] pentanoic acid was obtained 602 mg.

] H-NMR 8 (DMSO- d 6) 10. 95 (br - s, 1H), 8. 31 (d, 1 H, J = 8. 24Hz), 7. 58 (m, 2H), 7. 47 (m, 3H), 4. 46 (dd, 1 H, J = 8. 24Hz, 14. 51Hz), 2. 86 (t, 2H, J = 7. 59Hz), 2. 48 (m, 4H), 2. 09 (m, 2H), 1. 84 (m, 4H), 1. 58 (m, 2H)

Used as starting material (4 R) - 5 - according to (benzyl O carboxymethyl § mino) Single 5- Okiso one 4 one [(Kisanoiru to 6 phenyl) Amino] pentanoic acid benzyl second section of Example 1 It was prepared by a method analogous.

] H-NMR 5 (CDC 1. 9. 73 (s, 1H), 7. 28 (m, 12H), 7. 12 (m, 3H), 6. 48 (d, 1H, J = 7. 58Hz) , 5. 08 (s, 2H), 4. 86 (s, 2H), 4. 38 (dd, 1H, J = 7. 58Hz, 14. 51Hz), 2. 57 (t, 2H, J = 7. 59Hz), 2. 4 2 (m, 2H), 2. 09 (t, 2H, J = 7. 26Hz), 2. 00 (m, 2H), 1. 58 (m, 4 H), 1. 3 l (m, 2H) example 9

(4 R) - 5 - (hydroxymethyl § Mino) over 5 Okiso one 4 one [(the 6-phenyl hexa Noiru) ^ amino] pentanoic acid - sodium salt

In an analogous manner to that described in Example 2, (4 R) - 5 - (hydroxymethyl amino) _ 5 Okiso one 4 one [(6-phenyl to Kisanoiru) Amino] pentanoic acid (4 0 0 mg) from (4 R) - 5- (hydroxymethyl § Mino) Single 5- Okiso [(the 6-phenyl Kisanoiru) amino] one 4- to give 4 1 5 mg of sodium pentanoic acid salts.

^ -NMR δ (DMSO-d 6 ) 10. 22 (b rs, 1H), 8. 45 (d, 1 H, J = 7. 25Hz), 7. 27 (m, 2H), 7. 15 (m , 3H), 4. 04 (dd, 1 H, J = 7. 26Hz, 13. 86Hz), 2. 54 (t, 2H, J = 7. 59Hz), 2. 08 (m, 2H), 1. 96 (t, 2H, J = 6. 93Hz), 1. 73 (m, 2H), 1. 52 (m, 4H), 1. 26 (m, 2H) example 1 0

(4 R) - 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- j (7-- Hue.

Noiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4 one [(7-phenylalanine hept Noi Le) Amino] pentane acid base from Njiru (lg) (4 R) - 5- (hydroxymethyl amino) one 5-O Kiso one 4 one [(7-phenylalanine hept Noi Le) amino] pentanoic acid to give 488 mg. ] H-NMR δ (DMSO- d 6) 10. 6 (b rs, 1H), 7. 95 (d, 1 H, J = 8. 2 5Hz), 7. 2 l (m, 5H), 4. 15 (dd, 1 H, J = 8. 25, 14. 19Hz), 2. 55 (t, 2H, J = 7. 95Hz), 2. 13 (m, 4H), 1. 77 (m, 2H) , 1. 51 (m, 4H), 1. 27 (s, 4H)

Used as starting material (4 R) - 5- (the benzyl O carboxymethyl § mino) _ 5 Okiso 4- [(7-phenylalanine hept Noi Le) Amino] benzyl pentanoate second section of Example 1 It was prepared by analogous method to that described.

J H-NMR 5 (CDC 1 3) 9. 6 l (s, 1H), 7. 33 (m, 1 OH), 7. 26 (m, 2H), 7. 16 (m, 3H), 6. 4 l (d, 1 H, J = 8. 25Hz), 5. 08 (s, 2H), 4. 87 (s, 2H), 4. 37 (m, 1 H), 2. 57 (t, 2H , J = 7. 92Hz), 2. 44 (m, 2H), 2. 09 (t, 2H, J = 7. 26Hz), 1. 98 (m, 2H), 1. 56 (m, 4H), 1. 30 (b r- s, 4H) example 1 1

(4 R) Single 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- [(9-Hue.

I le) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4- [(9-phenylalanine nonanoyl I le) Amino] pentane acid Njiru (lg) from (4 R) - 5- (hydroxymethyl § Mino) Single 5 Okiso - 4 scratch [(9-phenylalanine nonanoyl I le) amino] pentanoic acid to give 58 Omg.

^ -NMR δ (DMSO- d 6) 10. 64 (b rs, 1H), 7. 98 (d, 1 H, J = 8. 24Hz), 7. 26 (m, 2H), 7. 19 (m , 3H), 4. 14 (dd, 1 H, J = 8. 24Hz, 14. 52Hz), 2. 55 (t, 2H, J = 7. 26Hz), 2. 17 (m, 2H), 2. 09 (m, 2H), 1. 77 (m, 2H), 1. 53 (m, 2H), 1. 46 (m, 2H), 1. 25 (b rs, 8 H)

Used as starting material (4 R) - 5 - (the benzyl O carboxymethyl § mino) _ 5 Okiso -4 one [(9 _ phenylalanine nonanoyl I le) Amino] benzyl pentanoate second section of Example 1 It was prepared by analogous method to that described.

] H-NMR δ (CDC 1 3) 9. 6 l (s, 1H), 7. 31 (m, 12H), 7. 17 (m, 3H), 6. 41 (d, 1H, J = 7. 92Hz), 5. 09 (s, 2H), 4. 87 (s, 2H), 4. 35 (dd, 1H, J = 7. 92Hz, 14. 85Hz), 2. 58 (t, 2H, J = 7. 26Hz), 2. 4 0 (m, 2H), 2. 03 (m, 4H), 1. 56 (m, 4H), 1. 29 (b rs, 8H) example 1 2

(4 R) - 5 - (hydroxymethyl § Mino) Single 5- Okiso one 4- [(1 1 one phenylene Ruun Dekanoiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4- [(1 1 one phenylalanine © down dec Noi Le) amino ] base pentanoic acid Njiru from (1. 48 g) (4 R) - 5- (hydroxymethyl amino) Single 5- Okiso one 4 one [(1 1 one phenylalanine © down dec Noi Le) amino] pentanoic acid 965 It was obtained mg.

H-NMR δ (DMSO - d 6) 12. 10 (b rs, 1H), 10. 63 (s, 1H), 8. 3 l (s, 1H), 7. 97 (d, 1H, J = 8 . 52Hz), 7. 24-7. 29 (m, 2H), 7. 12-7. 18 (m, 3H), 4. 1 (dd, 1 H, J = 8. 52Hz, 14. 19Hz), 2. 55 (t, 2H, J = 6. 86Hz), 2. 17 (m, 2H), 2. 09 (m, 2H), 1. 77 (m, 2 H), 1. 54 (m, 2H ), 1. 45 (m, 2H), 1. 23 (b rs, 12H)

Used as starting material (4 R) - 5 - (benzyl O carboxymethyl § mino) Single 5- Okiso 4- [(1 1 one phenylalanine © down dec Noi Le) Amino] Njiru base pentanoic acid, real 施例It was prepared by methods analogous to those described in 1 Section II.

^ -NMR 8 (CDC 1 3) 9. 7 l (s, 1H), 7. 30 (m, 12H), 7. 16 (m, 3H), 6. 45 (d, 1H, J = 8. 24Hz ), 5. 09 (s, 2H), 4. 87 (s, 2H), 4. 38 (dd, 1H, J = 8. 24Hz, 14. 84Hz), 2. 59 (t, 2H, J = 7 . 26Hz), 2. 4 4 (m, 2H), 2. 10 (m, 2H), 2. 01 (m, 2H), 1. 56 (m, H), 1. 24 (b r- s, 12H) example 1 3

(4 R) - 5- (hydroxymethyl) amino-5-Okiso one 4 [(1 2-phenylene Rudode Kanoiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5 - (benzyl Okishiamino) Single 5- Okiso one 4- [(1 2-phenylene Rudodekanoiru) Amino] base pentanoic acid Njiru from (1. 1 g) (4 R) - 5-(hydroxyamino) an 5 one Okiso _ 4 one [(1 2-phenylene Rudodekanoiru) amino] pentanoic acid to give 655 mg.

H-NMR δ (DMSO-d 6) 10. 64 (b rs, 1H), 7. 85 (d, 1 H, J = 8. 24Hz), 7. 26 (m, 2H), 7. 12 (m , 3H), 4. 14 (dd, 1 H, J = 8. 24Hz, 14. 52Hz), 2. 55 (t, 2H, J = 7. 59Hz), 2. 18 (m, 2H), 2. 09 (m, 2H), 1. 78 (m, 2H), 1. 55 (m, 2H), 1. 45 (m, 2H), 1. 22 (b rs, 1 4H) was used as the starting material ( 4 R) - 5- (benzyl O carboxymethyl § mino) Single 5- Okiso -4 one [(1 2-phenylene Rudodekanoiru) amino] Njiru base pentanoic acid, similar to the method described in Section II of example 1 It was prepared by the method.

One NMR 8 (CDC 1 3) 9. 71 (s, 1H), 7. 31 (m, 12H), 7. 17 (m, 3H), 6. 46 (d, 1H, J = 7. 91Hz), 5. 09 (s, 2H), 4. 87 (s, 2H), 4. 38 (dd, 1H, J = 7. 91Hz, 14. 51Hz), 2. 59 (t, 2H, J = 7. 59Hz ), 2. 4 l (m, 2H), 2. 10 (m, 2H), 2. 01 (m, 2H), 1. 57 (m, 4H), 1. 24 (b r- s, 14H) example 14

(4 R) Single 5- (hydroxyamino) Single 5- Okiso one 4- [(1 3 Fuenirutori Dekanoiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5 - (benzyl Okishiamino) Single 5- Okiso one 4 - [(1 3 phenylpropyl tridecanol Noi Le) § Mi Bruno ] base pentanoic acid Njiru (lg) from (4 R) - 5-(hydroxy § Mino) _ 5 one Okiso one 4 - [give (1 3-phenylpropyl tridecanol Noi Le) amino] pentanoic acid 66 7 mg .

] H - NMR δ (DMSO - d 6) 10. 63 (s, 1H), 7. 98 (d, 1 H, J = 8. 24H z), 7. 27 (m, 2H), 7. 19 ( m, 3H), 4. 14 (dd, 1 H, J = 8. 25Hz, 14. 19Hz), 2. 55 (t, 2H, J = 7. 26Hz), 2. 18 (m, 2H), 2 . 09 (m, 2H), 1. 8 Km, 2H), 1. 54 (m, 2H), 1. 45 (m, 2H), 1. 22 (b rs, 16H) was used as the starting material (4 R) - 5 - (benzyl O carboxymethyl § mino) Single 5- Okiso 4- [(1 3 phenylpropyl tridecanol Noi Le) amino] Njiru base pentanoic acid, according to the second section of the actual Example 1 It was prepared by a method analogous.

JH-NMR δ (CDC 1 3 ) 9. 73 (s, 1H), 7. 30 (m, 12H), 7. 16 (m, 3H), 6. 46 (d, 1H, J = 8. 24Hz) , 5. 08 (s, 2H), 4. 87 (s, 2H), 4. 38 (dd, 1H, J = 8. 24Hz, 14. 84Hz), 2. 59 (t, 2H, J = 7. 59Hz), 2. 4 l (m, 2H), 2. 10 (m, 2H), 2. 01 (m, 2H), 1. 57 (m, 4H), 1. 24 (b r- s, 16H ) example 1 5

(4 R) one 5 (hydroxyamino 5 Okiso one 4 one [(14 one phenylene Ruteto off Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4R) - 5- (benzyl Okishiamino) Single 5- Okiso _ 4 one [(14-phenylpropyl tetradecanol Noi Le) amino] pentanoic acid base from Njiru (1 g) (4 R) - 5-(hydroxyamino) one 5 - Okiso 4 scratch [(14 one-phenylalanine tetradecanol Noi Le) amino] pentanoic acid to give 7 06mg.

- NMR δ (DMSO - d 6 ) 10. 59 (s, 1H), 7. 94 (d, 1 H, J = 8. 58H z), 7. 26 (m, 2H), 7. 18 (m, 3H), 4. 15 (dd, 1 H, J = 8. 58Hz, 14. 51Hz), 2. 55 (t r 2H, J = 7. 26Hz), 2. 18 (m, 2H), 2. 09 (m, 2H), 1. 77 (m, 2H), 1. 55 (m, 2H), 1. 45 (m, 2H), 1. 23 (br- s, 18H) was used as the starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 5 Okiso - - [(14 one-phenylalanine tetradecanol Noi Le) amino] Njiru base pentanoic acid, similar to the method described in Section II of example 1 It was prepared by the method.^ -NMR 8 (CDC 1 3) 9. 92 (s, 1H), 7. 33 (m, 12H), 7. 19 (m, 3H), 6. 55 (d, 1H, J = 7. 92Hz) , 5. 08 (s, 2H), 4. 87 (s, 2H), 4. 42 (dd, 1H, J = 7. 92Hz, 14. 52Hz), 2. 59 (t, 2H, J = 7. 59Hz), 2. 4 0 (m, 2H), 2. 10 (m, 2H), 2. 00 (m, 2H), 1. 58 (m, 4H), 1. 23 (b r- s, 18H ) example 1 6

(3 R) one 4 one (hydroxyamino) 4- Okiso one 3- [- (1 0-phenylene Rudeka Noiru) Amino] butanoic acid

In an analogous manner to that described in the first section of Example 1, (3 R) - 4 one (benzyl Okishiamino) Single 4- Okiso one 3- [(1 0-phenylpropyl dec Noi Le) Amino] Bed Tan from the acid base Njiru (1 g) (3 R)-4-(hydroxy § Mino) Single 4 one Okiso one 3- [(1 0-phenylpropyl dec Noi Le) amino] was butanoic acid obtained 45 Om g.

- NMR δ (DMSO- d 6) 10. 59 (b rs, 1H), 8. 84 (s, 1H), 8. 30 (m, 1H), 8. 01 (m, 1H), 7. 26 ( m, 2H), 7. 18 (m, 3H), 4. 50 (m, 1 H), 2. 40-2. 64 (m, 4H), 2. 06 (t, 2H, J = 7. 3Hz ), 1. 55 (m, 2H), 1. 45 (m, 2H), 1. 13-1. 35 (m, 1 OH)

Used as starting material (3 R) - 4-(benzyl O carboxymethyl § mino) Single 4 one Okiso one 3- [(1 0-phenylpropyl dec Noi Le) Amino] Njiru base butanoic acid, the embodiment 1 It was prepared by methods analogous to those described in Section II.

^ -NMR δ (CDC 1 3) 9. 23 (s, 1H), 7. 36-7. 39 (m, 1 OH), 7. 26 (m, H), 7. 16 (m, 3H), 6. 72 (d, 1 H, J = 8. 91), 5. 13 (s, 2H), 4. 87 (s, 2H), 4. 66 (m, 1H), 2. 9 l (dd, 1 H, J = 4. 29Hz, 16. 83H z), 2. 68 (dd, 1H, J = 4. 29Hz, 16. 83Hz), 2. 59 (t, 2H, J = 7. 59Hz), 2 . 13 (m, 2H), 1. 54 (m, 4H), 1, 26 (b rs, 1 OH) example 1 7

N- {(1 R) - 1- [(hydroxy § amino) carbonyl] _ 5 Ureidopen chill} - 10-phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N-{(1 R) - 1 one [(benzyl O carboxymethyl § amino) carbonyl] - 5-Ureidopenchiru} one 1 0 phenylene Rudekanami de (lg) from N-{(1 R) - 1 one [(hydroxy § Mino) Cal Boniru] - 5- Urei Dopenchiru} - 1 0 Hue two Rudekanami de afford 758 mg.

^ -NMR δ (DMSO- d 6) 10. 6 l (s, 1H), 8. 81 (s, 1H), 7. 9 l (d, 1H, = 8. 10Hz), 7. 27 (m, 2H), 7. 16 (m, 3H), 5. 87 (t, 1 H, J = 5. 28Hz), 5. 36 (s, 2H), 4. 10 (dd, 1 H, J = 8. 10Hz, 14. 58Hz), 2. 91 (dd, 2H, J = 6. 75Hz, 12. 96Hz), 2. 56 (m, 2H), 2. 09 (m, 2 H), 1. 52 (ra , 6H), 1. 23 (b rs, 14H)

Used as starting material N- {(1 R) - 1 - [(benzyl O carboxymethyl § mino) Cal Boniru] - 5- Ureidopenchiru} one 1 0 Fuenirudekanami de are described in Section II of Example 1 It was prepared by a method analogous.

- NMR δ (CDC 1 3) 11. 23 (s, 1H), 7. 95 (d, 1 H, J = 8. 10Hz), 7. 37 (b rs, 5H), 7. 25 (m, 2H ), 7. 17 (m, 3H), 5. 88 (t, 1 H, J = 5. 67Hz), 5. 35 (s, 2H), 4. 77 (s, 2H), 4. 06 (dd , 1 H, J = 7. 59 Hz, 14. 85Hz), 2. 90 (dd, 2H, J = 6. 27Hz, 12. 87Hz), 2. 55 (t, 2H, J = 7. 26Hz) 2 . 10 (m, 2H), 1. 51 (m, 6H), 1. 23 (b rs, 1 4H) example 1 8

N- {(1 R) - 1 - [(hydroxyamino) carbonyl] _ 4 Urei Dobuchi Le} - 1 0- Fuenirudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N- {(1 R) - 1- [(benzyl O carboxymethyl § amino) carbonyl] -4 one Ureidobuchiru} - 1 0 phenylene Rudekanami de (lg) from N-- a {(1 R) 1 one [(hydroxyamino) carboxamide sulfonyl] _ 4 one Ureidobuchiru} one 1 0 Fuenirudekanami de afford 720 mg.J H-NMR δ (DMSO- d 6) 10. 57 (s, 1H), 8. 8 l (s, 1H), 7. 91 (d, 1H, J = 8. 25Hz), 7. 25 (m , 2H), 7. 11-7. 17 (m, 3H), 5. 92 (br one t, 1H), 5. 35 (s, 2H), 4. 14 (dd, 1H, J = 8. 25Hz , 14. 52Hz), 2. 94 (m, 2H), 2. 56 (m, 2H), 2. 09 (t, 2H, J = 7. 59Hz), 1. 53 (m, 2H), 1. 46 (m, 2H), 1. 11- 1. 39 (m, 12H)

Used as starting material N- {(1 R) - 1 - [(benzyl O carboxymethyl § mino) Cal Boniru] _4_ Ureidobuchiru} - 1 0 Fuenirudekanami de The method described in Section II of Example 1 It was prepared by analogous methods.

} H- NMR δ (DMSO- d 6 ) 11. 20 (s, 1H), 7. 96 (d, 1 H, J = 7. 92H z), 7. 33-7. 43 (m, 5H), 7. 22-7. 28 (m, 2H), 7. 11-7. 17 (m, 3H), 5. 91 ", J = 5. 61Hz), 5. 35 (s, 2H), 4. 77 (s, 2H), 4. 10 (dd, 1H, J = 7. 92Hz, 14. 19Hz), 2. 94 (m, 2H), 2. 55 (m, 2H), 2. 10 (m, 2H ), 1. 39-1. 65 (m, 6H), 1. 11-1. 39 (m, 12H) example 1 9

N- {(1 R) - 1- [(hydroxyamino) carbonyl] pentyl} one 1 0 phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N- {(1 R) - 1 one [(benzyl O carboxymethyl § amino) carbonyl] pentyl} one 1 0 phenylene Rudekanami de (1 g ) from N- to give 727mg of {(1 R) one 1- [(hydroxyamino) carbonyl] pentyl} one 1 0 Fuenirudekanami de.

] H-NMR δ (DMSO- d 6) 10. 58 (b rs, 1H), 8. 80 (b rs, 1H), 7. 89 (d, 1H, J = 8. 25Hz), 7. 25 ( m, 2H), 7. 15 (m, 3H), 4. 12 (dd, 1H, J = 8. 25Hz, 14. 52Hz), 2. 55 (m, 2H), 2. 09 (m, 2H) , 1. 52 (m, 6H), 1. 23 (b rs, 14H), 0. 84 (t, 3H, J = 6. 6Hz)

Used as starting material N- {(1 R) - 1 - [(benzyl O carboxymethyl § mino) Cal Boniru] pentyl} - 1 0 phenylene Rudekanami de is the method described in Section II of Example 1 It was prepared by a similar method.

] H-NMR δ (CDC 1 3) 9. 85 (s, 1H), 7. 34 (m, 5H), 7. 26 (m, 2H), 7. 16 (m, 3H), 6. 29 ( d, 1 H, J = 8. 25), 4. 89 (s, 2H), 4. 35 (dd, 1H, J = 7. 26Hz, 15. 5Hz), 2. 58 (m, 2H), 2 . 12 (t, 2H, J = 7. 5 9Hz), 1. 76 (m, 1H), 1. 59 (m, 5H), 1. 26 (b rs, 14H), 0. 87 (t, 3H , J = 6. 6Hz) example 20

(4 R) one 4 one {[8 (Benzoiruamino) Okutanoiru] amino} one 5- (human Dorokishiamino 5 one Okisopentan acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 4 one {[8 - (Benzoiruamino) Okutanoiru] amino} - 5- (benzyl O carboxymethyl § mino) Single 5- Okisopentan acid base from Njiru (lg) was obtained 690m g.

^ -NMR δ (DMSO-d 6 ) 12. 03 (br - s, 1H), 10. 6 l (s, 1H), 8. 8 3 (b rs, 1H), 8. 42 (t, 1 H , J = 5. 61Hz), 7. 95 (d, 1 H, J = 8. 25 Hz), 7. 84 (m, 2H), 7. 48 (m, 3H), 4. 15 (dd, 1 H, J = 7. 92Hz, 1 4. 19Hz), 3. 24 (m, 2H), 2. 19 (m, 2H), 2. 10 (m, 2H), 1. 79 (m, 2H) 1 . 48 (m, 4H), 1. 28 (b rs, 6H)

Used as starting material (4 R) -4 - {[8 - (Benzoiruamino) Okutano I le] amino} - 5 - (benzyl O carboxymethyl § mino) Single 5 Okisopentan acid base Nji Le is the embodiment 1 It was prepared by methods analogous to those described in Section II.

] H-NMR 5 (CDC 1 ) 9. 78 (b rs, 1 H) 7. 76 (m, 2H), 7. 40 (m, 3H), 7. 33 (b rs, 1 OH), 6. 60 (d, 1 H, J = 7. 59Hz), 6. 40 (b r- s, 1H), 5. 07 (s, 2H), 4. 85 (s, 2H), 4. 37 (m, 1H), 3. 40 (dd, 2 H, J = 6. 92Hz, 13. 52Hz), 2. 40 (m, 2H), 2. 11 (m, 2H), 2. 01 (m, 2H), 1. 55 (br- d, 4H), 1. 30 (br- s, 6H) example 2 1

N- {(1 R) - 1- [(hydroxy § amino) carbonyl] butyl} - 1 0 off Enirudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N- {(1 R) - 1 one [(benzyl O carboxymethyl § amino) carbonyl] butyl} one 1 0 phenylene Rudekanami de (1 g ) from N- to obtain 767 mg of {(1 R) - - 1 [(hydroxy § amino) carbonyl] butyl} one 1 0 phenylene Rudekanami de.

^ -NMR § (DMSO-d 6 ) 10. 61 (s, 1H), 8. 82 (s, 1H), 7. 9 l (d, 1

H, J = 8. 25Hz), 7. 26 (m, 2H), 7. 15 (m, 3H), 4, 14 (dd, 1 H, J = 8. 25Hz, 14. 51Hz), 2. 55 (m, 2H), 2. 08 (m, 2H), 1. 50 (m, 6H),

I. 22 (b rs, 12H), 0. 84 (t, 3H, J = 7. 26Hz)

Used as starting material N-{(1 R) - 1 one [(benzyl O carboxymethyl § mino) Cal Boniru] butyl} - 1 0 phenylene Rudekanami de is how described in Section II of Example 1 It was prepared by analogous methods.

] H-NMR § (CDC 1 3) 9. 59 (s, 1H), 7. 35 (m, 5H), 7. 25 (m, 2H), 7. 17 (m, 3H), 6. 13 ( d, 1 H, J = 8. 25Hz), 4. 88 (s, 2H), 4. 31 (m, 1 H), 2. 59 (m, 2H), 2. 12 (m, 2H), 1 . 75 (m, 2H), 1. 57 (m, H), 1. 26 (b rs, 12H), 0. 89 (t, 3H, J = 7. 26Hz) example 22

N-[(1 R) - 1 one benshi ^ one 2_ (hydroxymethyl § Mino) Single 2- Okisoechi le] one 1 0 phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N-[(1 R) - 1 _ benzyl - 2- (benzyl O carboxymethyl § amino) - 2-Okisoechiru] _ 1 0 Fuenirude Kanami from de (lg) N- [(1 R) - 1- benzyl-2- (hydroxy amino) Single 2- Okisoechiru] an 1 0 Fuenirudekanami de obtain 744m g.

] H - NMR § (DMSO-d 6) 10. 64 (s, 1H), 8. 84 (s, 1H), 8. 05 (d, 1 H, J = 8. 25Hz), 7. 26 (m , 4H), 7. 17 (m, 6H), 4. 16 (dd, 1 H, J = 8. 25Hz, 14. 52Hz), 2. 54 (m, 2H), 2. 13 (m, 2H) , 1. 82 (m, 2H), 1. 50 (m, 4H), 1. 24 (b rs, 1 OH)

Used as starting material N-[(1 R) Single 1 one base Njiru 2- (Benjiruokishi Amino) Single 2 Okisoechiru] - 1 0 phenylene Rudekanami de is the method described in Section II of Example 1 It was prepared by a similar method.

^ -NMR 5 (CDC 1 3) 9. 18 (s, 1H), 7. 28 (m, 9H), 7. 17 (m, 6H), 6. 2 l (d, 1H, J = 8. 58Hz ), 4. 80 (d, 1 H, J = 10. 88Hz), 4. 66 (d, 1 H, J = l 0. 88Hz), 4. 56 (m, 1H), 3. 03 (m, 2H), 2. 59 (m, 2H), 2. 08 (m, 2H), 1. 59 (m, 2H), 1. 47 (m, 2H), 1. 24 (b rd, 1 OH) carried example 23

N- {(1 R) U hydroxyamino) carbonyl] - 3 one Fuenirupuro pills} one 1 0 phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N-{(1 R) - 1 one [(benzyl O carboxymethyl § amino) carbonyl] one 3-phenylpropyl} - 1 0-phenylene Rudekanami de (1 g) from N-{(1 R) one 1 one [(hydroxy § Mino) Cal Boniru] - 3-phenylpropyl} - 1 0 Fuenirudekanami de was obtained 722 mg.

^ -NMR 5 (DMSO- d 6) 10. 68 (s, 1H), 8. 86 (s, 1H), 8. 09 (d, 1 H, J = 8. 91Hz), 7. 21 (m, 1 OH), 4. 39 (m, 1H), 2. 90 (dd, 1 H, J = 5. 28Hz, 13. 53Hz), 2. 75 (dd, 1 H, J = 9. 9Hz, 13. 53Hz), 2. 56 (m, 2H), 2. 0 (t, 2H, J = 7. 26Hz), 1. 54 (m, 2H), 1. 07-1. 3 5 (m, 14H)

Used as starting material N-{(1 R) - 1 one [(benzyl O carboxymethyl § mino) Cal Boniru] one 3-phenylpropyl} one 1 0 Fuenirudekanami de is described in Section II of Example 1 It was prepared by the methods analogous.

J H-NMR 5 (CDC 1 3) 9. 70 (s, 1H), 7. 34 (m, 4H), 7. 26 (m, 5H), 7. 17 (m, 6H), 6. 29 ( d, 1 H, J = 6. 59Hz), 4. 89 (s, 2H), 4. 36 (dd, 1H, J = 6. 59Hz, 14. 59Hz), 2. 58 (m, 4H), 2 . 10 (m, 3H), 1. 95 (m, 1H), 1. 55 (m, 4H), 1. 25 (b rs, 1 OH) example 24

(4 R) - 5 - (hydroxyamino) Single 5- Okiso one 4 one [(1 0-phenylene Rudeka Amino] Pentanami de

In an analogous manner to that described in the first section of Example 1, (4R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4- [(1 0-phenylpropyl dec Noi Le) Amino] Bae Ntanami de (lg) from (4 R) - 5 - (hydroxymethyl § Mino) Single 5- Okiso one 4 scratch [(1 0-phenylpropyl dec Noi Le) amino] Pentanami de afford 575 mg.] H-NMR 5 (DMSO- d 6) 10. 6 (s, 1H), 8. 83 (s, 1H), 7. 95 (d, 1 H, J = 8. 25Hz), 7. 26 (m , 2H), 7. 18 (m, 3H), 6. 75 (s, 2H), 4. 11 (dd, 1H, J = 8. 25Hz, 1. 19Hz), 2. 56 (m, 2H), 2.09 use (m, 4H), 1. 74 (m, 2H), 1. 54 (m, 2H), 1. 45 (m, 2H), as 1. 23 (b rs, 1 OH) starting material There was (4 R) - 5- (benzyl O carboxymethyl § mino) Single 5- Okiso one 4 one [(1 0-phenylpropyl dec Noi Le) amino] Pentanami de the method described in Section II of example 1 It was prepared by analogous methods.

1 H- NMR 5 (DMSO- d 6 ) 11. 25 (s, 1H), 8. 01 (d, 1 H, J = 7. 91Hz), 7. 38 (m, 5H), 7. 26 (m , 2H), 7. 15 (m, 3H), 6. 77 (s, 2H), 4. 77 (s, 2H), 4. 08 (dd, 1 H, J = 7. 91Hz, 14. 18Hz) 2. 55 (m, 2H), 2. 08 (m, 4H), 1. 71 (m, 2H), 1. 45 (m, 4H), 1. 24 (b rs, 1 OH) example 25

(3 R) _ 4 i (hydroxyamino) Single 4- Okiso one 3- [(1 0-phenylene Rudeka Amino] Butanami de

In an analogous manner to that described in the first section of Example 1, (3 R)-4-(benzyl Okishiamino) one 4 one Okiso one 3- [(1 0-phenylpropyl dec Noi Le) Amino] Bed Tanami de (lg) from (3 R)-4-(hydroxy § Mino) Single 4 one Okiso _ 3- [(1 0-phenylpropyl dec Noi Le) amino] Butanami de afford 45 Omg.

3H-NMR 5 (DMSO-d 6) 10. 50 (s, 1H), 8. 80 (s, 1H), 7. 90 (d, 1 H, J = 8. 25Hz), 7. 20-7. 30 (m, 2H), 7. 09- 7. 20 (m, 3H), 6. 8 4 (b rs, 2H), 4. 48 (m, 1H), 2. 27- 2. 61 (m, 4H), 2. 07 (t, 2H, 3 = 7. 42Hz), 1. 56 (m, 2H), 1. 46 (m, 2H), 1. 12-1. 37 (m, 1 OH) starting was used as the substance (3 R) - 4- (benzyl O carboxymethyl § mino) Single 4 Okiso - 3 - [(1 0-phenylpropyl dec Noi Le) amino] Butanami de is Section 2 of example 1 It was prepared by analogous method to that described.

One NMR δ (DMSO-d 6) 11. 10 (s, 1H), 8. 17 (s, 2H), 7. 92 (d, 1H, J = 7. 92Hz), 7. 30- 7. 43 ( m, 5H), 7. 19- 7. 28 (m, 2H), 7. 09-7. 17 (m, 3H), 6. 79 (b rs, 2H), 4. 49 (m, 1H), 2. 44-2. 5 9 (m, 4H), 2. 10 (t, 2H, J = 7. 59Hz), 1. 41- 1. 65 (m, 4H), 1. 2 5 (b rs, 1 OH) example 26

N-[(1 R) Single 2- (hydroxymethyl § amino) Single 1 one (hydro 2 one Okisoechiru] one 1 0 phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N-[(1 R) - 2- (base Nji Ruo carboxymethyl § mino) Single 1- (hydroxymethyl) Single 2 Okisoechiru] - 1 0 one phenylene Rudekanami de (1 g) from N-[(1 R) Single 2- (hydroxymethyl § amino) - 1 - (hydroxymethyl) Single 2- Okisoechiru] to give 38 mg of an 1 0 Fuenirudekanami de.

^ -NMR δ (DMSO- d 6) 10. 54 (b rs, 1 H), 8. 81 (s, 1H), 8. 23 (m, 1H), 7. 73 (m, 1H), 7. 20-7. 30 (m, 2H), 7. 08-7. 20 (m, 3 H), 4. 2 l (m, 1H), 3. 52 (b rs, 2H), 2. 56 (m , 2H), 2. 12 (t, 2H, J = 7. 59Hz), 1. 56 (m, 2H), 1. 48 (m, 2H), as 1. 24 (b rs, 1 OH) starting material using the N-[(1 R) - 2- (benzyl O carboxymethyl § amino) Single 1 i (hydroxymethyl) - 2-Okisoechiru] one 1 0 _ Fuenirudekanami de the method described in Section II of example 1 It was prepared by analogous methods.

-.. NMR § (CDC1 9. 07 (s, 1H), 7. 28-7 40 (m, 1 OH), 7. 22- 7. 28 (m, 2H), 7. 13-7 22 (m , 3H), 6. 27 (b rd, 1H), 4. 88 (s, 2H), 3. 43-3. 54 (m, 3H), 3. 79 (dd, 1 H, J = 4. 79Hz , 9. 41Hz), 3. 45 (m, 1H), 2. 59 (m, 2H), 2. 17 (t, 2H, J = 7. 78Hz), 1. 48- 1. 70 (m, 4H ), 1. 26 (br- s, 1 OH) example 27

N-{(1 R) 4 one amino-1 one [(hydroxy § amino) carbonyl] Petit Le} one 1 0 Fuenirudekanami de acetate

In an analogous manner to that described in the first section of the embodiment 1, N- {(1 R) - 4 one (2 one black port base Nji Ruo alkoxycarbonyl) amino-1- [(benzyl O carboxymethyl § amino) carbonyl ] butyl} - 1 0- Fuenirudekanami from de (lg) N-{(1 R) one 4 one amino-1 one [(hydroxy § amino) carbonyl] butyl} - 1 0 phenylene Rudekanami de acetate the 45 Omg give It was.

] H-NMR δ (DMSO- d 6) 10. 73 (s, 1H), 8. 01 (d, 1 H, J = 8. 25H z), 7. 93 (b rs, 3H), 7. 23 -7. 29 (m, 2H), 7. 09- 7. 18 (m, 3H), 4. 20 (m, 1H), 2. 76 (m, 2H), 2. 59 (m, 2H), 2. 10 (s, 3H), 2. 04 -2. 15 (m, 2H), 1. 40-1. 70 (m, 6H), 1. 17-1. 36 (m, 12H) as the starting material using the N-{(1 R) -4 i (2 black port base Njiruokishikaru Boniru) amino-1- [(benzyl O carboxymethyl § amino) carbonyl] butyl} - 1 0 one phenylene Rudekanami de is the embodiment 1 It was prepared by methods analogous to those described in Section II.

J H-NMR 5 (CDC1 3 ) 9. 70 (s, 1H), 7. 15-7. 38 (m, 14H), 6. 35 (d, 1H, J = 7. 92Hz), 5. 14 ( s, 2H), 5. 06 (m, 1H), 4. 9 l (d, 1 H, J = 10. 89Hz), 4. 85 (d, 1 H, J = l 0. 89Hz), 4. 46 (m, 1H), 3. 34 (m, 1H), 3. 1 (m, 1H), 2. 59 (t, 2H, 3 = 1. 89Hz), 2. 18 (m, 2H), 1 . 40-1. 90 (m, 6H), 1. 26 (b r_s, 12H) example 2 8

(4 R) Single N- hydroxy-^ _ (hydroxymethyl § Mino) Single 5- Okiso one 4 __ [(1

0-phenylene Amino] Pentanami de

In an analogous manner to that described in the first section of Example 1, (4 R) - N-Benjiruo carboxymethyl one 5- (benzyl O carboxymethyl § mino) _ 5 Okiso one 4 one [(1 0-Fuenirude Kanoiru ) amino] from Pentanami de (0. 7 6 g) (4 R) - N- hydroxy - 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- [(1 0-phenylene Rudekanoi Le) amino] Pentanami de It was obtained 5 0 0 mg.

^ -NMR δ (DMSO - d 6 ) 9. 80 (b rs, 2H), 7. 96 (b rs, 1H), 7.

05-7. 33 (m, 5H), 4. 15 (m, 1H), 2. 56 (m, 2H), 2. 10 (t, 2H, J = 7. 26Hz), 1. 66-2. 04 (m, 4H), 1. 0- 1. 63 (m, 4H), 1. 25 (br - s, 1 OH)

Used as starting material (4 R)-N-Benjiruokishi 5- (Benjiruokishi Amino) Single 5- Okiso one 4 one [(1 0-phenylpropyl dec Noi Le) Amino] Pentana Mi De is the second Example 1 It was prepared by methods analogous to those described in sections.

] H-NMR 5 (COC 1 3) 10. 18 (s, 1H), 9. 56 (s, 1H), 7. 30-7. 43 (m, 1 OH), 7. 24-7. 30 ( m, 2H), 7. 12-7. 18 (m, 3H), 6. 79 (d, 1 H, J = 7. 26Hz), 4. 84-4. 95 (m, 4H), 4. 26 (m, 1H), 2. 59 (t, 2 H, J = 7. 76Hz), 2. 15 (m, 2H), 2. 02-2. 12 (m, 2H), 1. 80- 2. 0 0 (m, 2H), 1. 45-1. 66 (m, 4H), 1. 17-1. 40 (m, 1 OH) example 29

N- [(1 R) - 2- (hydroxy § amino) Single 1 one methyl one 2-year old Kisoechiru] - 1 0 phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N- [(1 R) - 2- (base Nji Ruo carboxymethyl § amino) one 1-methyl-2-Okisoechiru] - 1 0 phenylene Rudeka Nami from de (lg) N-[(1 R) Single 2- (hydroxyamino) one 1-methyl 2 Okisoechiru] - 1 0 a phenylene Rudekanami de obtain 780m g.

JH-NMR δ (DMSO- d 6 ) 10. 56 (s, 1H), 8. 80 (s, 1H), 7. 20-7.

29 (m, 2H), 7. 08-7. 20 (m, 3H), 4. 19 (m, 1H), 2. 56 (m, 2H), 2. 08 (t, 2H, J = 7. 48Hz), 1. 55 (m, 2H), 1. 45 (m, 2H), 1. 09-1.

37 (m, 1 OH), 1. 16 (d, 3H, J = 6. 93Hz)

Used as starting material N-[(1 R) one 2- (benzyl O carboxymethyl § amino) -1 one-methyl-2-Okisoechiru] _ 1 0 Fuenirudekanami de is the method described in Section II of Example 1 It was prepared by a similar method.

^ -NMR § (CDC 1 3) 9. 54 (s, 1H), 7. 32-7. 43 (m, 5H), 7. 21- 7. 32 (m, 2H), 7. 10-7. 21 (m, 3H), 6. 1 (d, 1 H, J = 7. 59Hz), 4. 89 (s, 2H), 4. 38 (m, 1H), 2. 59 (m, 2H), 2. 12 (m, 2H), 1. 42-1. 66 (m, 4H), 1. 1 -1. 1 (m, 1 OH), 1. 33 (d, 3H, J = 6. 93Hz) example 30 N- {(1 R) - 5- amino-1 one [(hydroxyamino) carbonyl] pentyl} one 1 0 Fuenirudekanami de Torifuruoro acetate

In an analogous manner to that described in the first section of the embodiment 1, N- {(1 R) - 5- (base Nji Ruo alkoxycarbonyl) amino-1 one [(benzyl O carboxymethyl § mino) carbonylation le] pentyl } - 1 0 phenylene Rudekanami from de (1 g) N-{(1 R) - 5-amino-1- [(hydroxyamino) carbonyl] pentyl} one 1 0- phenyl Dekanami de Torifuruoro acid salt 1 03M g Obtained.

^ -NMR δ (DMSO- d 6) 8. 83 (s, 1H), 7. 94 (d, 1 H, J = 8. 25Hz), 7, 8 Kb rs, 3H), 7. 26 (m, 2H), 7. 15 (m, 3H), 4. 12 (m, 1H), 2.

74 (t, 2H, J = 7. 59Hz), 2. 56 (m, 2H), 2. 09 (m, 2H), 1. 47 (m, 8

H) 1. 25 (br- d, 12H)

Used as starting material, N-{(1 R) - 5 - (benzyl O butoxycarbonyl) amino-1- [(benzyl O carboxymethyl § amino) carbonyl] pentyl} - 1 0 phenylene Rudekanami de is Example 1 It was prepared by methods analogous to those described in Section II of.

^ -NMR 5 (CDC1 3) 9. 59 (b rs, 1H), 7. 32 (br ~ s, 1 OH), 7. 26 (m, 2H), 7. 16 (m, 3H), 6. 29 (br - s, 1H), 5. 06 (s, 2H), 4. 94 (b rs, 1H), 4. 88 (s, 2H), 4. 27 (b rd, 1H), 3. 13 (m, 2H), 2. 58 (m, 2H), 2. 12 (m, 2H), 1. 77 (m, 2H), 1. 56 (m, 6H), 1. 25 (b rs, 12H ) example 3 1 N- {(1 R) - 4 one Guanijino one 1 one [(hydroxy § amino) carbonyl] Bed chill} one 1 0 _ phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N_ {(1 R) - 4 one (1, 3-dibenzyl O alkoxycarbonyl) Guanijino 1 one [(benzyl O carboxymethyl amino) carbonyl] butyl} - 1 0- Fuenirudekanami de (1 g) from N-{(1 R) - 4 Guanijino 1 _ [(hydroxy § amino) carbonyl] butyl} - 1 0 phenylene Rudekanami de was obtained 6 1 0 mg .

J H-NMR 5 (CD 3 OD) 7. 23 (m, 2H), 7. 1 3 (m, 3H), 4. 27 (t, 1 H, J = 7. 26Hz), 3. 1 8 ( t, 2H, J = 6. 93Hz), 2. 58 (t, 2H, J = 7. 59 Hz), 2. 23 (t, 2H, J = 7. 26), 1. 44- 1. 90 ( m, 8H), 1. 30 (b rs, 1 OH)

Used as starting material N-{(1 R) one 4 one (1, 3-Jibenjiruokishi) grayed Anijino 1 one [(benzyl O carboxymethyl § amino) carbonyl] butyl} one 1 0 phenylene Rudekanami de is Example It was prepared by methods analogous to those described in 1 Section II.

] H-NMR 5 (COC 1 3) 9. 78 (b rs, 1H), 9. 43 (b rs, 1H), 9. 3 1 (b rs, 1H), 7. 26-7. 42 (m , 17H), 7. 1 6 (m, 3H), 5. 28 (s, 2H), 5. 12 (d, 1H, J = l 2. 2Hz), 5. 02 (d, 1 H, J = l 2. 2Hz), 4. 75 (s, 2H), 4. 44 (m, 1H), 4. 00 (m, 1H), 3. 75 (m, 1H), 2. 59 (m, 2H) , 2. 05 (m, 2H), 1. 66 (m, 2H), 1. 59 (m, 2H), 1. 51 (m, 2H), 1. 23 (br one d, 12H) example 32

N-{(1 R) - 1 - [(hydroxy § amino) carbonyl] - 3- (Mechiruchi O) propyl} one 1 0 phenylene Rudekanami de

N-{(1 R) - 1 - [(t one Butokishiamino) carbonyl] 3- (Mechiruchi O) propyl} - 1 0 phenylene Rudekanami de (1. 0 g, 2. 22 mm o 1) Torifuruoro to acid (TFA) (1 9m l), water (0. 5 m l), a reagent prepared from Etanjichio one Le (0. 5m l) was added under ice-water cooling, after stirring for 2 hours, stirred at room temperature for 4 hours did. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography Dhara Fi one (stationary phase: silica gel 60, 70 _ 230 mesh, 1 00 g, mobile phase: black port Holm methanol = 20 Roh 1) purified by, N - {(1 R) - 1 - [(hydroxy § amino) carbonyl] - 3- (methylthio) prop le} - 1 0 a phenylene Rudekanami de afford 170 mg.

] H-NMR δ (DMSO - d 6) 10. 64 (s, 1Η) '8. 82 (b rs, 1H), 7. 99 (d, 1H, J = 8. 24Hz), 7. 29 (m , 2H), 7. 14 (m, 3H), 4. 23 (dd, 1H, J = 8. 25Hz, 14. 19Hz), 2. 55 (m, 2H), 2. 50 (m, 2H), 2. 12 (m, 2H), 2. 02 (s, 3H), 1. 79 (m, 2H), 1. 48 (m, 4H), 1. 24 (b rs, 1 OH)

Used as starting material N-{(1 R) - 1 - [(t one Butokishiamino) carboxymethyl sulfonyl] - 3- (methylthio) propyl} - 1 0 Fuenirudekanami de are described in Section II of Example 1 It was prepared by a method analogous.

] H- NMR § (CDC1) 9. 35 (s, 1H), 7. 26 (m, 2H), 7. 17 (m, 3H), 6. 62 (d, 1H, J = 8. 57Hz), 4. 63 (m, 1H), 2. 56 (m, 4H), 2. 26 (m, 2 H), 2. 10 (s, 3H), 1. 95 (m, 2H), 1. 60 ( b rs, 4H), 1. 26 (b rs, 19H) example 33

(4 R) - 5 - (hydroxymethyl § Mino) Single 4- [(3-main butoxy one 1 2 phenylene field Dekanoiru) Amino] -5- Okisopentan acid

In an analogous manner to that described in the first section of Example 1, (4R) - 5 - (benzyl Okishiamino) _ 4 one [(3-main butoxy one 1 2 phenylene Rudodekanoiru) amino] one 5- Okisopentan acid base Njiru from (1. 66 g) (4 R) - 5- (hydrate port Kishiamino) Single 4 one [(3-main butoxy one 1 2 phenylalanine dodeca Noi Le) § Mi Bruno] one 5- Okisopentan acid 1. obtained 1 7 g.

'H-NMR δ (CD.OD) 7. 19-7. 28 (m, 2H), 7. 08- 7. 19 (m, 3H), 4. 34 (m, 1H), 3. 62 (m , 1H), 3. 351, 3. 350 (s, 3H), 2. 59 (m, 2 H), 2. 27-2. 50 (m, 4H), 2. 08 (m, 1H), 1 . 93 (m, 1H), 1. 43-1. 68 (m, 4H), 1. 3 l (b rs, 12H)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 4- [(3 - Main butoxy one 1 2 phenylene Rudodekanoiru) Amino] one 5-Okisopentan acid base Njiru is Example 1 It was prepared by methods analogous to those described in Section II of.

^ -NMR 5 (CDC ") 9. 32, 9. 28 (b rs, 1H), 7. 28-7. 32 (m, 1 OH), 7. 20-7. 28 (m, 2H), 7 . 11- 7. 20 (m, 3H), 6. 83, 6. 77 (b rd, 1H, J = 7. 91Hz), 5. 10 (s, 2H), 4. 88 (s, 2H), 4. 33 (m, 1 H), 3. 49 (m, 1H), 3. 29, 3. 27 (s, 3H), 2. 59 (m, 2H), 1. 92-2. 56 (m , 6H), 1. 47-1. 66 (m, 4H), 1. 26 (br- s, 12H) example 34

(4 R)-4-(Domino) Single 5- (hydroxymethyl § Mino) _ 5 Okiso pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 4 one (Dodekano Iruamino) Single 5- (benzyl O carboxymethyl § mino) Single 5 Okisopentan acid base Njiru (1 g) (4R)-4-(dodecamethylene Noi Rua mino) Single 5- (hydroxymethyl § Mino) was an 5 Okisopentan acid obtained 0. 5 g.

] H-NMR δ (DMSO- d 6) 10. 62 (b rs, 1H), 8. 82 (s, 1H), 7. 94 (d, 1H, J = 8. 91Hz), 4. 17 (m , 1H), 2. 19 (t, 2H, J = 6. 60Hz), 2. 10 (t, 2H, J = 6. 27Hz), 1. 77 (m, 2H), 1. 48 (m, 2H ), 1. 24 (b rs, 16H), 0. 87 (t, 3H, J = 6. 44Hz)

Used as starting material (4 R) - 4 one (dodecamethylene Noi Rua mino) Single 5- (benzylidene Ruokishiamino) Single 5 Okisopentan acid base Njiru by methods analogous to those described in Section II of Example 1 It was prepared.

NMR 5 (CDC1Q) 9. 48 (s, 1H), 7. 34 (b rs, 1 OH), 6. 36 (d, 1H, J = 7. 26Hz), 5. 10 (s, 2H), 4 . 88 (s, 2H), 4. 33 (m, 1H), 2. 5 Km, 1H), 2. 35 (m, 1H), 1. 90-2. 18 (m, 4H), 1. 55 (m, 2H), 1. 25 (b rs, 18H), 0. 88 (t, 3H, J = 6. 60Hz) example 35 (4 R) - 5 - (hydroxymethyl § Mino) Single 5- Okiso one 4 - [(1 0-phenylene Ruun Dekanoiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4- [(1 0-phenylpropyl © down dec Noi Le) amino] from base pentanoic acid Njiru (1 g) (4 R) - 5 - to give (hydroxyamino) Single 5 one Okiso one 4- [(1 0-phenylpropyl © down dec Noi Le) amino] 39 0 mg pentanoic acid .

^ -NMR δ (DMSO- d 6) 10. 6 l (b rs, 1H), 8. 81 (br- s, 1H), 7. 93 (br- d, 1H), 7. 21-7. 33 (m, 2H), 7. 10- 7. 20 (m, 3H), 4. 1 6 (m, 1H), 2. 65 (m, 1 H, J = 7. 10Hz, 14. 35Hz), 2 . 19 (m, 2H), 2. 09 (m, 2H), 1. 79 (m, 2H), 1. 35-1. 60 (m, 4H), 1. 20 (br- s, 13H)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 5- Okiso 4- [(1 0-phenylpropyl © down dec Noi Le) Amino] Njiru base pentanoic acid, real 施例It was prepared by methods analogous to those described in 1 Section II.

H-NMR 5 (CDC 1 3 ) 9. 33 (s, 1H), 7. 34 (b rs, 1 OH), 7. 22-7.

30 (m, 2H), 7. 12-7. 22 (m, 3H), 6. 30 (d, 1 H, J = 7. 91Hz), 5.

10 (s, 2H), 4. 88 (s, 2H), 4. 31 (m, 1H), 2. 65 (dd, 1 H, J = 6. 93 Hz, 14. 18Hz), 3. 55 ( m, 1H), 2. 32 (m, 1H), 1. 94- 2. 15 (m, 4

H), 1. 54 (b rs, 4H), 1. 08-1. 34 (m, 13H) Example 36

N- _ {(1 R, 2 R) - 2- hydroxy-one 1-- [(hydroxy § Mino) carbonylation] propyl} one 10-phenylene Rudekanami de

In an analogous manner to that described in the first section of the embodiment 1, N- {(1 R, 2 R) - 2 one Benjiruokishi 1 one [(benzyl O carboxymethyl § amino) carbonyl] propyl} one 1 0 Hue two Rudekanami from de (lg) N- {(1 R, 2 R) one 2-hydroxy-1 one [(hydroxy § amino) carbonyl] propyl} to obtain 5 1 0 mg of an 1 0 phenylene Rudekanami de.

] H-NMR δ (DMSO - d 6) 10. 46 (b rs, 1H), 8. 78 (b rs, 1H), 7.

5 Kb rs, 1H), 7. 20-7. 35 (m, 2H), 7. 09-7. 20 (m, 3H), 4. 7 4 (br- s, 1H), 4. 10 (m , 1H), 3. 94 (m, 1H), 2. 57 (m, 2H), 2. 16

(T, 2H, J = 7. 26Hz), 1. 40-1. 64 (m, 4H), 1. 27 (b rs, 1 OH),

1. 02 (d, 3H, J = 6. 27Hz)

Used as starting material N- {(1 R, 2 R) one 2- Benjiruokishi one 1 one

[(Benzyl O carboxymethyl § amino) carbonyl] propyl) one 1 0 phenylene Rudekanami de was prepared by methods analogous to those described in Section II of Example 1.

One NMR 5 (CDC 1 3) 8. 99 (s, 1H), 7. 21-7. 40 (m, 12H), 7. 11-

7. 2 l (m, 3H), 6. 4 l (d, 1 H, J = 6. 27Hz), 4. 9 l (d, 1H, J = l 1. 2

2Hz), 4. 85 (d, 1H, J = 11. 22Hz), 4. 60 (d, 1H, J = l l. 55Hz),

4. 54 (d, 1H, J = l 1. 55Hz), 4. 52 (m, 1H), 4. 05 (m, 1 H), 2. 6 0 (t, 2H, J = 7. 59Hz) , 2. 2 l (t, 2H, J = 7. 59Hz), 1. 49-1. 68

(M, 4H), 1. 28 (b rs, 1 OH), 1. 09 (d, 3H, J = 6. 60Hz) Example 37

N-[_ (1 R) Single 2- (hydroxymethyl § amino) Single 1 (4-hydroxybenzyl) Single 2- Okisoechiru Ί one 1 0- phenylalanine dec cyanamide

In an analogous manner to that described in the first section of the embodiment 1, Ν- {(1 R) - 2- (base Nji Ruo carboxymethyl § amino) - 1 - [4 one (Benjiruokishi) benzyl] one 2- Okiso Echiru} - 1 0- Hue two Rudekanami de (lg) Ν- [(1 R) _ 2- (hydrate Rokishiamino) Single 1 _ (4-hydroxybenzyl) Single 2- Okisoechiru] one 1 0 - Hue two Rudekanamido 606 was obtained mg.

J H-NMR δ (DMSO- d 6) 10. 61 (s, 1 H), 9. 16 (s, 1 H), 8. 83 (s, 1H), 8. 00 (d, 1H, J = 8. 90Hz), 7. 25 (m, 2H), 7. 16 (m, 3H), 7. 00 (d, 2H, J = 8. 58HZ), 6. 62 (d, 2H, J = 8. 58Hz), 4. 29 (dd, 1H, J = 8. 92Hz, 14. 52Hz), 2. 75 (dd, 1 H, J = 5. 61Hz, 13. 53Hz), 2. 63 (m, 1 H ), 2. 55 (m. 2H), 2. 01 (t, 2 H, J = 7. 26Hz), 1. 55 (m, 2H), 1. 36 (m, 2H), 1. 21 (b rd, 1 OH)

Used as starting material N-{(1 R) - 2- (benzyl O carboxymethyl § mino) one 1- [4 - (Benjiruokishi) benzyl] one 2- Okisoechiru} one 10-phenylene Rudeka Namido is Example 1 It was prepared by methods analogous to those described in Section II of.

^ -NMR δ (CDC1 3) 9. 75 (s, 1 H), 7. 19-7. 45 (m, 13H), 7. 05-7. 19 (m, 4H), 6. 85 (d, 2H, J = 8. 91HZ), 6. 53 (d, 1 H, J = 8. 25Hz), 4. 96 (s, 2H), 4, 78 (d, 1 H, J- 11. 21Hz), 4. 66 (d, 1H, J = l 1. 21Hz), 4. 62 (m, 1 H), 2. 95 (m, 2H), 2. 5 6 (m. 2H), 2. 06 (m , 2H), 1. 57 (m, 2H), 1. 46 (m, 2H), 1. 2 3 (b rd, 1 OH) example 38

(5 R) - 6- (hydroxyamino) Single 6- Okiso one 5- [(1 0-phenylene Rudeka Noiru) Amino] hexane acid

In an analogous manner to that described in the first section of Example 1, (E, 5 R) - 6- (Ben Jiruokishiamino) Single 6- Okiso one 5- (1 0 phenylpropyl dec Noi Le amino) Single 2 from base cyclohexene acid into single Njiru (0. 5 g) (5 R) - 6- (hydroxymethyl § amino) - 6- Okiso one 5- [(1 0-phenylpropyl dec Noi Le) amino] hexane acid 28 It was obtained Omg.

! H-NMR δ (DMSO - d 6) 10. 61 (s, 1H), 8. 80 (s, 1H), 8. 27 (br - s, 1H), 7. 90 (br- s, 1H) , 7. 19-7. 29 (m, 2H), 7. 10-7. 19 (m, 3H), 4. 14 (m, 1H), 2. 56 (m, 2H), 2. 18 (m , 2H), 2. 09 (m, 2 H), 1. 38-1. 54 (m, 8H), 1. 15-1. 32 (m, 1 OH)

Used as starting material (E, 5 R) - 6 - (benzyl O carboxymethyl § amino) - 6-O Kiso one 5- (1 0 phenylpropyl dec Noi Rua amino) - base hexene acid to 2-Njiru is It was prepared by methods analogous to those described in Section II of example 1.

^ -NMR 5 (CDC 1 3) 9. 76 (s, 1H), 7. 33 (b rs, 1 OH), 7. 20-7. 28 (m, 2H), 7. 05-7. 20 ( m, 3H), 6. 85 (td, 1 H, J = 8. 25Hz, 15. 68Hz), 6. 28 (b rd, 1H), 5. 9 l (d, 1 H, J = l 5. 68Hz), 5. 14 (s, 1H), 4. 84 (s, 1H), 4. 49 (m, 1H), 2. 41-2. 72 (m, 4H), 2. 11 (t, 2H , J = 7. 26Hz), 1. 40-1. 68 (m, 4H), 1. 24 (b rs, 1 OH) example 39

(4 R) - 5- (hydroxymethyl § Mino) Secondary 5 _- Okiso one 4 [{6- Okiso one 6-

Kisanoiru to [(3-phenylpropyl) Amino]} - amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4 one [{6 _ Okiso one 6- [(3-Fuenirupuro pill) Amino] to Kisanoiru} Amino] pentanoic acid base Njiru from (1 g) (4 R) - 5- (human Dorokishiamino) Single 5- Okiso one 4 one [{6 _ Okiso one 6 _ [(3-phenylpropyl) Amino] the Kisanoiru} Amino] pentanoic acid to give 552 mg to.

^ -NMR δ (DMSO-d 6 ) 11. 99 (b rs, 1H), 10. 62 (s, 1H), 8. 8 3 (b rs, 1H), 7. 96 (d, 1 H, J = 7. 92Hz), 7. 78 (t, 1 H, J = 6. 93 Hz), 7. 27 (m, 2H), 7. 20 (m, 3H), 4. 15 (m, 1 H, J = 7. 92Hz, 14. 52Hz), 3. 04 (dd, 2H, J = 6. 93Hz, 12. 87Hz), 2. 56 (m, 2H), 2. 18 (m, 2H), 2. 11 (m, 2H), 2. 05 (m, 2H), 1. 80 (m, 2H), 1. 68 (t, 2H, J = 7. 26Hz), 1. 46 (b rs, 4H)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 5- Okiso 4- [{6 _ Okiso one 6- [(3-phenylpropyl) Amino] to Kisanoi Le} Amino] base pentanoic acid Njiru was prepared by an analogous way as described in Section II of example 1.

J H-NMR δ (DMSO- d 6) 11. 25 (s, 1H), 8. 02 (d, 1 H, J = 7. 92H z), 7. 76 (t, 1H, J = 6. 93Hz ), 7. 35 (b rs, 1 OH), 7. 28 (m, 2H), 7. 18 (m, 3H), 5. 07 (s, 2H), 4. 76 (s, 2H), 4 . 13 (dd, 1 H, J = 7. 92Hz, 13. 86Hz), 3. 04 (dd, 2H, J = 6. 93Hz, 12. 87Hz), 2. 5 8 (m, 2H), 2. 30 (m, 2H), 2. 12 (m, 2H), 2. 05 (m, 2H), 1. 80 (m, 2 H), 1. 65 (t, 2H, J = 7. 26Hz), 1. 47 (b rs, 4H) example 40

(4 R) -4 - {[8 - (Benjiruamino) Single 8- O Kiso O Kuta Noi le] Amino) - 5 - (hydroxymethyl § Mino) Single 5- Okisopentan acid

In an analogous manner to that described in the first section of Example 1, (4 R) -4 - {[8 - (Benjiruamino) _ 8 O Kiso O Kuta Noi le] amino} - 5 - (Benjiruokishi Amino) from a 5 _ Okisopentan acid base Njiru (1 g) (4 R) - 4- {[8- (Benjiruamino) Single 8- O Kiso O Kuta Noi le] amino} - 5 - (hydroxymethyl amino) Single 5- Okisopentan acid was obtained 54 Om g.

^ -NMR δ (DMSO-d 6 ) 11. 96 (b rs, 1H), 10. 62 (b rs, 1H), 8. 82 (b rs, 1H), 8. 26 (b rs, 1H), 7. 94 (b rs, 1H), 7. 20- 7. 35 (m, 5H), 4. 27 (d, 2H, J = 6. 27Hz), 4. 17 (m, 1H), 2. 00 -.. 2. 28 (m, 6H), 1. 64-1 95 (m, 2H), 1. 36-1 50 (m, 4H), 1. 26 (br- s, 4H)

Used as starting material (4 R) -4- {[8- (Benjiruamino) Single 8- O key Sookutanoiru] amino} - 5- (benzyl O carboxymethyl § mino) Single 5 Okisopenta phosphate benzyl, Example 1 It was prepared by methods analogous to those described in Section II of.

One NMR δ (DMSO- d 6) 11. 25 (s, 1H), 8. 27 (s, 1H), 8. 02. (Br - d, 1H), 7. 26-7 42 (m, 12H) , 7. 13-7. 25 (m, 3H), 5. 08 (s, 2H), 4. 77 (s, 2H), 4. 26 (d, 2H, J = 5. 94Hz), 4. 1 (m, 1H), 2. 3 l (m, 2H), 2. 01-2. 17 (m, 4H), 1. 64-1. 95 (m, 2H), 1. 49 (brs, 4H) , 1. 24 (b rs, 4H) example 4 1

(4 R) - 4 [(9-Anirino _ 9 Amino] - 5- _ (hydrate port Kishiamino) Single 5- Okisopentan acid

In an analogous manner to that described in the first section of Example 1, (4 R) -4- [(9 over § two Reno one 9-1 O Kiso nonanoyl I le) Amino] - 5- (Benjiruokishia mino) Single 5 - Okisopentan acid base Njiru (1 g) from (4 R) - 4-[(9 one Anirino 9-1 O Kiso nonanoyl I le) amino] - 5- (hydroxymethyl § Mino) Single 5 Okisopenta phosphate to give 62 Om g.

Ichi匪R δ (DMSO-d 6) 11. 99 (b rs, 1H), 10. 62 (s, 1H), 9. 8 Kb rs, 1H), 8. 83 (b rs, 1H), 7. 90 (b rs, 1H), 7. 58 (m, 2 H), 7. 25 (m, 2H), 7. 00 (m, 1H), 4. 17 (m, 1H), 2. 04-2 . 34 (m, 6H), 1. 77 (m, 2H), 1. 56 (m T 2H), 1. 9 (m, 2H), 1. 29 (b rs, 6 H)

Used as starting material (4 R) -4- [(9 Anirino one 9-Okisononanoi Le) Amino] - 5- (benzyl O carboxymethyl § mino) Single 5 Okisopentan acid base Njiru, the second section of Example 1 It was prepared by methods analogous to those described in.

One NMR δ (DMSO-d 6) 11. 25 (s, 1H), 9. 80 (s, 1H), 8. 01 (d, 1H, J = 7. 59Hz), 7. 58 (d, 2H, J = 7. 92Hz), 7. 14- 7. 43 (m, 1 2H), 7. 00 (m, 1H), 5. 07 (s, 2H), 4. 77 (s, 2H), 4. 14 (dd, 1 H, J = 7. 59Hz, 14. 19Hz), 2. 18-2. 38 (m, 4H), 2. 1 l (t, 2H, J = 7. 26Hz), 1. 8 l (m, 2H), 1. 58 (m, 2H), 1. 51 (m, 2H), 1. 28 (br - s, 6H) example 42

(4 R) one 5 (hydroxymethyl § Mino) _ 5 _ Okiso one 4 one {[1 0- (4-pyrid-Le) Dekanoiru] - amino} pentanoic acid

In an analogous manner to that described in the first section of the embodiment 32, (4 R) - 5- (t chromatography Bed Tokishiamino) Single 5- Okiso one 4 one {[1 0- (4 one-pyridyl) Dekanoiru] § amino} pentanoic acid t- butyl (lg) from (4 R) - 5- (hydroxymethyl § amino) - 5- Okiso one 4 one {[1 0- (4 one-pyridyl) Dekanoiru] amino} pentanoic acid was obtained 209mg .

One NMR δ (DMSO-d 6) 10. 09 (s, 1H), 8. 43 (d, 2H, J = 5. 94H z), 8. 28 (d, 1H, J = 8. 25Hz), 7 . 21 (d, 2H, J = 5. 94Hz), 4. 69 (m, 1H), 2. 86 (m, 1H), 2. 47-2. 70 (m, 3H), 2. 12 (t , 2H, J = 7. 26Hz), 1. 94 (m, 2H), 1. 51 (m, 4H), 1. 26 (b rs, 1 OH)

Used as starting material (4 R) - 5- (t-Butokishiamino) Single 5- Okiso - 4-t-butyl {[10- (4 one-pyridyl) Dekanoiru] amino} pentanoic acid, of a second embodiment 1 It was prepared by methods analogous to those described in sections.

] H-NMR 8 (CD 3 OD) 8. 40 (d, 2H, J = 5. 94Hz), 7. 26 (d, 2H, J = 5. 94Hz), 4. 31 (m, 1H), 2 . 65 (t, 2H, J = 7. 59Hz), 2. 3 Km, 2H), 2. 23 (m, 2H), 1. 94 (m, 2H), 1. 62 (m, 4H), 1 . 44 (s, 9H), 1. 3 l (b rs, 1 OH), 1. 24 (s, 9H) example 43 (4 R) - 5 - (hydroxymethyl § Mino) over 5 Okiso one 4- [(9 one Fuenokishinona Noiru) Amino] pentanoic acid

In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) Single 5- Okiso one 4 one [(9-safe enoki Sino nano I le) Amino] pentane acid base from Njiru (lg) (4 R) - 5- (hydroxyamino) one 5-O Kiso one 4 scratch [(9-off enoki Sino nano I le) amino] pentanoic acid to give 6 1 Omg.] H-NMR δ (DMSO - d 6) 12. 06 (b rs, 1H), 10. 63 (s, 1H), 8. 8 4 (br- s, 1H), 7. 96 (d, 1 H , J = 7. 59Hz), 7. 26 (m, 2H), 6. 90 (m, 3H), 4. 16 (m, 1H), 3. 93 (t, 2H, J = 6. 27Hz), 2. 19 (m, 2H), 2. 1 l (m, 2H), 1. 82 (m, 2H), 1. 71 (t, 2H, J = 6. 77Hz), 1. 25-1. 59 (m, 1 OH)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 5- Okiso -4 one [(9-safe enoki Sino nano I le) Amino] Njiru base pentanoic acid, of a second embodiment 1 It was prepared by methods analogous to those described in sections.

^ -NMR 5 (CDC1 3) 9. 45 (s, 1H), 7. 19-7. 41 (m, 12H), 6. 83- 6. 95 (m, 3H), 6. 35 (b rd, 1H), 5. 10 (s, 2H), 4. 88 (s, 2H), 4. 33 (m, 1H), 3. 93 (t, 2H, J = 6. 60Hz), 2. 51 (m , 1H), 2. 33 (m, 1 H), 1. 92-2. 17 (m, 4H), 1. 77 (m, 2H) 1. 55 (m, 2H), 1. 41 (m, 2 H), 1. 30 (br- s, 6H) example 44

(4 R) - 4 one [{1 1- [(t- butoxycarbonyl) Amino] Undekanoi Le} amino] one 5- (hydroxymethyl § Mino) Single 5- Okisopentan acid In an analogous manner to that described in the first section of Example 1, (4 R) - 5- (benzyl Okishiamino) one 4 one [{1 1 one [(t-butoxycarbonyl) Amino] Unde Kanoiru} Amino] one 5-Okisopentan acid base Njiru from (1. 4 7 g) (4 R) - 4 - [{1 1 - [(t one butoxycarbonyl) amino] Undekanoiru} amino] one 5- (hydroxymethyl § Mino) Single 5 - quantitatively obtain Okisopentan acid.J H-NMR δ (DMSO- d 6) 12. 08 (b rs, 1H), 10. 61 (s, 1H), 8. 8 5 (b rs, 1H), 7. 94 (d, 1 H, J = 8. 25Hz), 6. 72 (b rs, 1H), 4. 15 (dd, 1H, J = 8. 25Hz, 14. 18Hz), 2. 88 (dd, 2H, J = 6. 60Hz, 13. 2Hz), 2. 18 (m, 2H), 2. 09 (m, 2H), 1. 75 (m, 2H), 1. 46 (br one s, 4H), 1. 37 (s, 9H ), 1. 23 (b rs, 12H)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 4 one [{1 1 - [(t- butoxycarbonyl) Amino] Undekanoiru} Amino] - 5-O Kisopentan acid base Njiru is It was prepared Te cowpea in a manner similar to that described in Section II of example 1.

] H-NMR 5 (CDC 1 3) 10. 29 (s, 1H), 7. 28-7. 36 (m, 1 OH), 6. 84 (b rs, 1H), 5. 07 (s, 2H ), 4. 86 (s, 2H), 4. 62 (b rs, 1H), 4. 47 (m, 1H), 4. 11 (dd, 2H, J = 6. 93Hz, 14. 19Hz), 3 . 06 (m, 2 H), 2. 37 (m, 2H), 2. 18 (m, 2H), 1. 98 (m, 2H), 1. 52 (m, 2H), 1. 43 (s , 9H), 1. 25 (b rs, 12H) example 45

(4 R) - 4 - f {1 0- [3- (aminomethyl) phenyl] Dekanoiru} amino] one 5- (hydroxyamino) Single 5- Okisopentan acid

In a similar manner to that described in the first section of Example 1, (4 R) - 4 one [{1 0- [3- Shianofueniru] - 9 Desenoiru} Amino] one 5- (benzyl O carboxymethyl amino) from a 5-Okisopentan acid base Njiru (1. 0 g), (4R) -4- [{1 0 - [3- (aminomethyl) phenyl] Dekanoiru} amino] one 5- (hydroxymethyl Shiamino) Single 5- Okisopentan acid was obtained 540 mg.

'Η- NMR δ (TFA-d) 7. 32- 7. 46 (m, 2H), 7. 20-7. 32 (m, 2 H), 4. 80-4. 90 (m, 1 H) , 4. 37 (s, 2H), 2. 66-2. 81 (m, 4 H), 2. 50-2. 61 (m, 2H), 2. 24-2. 40 (m, 2H), 1. 62-1. 81 (m, 4H), 1, 33-1. 49 (m, 1 OH)

Used as starting material ((4 R)-4-[{1 0- [3- Shianofueniru] - 9-Desenoiru} Amino] over 5- (benzyl O carboxymethyl § mino) Single 5 Okisopenta phosphate benzyl embodiment was prepared by methods analogous to those described in 1 Section II.] H-NMR δ (CDC 1 3) 9. 44 (s, 1 H), 7. 14-7. 62 (m, 1 Η) , 6. 20-6. 45 (m, 2. 7H), 5. 76 (td, 0. 3H, J = 7. 4Hz, 11. 5Hz), 5. 09 (s, 2H), 4. 88 ( s, 2H), 4. 23-4. 40 (m, 1 H), 1. 9 0-2. 57 (m, 8H), 1. 40-1. 54 (m, 2H), 1. 37- 1. 40 (m, 2 H), 1. 10-1. 37 (m, 6H) example 46

(4 R) Single 4 {- (4-Aminofue sulfonyl) Dekanoiru] Amino) Single 5

(Hydroxy § Mino) Single 5- Okisopentan acid

In a similar manner to that described in the first section of Example 1, (4 R) - 5 - (Benjiruo Kishiamino) one 4- {[1 0- (4 twelve Torofueniru) Single 9 one Desenoiru] amino} from a 5-Okisopentan acid base Njiru (1. 0 g), (4R) - 4 - {[1 0- (4- Aminofueniru) Dekanoiru] amino) - 5 - (hydroxymethyl § amino) - 5 _ Okisopentan acid 466mg Obtained.

] H-NMR δ (DMSO - d 6) 8. 14 (. B rd, 1H, J = 7 3H z), 6. 81 (. Br- d, 2H, J = 8 3 Hz), 6. 47 ( b rd, 2H, J = 8. 3Hz), 4. 06-4. 13 (m, 1H), 2. 37 (t, 2H, J = 7. 3Hz), 2. 01-2. 20 (m, 4H), 1. 67-1. 82 (m, 2H), 1. 35-1. 52 (m, 4H), 1. 10-1. 32 (m, 10 H)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 4 one {[1 0- (4 twelve Torofueniru) Single 9 one Desenoiru] amino} one 5- Okisopentan benzyl Example 1 It was prepared by methods analogous to those described in Section II of.

] H-NMR δ (CDC 13) 9. 42 (s, 1 H), 8. 12-8. 21 (m, 2H), 7. 18-7. 5 0 (m, 12H), 6. 25- 6. 51 (m, 2. 5H), 5. 84 (0. 5 H, dt, J = 7. 3Hz, 11. 7H z), 5. 09 (s, 2H), 4. 88 (s, 2H ), 4. 24 -4. 40 (m, 1H), 2. 19-2. 60 (m, 4H), 1. 90-2. 19 (m, 4H), 1. 38-1. 63 (m , 4H), 1. 10-1. 38 (m, 6H) example 47

(4 R) - 5 - (hydroxymethyl § Mino) Single 4- {[1 0 (4-_-hydroxy-phenylene Le) Dekanoiru] amino} one _5- Okisopentan acid

In a similar manner to that described in the first section of Example 1, (4 R) - 5 - (Benjiruo Kishiamino) one 4- {[1 0 - (4-hydroxyphenyl) Dekanoiru] amino} - 5 - from Okisopentan acid base Njiru (1. 7 3 g), (4 R) - 5- (human Dorokishiamino) one 4- {[1 0 - (4-hydroxyphenyl) Dekanoiru] § amino} - 5- Okisopentan acid to give 1. 02 g.

NMR 8 (DMSO-d 6) 8. 25 (b rd, 1 H, J = 6. 9H z), 6. 93 (br one d, 2H, J = 8. 2Hz ), 6. 65 (b rd, 2H, J = 8. 2Hz), 4. 03- 18 (m, 1H), 2. 44 (t, 2H, J = 7. 4H z), 2. 05-2. 13 (m, 4H), 1 . 60 - 1. 90 (m, 2H), 1. 36- 1. 60 (m, 4 H), 1. 08- 1. 36 (m, 10 H)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 4- {[1 0- (4-hydroxyphenyl) Dekanoiru] amino} - 5-Okisopentan benzyl Example 1 second It was prepared by methods analogous to those described in Section II.

] H- NMR δ (CDC 1 3) 9. 59 (b rs, 1 H), 7. 26- 7. 35 (m, 1 OH), 6. 99- 7. 02 (m, 2H), 6. 73- 6. 77 (m, 2H), 6. 45 (b rd, 1 H, J = 8. 3 Hz), 6. 02 (br- s, 1 H), 5. 09 (s, 2H), 4. 87 (s, 2H), 4. 31-4. 40 (m, 1H), 2. 28- 2. 54 (m, 4H), 1. 90-2. 17 (m, 4 H), 1 . 42-1. 62 (m, 4H), 1. 08-1. 33 (m, 1 OH) example 48

(4 R) one 5 hydroxyamino 4 {[1 0- (4 Metokishifue sulfonyl) Dekanoiru Ί amino} one 5 _ Okisopentan acid

In a similar manner to that described in the first section of Example 1, (4 R) - 5- (Benjiruo Kishiamino) one 4- {[1 0- (4-menu Tokishifueniru) Dekanoiru] amino} - 5- Okisopentan from the acid base Njiru (1 g), (4R) - 5 - (hydroxymethyl § Mino) Single 4- {[1 0_ (4 main Tokishifueniru) Dekanoiru] amino} - 5 - the Okisopentan acid to give 620 m g.

} H-NMR 5 (DMSO- d 6) 10. 58 (b rs, 1 H), 8. 79 (br- s, 1 H), 7. 89 (b rd, 1H, J = 7. 9H z) , 7. 05-7. 08 (m, 2H), 6. 79- 6. 82 (m, 2H), 4. 11-4. 19 (m, 1 H), 3. 71 (s, 3 H) , 2. 46-2. 50 (m, 2H), 2. 13-2. 26 (m, 2H), 2. 09 (t, 2H, J = 6. 9Hz), 1. 64-1. 91 ( m, 2H), 1. 36-1. 58 (m, 4H), 1. 11-1. 33 (m, 10 H)

Used as starting material (4 R) - 5- The (benzyl O carboxymethyl §) -4 {[1 0- (4-menu Tokishifueniru) Dekanoiru] amino} one 5- Okisopentan acid base Njiru the embodiments 1 It was prepared by methods analogous to those described in Section II.

] H-NMR δ (CDC 1 3) 9. 16 (s, 1 H), 7. 26-7. 37 (m, 1 OH), 7. 07-7. 10 (m, 2H), 6. 80 - 6. 83 (m, 2H), 6. 26 (. br- d, 1 H, J = 7 6H z), 5. 10 (s, 2H), 4. 88 (s, 2H), 4. 20 -4. 33 (m, 1 H), 3. 78 (s, 3H), 2. 53 (t, 2H, J = 7. 6Hz), 2. 47-2. 59 (m, 1H), 2. 28-2. 42 (m, 1 H), 1. 94-2. 17 (m, 4H), 1. 45-1. 6 8 (m, 4H), 1. 17-1. 37 (m, 1 OH) example 49

(4 R) - 5 (hydroxy § Mino) Single 5- Okiso one 4 - [(1-0- Piperijinode Amino] pentanoic acid

In a similar manner to that described in the first section of Example 1, (4 R) - 5- (Benjiruo Kishiamino) Single 5- Okiso one 4- {[1 0- Piberijino 2 Desenoiru] amino} pentanoic acid from base Njiru (1. 5 g), (4 R) - 5- give (hydroxy amino) Single 5- Okiso one 4 one [(1 0-piperidinophenyl deca Noi Le) amino] 767 mg pentanoic acid .

] H-NMR δ (DMSO - d 6) 12. 3 (br- s, 1H), 10. 63 (s, 1 H), 8.

88 (b rs, 1H), 7. 95 (d, 1 H, J = 8. 25Hz), 4. 15 (m, 1 H), 3. 39-3. 43 (m, 4H), 2. 99 (b r- 1, 2H), 2. 19 (t, 2H, J = 8. 58

Hz), 2. 10 (t, 2H, J = 7. 59Hz), 1. 58- 1. 88 (m, 1 OH), 1. 4

7 (m, 2H), 1. 26 (b rs, 1 OH)

Used as starting material (4 R) - 5- (benzyl O carboxymethyl § mino) Single 5- Okiso

- 4 one {[1 0- piperidino one 2- Desenoiru] amino} pentanoic acid base Njiru was prepared by methods analogous to those described in Section II of Example 1.

- NMR δ (CDC 1 3) 7. 34 (b rs, 1 OH), 7. 06 (b rs, 1 H), 6.

77 (td, 1H, J = 6. 6Hz, 15. 2Hz), 5. 85 (d, 1 H, J = l 5. 2Hz),

5. 08 (s, 2H), 4. 87 (s, 2H), 2. 85 (b rs. H), 2. 72 (m, 2

H), 2. 43 (m, 2H), 2. 13 (m, 4H), 1. 85 (m, H), 1. 71 (b r- s, 2H), 1. 60 (m, 2H) , 1. 40 (b rs, 2H), 1. 28 (b rs, 10

H) Example 50

(4 R) -4- {[1 0- (to Kisahidoro one - 1 H- 1-Azepiniru) _ Dekanoiru Ί amino} one 5- (hydroxymethyl § Mino) 5 one Okisopentan acid

In a similar manner to that described in the first section of Example 1, (4 R) - 4 one {[1 0- (to Kisahidoro 1 H- 1-Azepiniru) Single 2 Desenoiru] amino} - 5 - ( from base Nji Ruo Kishikishi § mino) Single 5 Okisopentan acid base Njiru (1. 5 g), (4 R) - 5 - (hydroxymethyl § Mino) Single 5- Okiso one 4- {[1 0- (to Kisahido low 1 H- 1 _ Azepiniru) Dekanoiru] amino} pentanoic acid was obtained 767 mg.] H-NMR 5 (DMSO - d 6) 12. 10 (b rs, 1 H), 10. 63 (s, 1 H), 9. 90 (s, 1H), 8. 84 (s, 1 H) , 7. 96 (d, 1 H, J = 8. 3Hz), 4. 13 (m, 1H), 3. 36 (b rs, H), 3. 02 (b rs, 4H), 2. 19 ( t, 2H, J = 6. 26Hz), 2. 10 (t, 2H, J-7. 26Hz), 1. 79 (m, 4H), 1. 6 2 (m, 6H), 1. 47 (b rt, 2H), 1. 25 (b rs, 1 OH) example 5 1

(4 R) one 5- (hydroxymethyl § amino) - A 4 [(1 0 one morph cage Roh deca Noi Le) Amino] one 5- Okisopentan acid

In a similar manner to that described in the first section of Example 1, (4 R) - 5- (base: Kishiamino) Single 4- [(1 0-morph cage Roh deca Noi Le) Amino] - 5- Okiso from base pentanoic acid Njiru (1. 5 g), (4 R) - 5 - (hydroxymethyl § Mino) Single 4- [(1 0-morph cage Roh deca Noi Le) amino] one 5-Okisopentan acid 8 94 mg Obtained.

] H-NMR δ (CD 3 OD) 4. 26 (m, 1 H), 3. 31 (t, 4H, J = l. 65Hz) 3. 14 (m, 2H), 2. 33 (t, 2H , J = 7. 59Hz), 2. 23 (t, 2H, J = 7. 58Hz), 2. 07 (m, 4H), 1. 97 (m, 2H), 1. 71 (b rt, 2H) , 1. 61 (b rt, 2H), 1. 40 (br- s, 1 OH) example 52

N- [2- (hydroxy § amino) one 1 - methyl _ 2 Okisoechiru] - A 1 0-

(4 one Shianofue sulfonyl) Single 9- Desenami de

2 - {[1 0- (4-Shianofue sulfonyl) Single 9- Desenoiru] amino} propanoic acid (2. 8 9 g) was dissolved in THF (2 5 m l), N-methylmorpholine (0. 93 ml ) was added, black hole isobutyl the (1. 0 m l) was added in one 1 5 degrees and stirred for 1 5 minutes. Thereto, 0- t-butyldimethylsilyl hydroxy § Min of (1. 2 4 g) was added, and stirred for 30 minutes, further stirred at room temperature for 30 minutes. Saturated sodium hydrogen carbonate aqueous solution was added, followed by extraction with acetic acid Echiru, the organic layer 1 N-hydrochloric acid, washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, by recrystallization from hexane the residue to E one ether one, N-[2- (hydroxy § Mino) one 1-methyl-2-Okisoechiru] one 1 0- (4-Shianofu Eniru) - 9-Desenami de 2. give 42 g.

] H-NMR δ (CDC 1 3) 10. 58 (s, 1 H), 8. 82 (s, 1 H), 7. 48-8. 00 (m, 5H), 6. 40-6. 44 (m, 1. 6H), 5. 87 (dt, 0. 4H, J = 7. lHz, 11. 8Hz), 4. 18- 4. 28 (m, 1 H), 1. 95-2. 42 (m, 4H), 1. 25 (d, 3H, J = 7. 2Hz), 1. 03-1. 71 (m, 1 OH) was used as starting material 2- {[1 0- (4-Shianofueniru ) Single 9- Desenoi le] amino} propanoic acid was prepared as follows.

(A) 2- (9- Desenoiruamino) base propanoic acid Njiru

2 Aminopuropan acid base Njiru the (33. 9 g) and 9 Desen acid (32. 2 g) was dissolved in dichloromethane (400m l), WSC · HC 1 under ice-cooling (36. 3 g) was added 4 hours and the mixture was stirred. 1 N-hydrochloric acid was added, followed by extraction with acetic acid Echiru, the organic layer was washed with saturated aqueous sodium bicarbonate, washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, LKG, mobile phase: Kisan'no acetate Echiru = 5 1 to) to give the by a 2- (9-Desenoiruamino) benzyl propanoate

60. was obtained 6 g.

One NMR δ (CDC 1 3) 7. 14-7. 42 (m, 5H), 6. 02 (b rd, 1 H, J = 7. 3Hz), 5. 73-5. 88 (m, 1 H ), 5. 20 (d, 1 H, J = 12. 4Hz), 5. 15 (d, 1H, J = l 2. 4Hz), 4. 90-5. 03 (m, 2H), 4. 60 -4. 7 0 (m, 1H), 2. 20 (t, 2H, J = 7. 6Hz), 1. 99-2. 05 (m, 2H), 1. 49-1. 70 (m, 2H ), 1. 1 (d, 3H, J = 6. 9Hz), 1. 15-1. 49 (m, 8H)

(B) 2- [(9 over O Kiso nonanoyl I le) Amino] base propanoic acid Njiru

2- (9-Desenoiruamino) base propanoic acid Njiru (60. 6 g) and Sudan III (37 mg) was dissolved in methanol (550 meters l), it was blown for 3 hours in one 78 ° C and O Zon. Dimethyl Huy de the (1 3. 4m l) was added gradually warm to room temperature and then left overnight. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography photography one (stationary phase: silica gel 6 0, 70-2 30 mesh, 1 kg, mobile phase: hexane acetate Echiru = 3Z; ~ 2 Bruno 1-1 1) in the purification, 2 - [(9-1 O Kiso nonanoyl I le) Amino] benzyl propanoic acid was obtained 27. 5 g.^ -NMR δ (CDC1 3) 9. 76 (t, 1 H, J = 2. 0Hz), 7. 18-7 49 (m, 5H), 6. 00 (br -. D, 1 H, J = 7. 3Hz), 5. 21 (d, 1 H, J = 12. 2H z), 5. 15 (d, 1H, J = 12. 2Hz), 4. 60-4. 71 (m, 1 H) , 2. 41 (td, 2H, J = 2. 0Hz, 7. 3Hz), 2. 20 (t, 2H, J = 7. 6Hz), 1. 51 -1. 75 (m, 4H). 1. 41 (d, 3H, J = 7. 3Hz), 1. 23-1. 37 (m, 6 H)

(C) 2- {[10- (4 one Shianofueniru) Single 9 one Desenoiru] amino} base propanoic acid Njiru

Bromide - 4 in one Xia Bruno benzyl phosphonyl © arm (5. 5 g) and 85 ° C, dried under reduced pressure for 1 hour, after suspended in THF (50 m l), sodium hydride (60%, 0. 4 8 g) and the mixture was stirred for 1 hour at room temperature. 2- [(9-1 O Kiso nonanoyl I le) amino] base propanoic acid Njiru (3. 3 g) and the mixture was stirred overnight at room temperature. The reaction solution under ice-cooling, poured into 1 N-hydrochloric acid, and extracted with acetic acid Echiru, the organic layer was washed with saturated sodium hydrogen carbonate © anhydrous solution, washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 250 g, mobile phase: hexane / acetic acid Echiru = 2/1) in by afford 2- {[1 0- (4 Shianofu Eniru) Single 9 _ Desenoiru] amino} benzyl propanoic acid 3. 7 3 g.

One NMR δ (CDC 1 3) 7. 55- 7. 63 (m, 2H), 7. 30- 7. 43 (m, 7 H), 6. 35-6. 44 (m, 1. 5H), 6. 01 (b rd, 1 H, J = 7. 3Hz), 5. 81 (td, 0. 5H, J = 7. 4Hz, 11. 7Hz), 5. 20 (d, 1 H, J = l 2. 2H z), 5. 15 (d, 1H, J = 12. 2Hz), 4. 60-4. 71 (m, 1 H), 2. 08- 2. 35 (m, H), 1. 53-1. 73 (m, 2H), 1. 41 (d, 3H, J = 6. 9H). 1. 12-1. 53 (m, 8H)

(D) 2 - {[1 0- (4- Shianofueniru) Single 9- Desenoiru] amino} propanoic

2- {[1 0- (4 one Shianofue sulfonyl) Single 9- Desenoiru] amino} propanoic acid benzyl (3. 7 3 g) was dissolved in methanol (1 7m 1), 5 N_ sodium hydroxide aqueous solution (3. 4m l) was added and stirred at room temperature for 2.5 hours. Water and ether were added and the aqueous layer with 1 N-hydrochloric acid (1 5 m l), acidified, extracted with acetic acid Echiru, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent removed by filtered filtration, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 1 00 g, mobile phase: hexane acetate Echiru = 1/1 to black hole Holm Roh methanol // acetate = 1 0/1/0. purification by 1), 2- {[1 0- (4-Shianofue sulfonyl) Single 9 Desenoi le] amino} 2 propanoic acid. It was obtained 8 9 g.

J H-NMR δ (CDC " ) 7. 55-7. 63 (m, 2H), 7. 33-7. 42 (m, 2 H), 6. 31-6. 44 (m, 1. 5H) , 6. 10 (b rd, 1 H, J = 7. 3Hz), 5. 80 (dt, 0. 5H, J = 7. 3 Hz, 11. 7Hz), 4. 51-4. 62 (m, 1 H), 2. 10-2. 36 (m, 4H), 1. 53-1. 72 (m, 2H), 1. 45 (d, 3H, J = 7. 3Hz), 1. 01- 1 . 53 (m, 8H) example 5 3

N-_ [2- _ (hydroxy § amino) Single 1 Mechiru one 2- Okisoechiru] 1 0 one

(4 Shianofueniru) Dekanami de

N- [2- (hydroxy § amino) Single 1 Mechiru one 2-Okisoechiru] - 1 0 (4 Shianofueniru) Single 9- Desenami de (2 0 0 mg) was dissolved in methanol (5 ml), 1 0 % palladium Z carbon (2 0 mg) was added, and 7 h stirred at under a hydrogen atmosphere. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, The residue was purified by thin-layer chromatography one (stationary phase: Merck, Silica gel 6 0, 0. 5 mm thick, mobile phase: acetic acid Echiru acetone = 5Z 1) give by, N-[2 - (hydroxy amino) one 1-methyl-2-Okisoechiru] - 1 0- (4-Shianofueniru) Dekana Mi de was obtained 1 7 2 mg.

! H-NMR δ (DMSO- d 6) 10. 56 (br - s, 1 H), 8. 78 (b rs, 1 H), 7, 67 (d, 2H, J = 7.9 Hz), 7. 37 (br- d, 2H, J = 7. 9Hz), 4. 1 5 one 4. 27 (m, 1H), 2. 65 (t, 2H, J = 7. 6Hz), 2. 09 (t, 2H, J = 7. 4Hz), 1. 37- 1. 58 (m, 4H), 1. 1 8 (d, 3H, J = 6. 9Hz), 0. 9 1 one 1. 37 (m, 1 OH) example 54

N- [2- (hydroxy § amino) 1-methyl-2-Okisoechiru] 1 0

[4 one (aminomethyl) phenyl] Dekanami de acetate

N-[2 - (hydroxymethyl § amino) one 1-methyl-2-Okisoechiru] - 1 0- [4- (aminomethyl) phenyl] _ 9 Desenami de (20 Omg) in methanol (5 m l), water (0. 25 m 1) and was dissolved in a mixed solvent of acetic acid (0. 25 m 1), 1 0% palladium Z carbon (l Omg) and the mixture was stirred for 14 hours under a hydrogen atmosphere. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, by a child crystallized by adding ether to the residue, N-[2- (hydroxy § Mino) one 1-methyl-2-Okisoechi Le - 1 0- [4- (aminomethyl) phenyl] Dekanami de acetate to give 1 76 mg.

J H-NMR δ (DMSO- d 6) 7. 94 (d, 1 H, J = 7. 6Hz), 7. 24 (br- d, 2H, J = 7. 9Hz), 7. 12 (br- d, 2H, J = 7. 9Hz), 4. 13-4. 24 (m, 1H), 6. 74 (s, 2H), 2. 54 (t, 2H, J = 7. 6Hz), 2. 08 (t, 2 H, J = 7. 4Hz) 1. 86 (s, 3H), 1. 36- 1. 64 (m, 4H), 1. 16 (t, 3H, J = 7. 3Hz), 0. 94-1. 36 (m, 1 OH) example 55

N-- [2- (hydroxy § amino) - A 1-methyl-- 2 Okisoechiru] - 1 0-

In an analogous manner to that described in Example 52, 2- {[1 0- (3-Shianofue two Le) -9 Desemeiru] amino} N-[2- (hydroxy § amino) propanoic monobasic 1-methyl-2 -. Okisoechiru] one 1 0 (3 Shianofueniru) an 9 Dese cyanamide 1 to give 8 9 g.

-. NMR δ (DMSO-d 6) 1 0. 58 (s, 1 H), 8. 82 (s, 1 H), 7. 51- 8. 00 (m, 5H), 6. 32-6 58 (m, 1. 5H), 5. 77- 5. 87 (m, 0. 5 H), 4. 18- 4. 29 (m, 1 H), 1. 97-2. 38 (m, 4H) , 1. 2 1 (d, 3H, J = 6. 9Hz), 1. 10- 1. 62 (m, 1 OH)

Was used as starting material 2 - {[1 0 - (3 - Shianofueniru) Single 9 - Desenoi le] amino} propanoic acid was prepared in a manner similar to that described in Example 5 2.] H-NMR δ (CDC 1 3) 7. 23-7. 60 (m, 4H), 6. 22-6. 42 (m, 1. 5H), 6. 1 0-6. 2 1 (m, 1 Η), 5. 78 (dt, 0. 5Η, J = 7. 4Hz, 1 1. 7Hz), 4. 54-4. 60 (m, 1 H), 2. 1 1 (m, 4H), 1. 53- 1. 73 (m, 2H), 1. 45 (d, 3H, J = 7. 3Hz), 1. 1 7- 1. 53 (m, 8H) example 5 6

N- [2- (hydroxy § amino) one 1 - methyl-2 Okisoechiru] - 1 0- (3-Shianofueniru) Dekanami de

In an analogous manner to that described in Example 5 3, N- [2- (hydroxy § amino) one 1-methyl-2-Okisoechiru] one 1 0 (3 Shianofueniru) Single 9 dec cyanamide (2 0 from 0 mg) N- [2 - (hydroxyamino) Single 1 Mechiru one 2- Okisoechiru] one 1 0 (3 Shianofue sulfonyl) Dekanami de was obtained 1 0 9 mg.

One NMR δ (DMSO - d 6) 10. 51 (br- s, 1 H), 8. 77 (s, 1 H), 7. 90 (d, 1H, J = 7. 9Hz), 7. 74- 7. 89 (m, 1 H), 7. 58-7. 64 (m, 1H), 7. 35-7. 45 (m, 2H), 4. 14-4. 25 (m, 1 H), 2. 78 (t, 2 H, J = 7. 6Hz), 2. 08 (t, 2H, J = 7. 4Hz), 1. 38- 1. 7 1 (m, 4 H), 1. 17 ( d, 3H, J = 7. 3Hz), 0. 90- 1. 38 (m, 1 OH) example 57

N- [2- (hydroxy § amino) one 1 - methyl one 2- Okiso: ^ Ji 1 - 1 0 - [(3-aminomethyl) phenyl] Dekanami de acetate

In an analogous manner to that described in Example 54, N-1 0- (3-Shianofueniru) Single 9 dec cyanamide (2 200 mg) - [2 - (hydroxy amino - One-methyl-2 Okisoechiru] N- [2- (hydroxyamino) one 1-methyl-2 - Okisoechiru] - 1 0- [(3-aminomethyl) phenyl] the Dekanami de acetate to give 1 92 mg.

] H - NMR δ.. (DMSO - d 6) 7. 93 (d, 1 H, J = 7. 9Hz), 7. 12-7 23 (m, 3H), 6. 97-7 04 (m, 1 H) 4. 17-4. 25 (m, 1 H), 3. 74 (s, 2H), 2. 55 (t, 2HJ = 7. 6Hz), 2. 08 (t, 2H, J = 7 . 3Hz), 1. 8 7 (s, 3H), 1. 38-1. 65 (m, 4H), 1. 17 (d, 3H, J = 7. 3Hz), 1. 08-1. 38 ( m, 1 OH) example 58

N-[2 - (hydroxyamino) Single 1 Mechiru one 2-Okisoechiru] - 1 0 _ (2

- Shianofueniru) one 9 Desenami de

In an analogous manner to that described in Example 52, 2- {[1 0- (2-Shianofue two Le) Single 9 Desenoiru Ί amino} propanoic acid 3.0 from a [2- (hydroxymethyl Amino) Single 1- methyl one 2- Okisoechiru] - 1 0- (2-Shianofue sulfonyl) an 9 one Desenami de give 1. 8 g.

! H-NMR δ (DMSO - d 6) 10. 54 (s, 1 H), 8. 78 (m, 1 H), 7. 30 - 7. 96 (m, 5H), 6. 44-6. 69 (m, 1. 5H), 5. 83-6. 02 (m, 0. 5 H), 4, 09-4. 26 (m, 1 H), 1. 87-2. 32 (m, 4H ), 1. 17 (d, 3H, J = 7. 3Hz), 0. 92-1. 59 (m, 1 OH) example 59

N-[2 - (hydroxymethyl § amino) Single 1 one methyl one 2- Okisoechiru] - 1 0 two (2 one Shianofue two Runode force cyanamide

In an analogous manner to that described in Example 53, N-[2- (hydroxy § amino) Single 1 Mechiru one 2-Okisoechiru] - 1 0- (2-Shianofueniru) N from a 9- Desenami de (200 mg) - [2- (hydroxymethyl § Mino) Single 1-methyl one 2-O key Soechiru] -1 0- (2-Shianofueniru) Dekanami de was obtained quantitatively.

] H_NMR δ (DMSO- d 6) 10. 53 (s, 1 H), 8. 77 (s, 1 H), 7. 91 (d, 1H, J = 4. 3Hz), 7. 60- 7. 63 (m, 2H), 7. 44-7. 55 (m, 2 H), 4. 16-4. 22 (m, 1 H), 2. 63 (t, 2H, J = 7. 6Hz), 2. 08 (t, 2H, J = 7. 4Hz), 1. 37- 1. 66 (m, 4H), 1. 17 (d. 3H, J = 6. 9H z) 1. 15-1. 37 (m, 1 OH) example 60

N - [2 - (hydroxyamino) Single 1 one methyl - 2 Okisoechiru] - 1 0 - [2 one _ (aminomethyl) phenyl] Dekanami de

In an analogous manner to that described in Example 54, N- [2 - (hydroxymethyl § amino) - 1-methyl one 2- Okisoechiru] - 1 0- (2-Shianofueniru) Single 9 Desenami N from de (200 mg) - [2- (hydroxy § amino) Single 1 one methyl one 2-O key Soechiru] - 1 0- [2- (aminomethyl) phenyl] Dekanami de afford 1 38 mg.

'H-NMR δ (DMSO- d 6) 7. 95 (b rd, 1 H, J = 7. 6Hz), 7. 30-7. 41 (m, 1H), 7. 01-7. 22 (m , 3H), 4. 11-4. 27 (m, 1 H), 3. 7 4 (s, 2H), 2. 58 (t, 2H, J = 7. 8Hz), 2. 08 (t, 2H , J = 7. 1 H z), 1. 39-1. 66 (m, 4H), 1. 16 (d, 3H, J = 6. 9Hz), 0. 84-1. 39 (m, 1 OH ) example 6 1

4 one - [1 0- {[2- one (hydroxy § amino) 1 - methyl-one Okisoechiru] amino} - 1 0 Okiso one 1-decenyl] benzoate

In an analogous manner to that described in Example 52, 2- [1 0 - {[4 one (main butoxy carbonyl) phenyl] - 9 Desenoiru} Amino] propanoic acid 2.4 from 58 g - (1 0- { the - [2 (hydroxyamino) one 1-methyl-2-Okisoechiru] § amino} one 1 0 _ Okiso one 1 Deseniru] benzoate was obtained 1. 0 g.

] H-NMR 8 (DMSO- d 6) 10. 55 (s, 1 H), 8. 78 (s, 1 H), 7. 87- 7. 95 (m, 2H), 7. 39-7. 52 (m, 2H), 6. 32-6. 56 (m, 1. 7H), 5. 78 (td, 0. 3H, J = 7. 3Hz, 11. 6Hz), 4. 14-4. 24 (m, 1 H), 3. 85 (s, 1H), 3. 84 (s, 2H), 2. 13-2. 36 (m, 2H), 1. 92-2. 13 (m, 2H) , 1. 37-1. 57 (m, H), 1. 16 (d, 3H, J = 6. 9Hz), 0. 93-1. 37 (m, 6H) example 62

4 one [1 0- {[2- (hydroxymethyl § amino) 1 one methyl one 2- Okisoechiru] amino} - 1 0 Okisodeshiru] benzoate

In an analogous manner to that described in Example 53, 4 one [1 0- {[2- (hydroxymethyl Shiamino) one 1-methyl-2-Okisoechiru] Amino) one 1 0 Okiso one 1-de Seniru] benzoic acid one 4 methyl (200mg) [1 0- {[2 - (hydroxymethyl Amino) one 1-methyl-2-Okisoechiru] Amino) - 1 0 one Okisodeshiru] depreciation Ikikosan methyl afford 1 9 Omg.

] H-NMR δ (DMSO - d 6) 10. 54 (s, 1 H), 8. 78 (s, 1 H), 7. 91 (b rd, 1H, J = 7. 9Hz), 7. 87 (b rd, 2H, J = 8. 3Hz), 7. 32 (b rd, 2H, J = 7. 9Hz), 4. 14-4. 25 (m, 1 H), 3. 84 (s, 3H ), 2. 64 (t, 2H, J = 7. 6Hz), 2. 08 (t, 2H, J = 7. 6Hz) 1. 37-1. 76 (m, 4H), 1. 17 (d, 3H, J = 6. 9Hz), 0. 90-1. 37 (m, 1 OH) example 63

4 one [1 0 {[2 - (hydroxymethyl § Mino) one 1-methyl-2-Okisoechiru] amino} one 1 0 Okiso one _1- decenyl] benzoic acid

4 - dissolved [1 0- {[2- (hydroxymethyl § amino) Single 1 Mechiru one 2- Okisoechi le] amino} one 1 0 Okiso one 1 Deseniru] benzoate (92 Omg) in methanol 1 0 m 1 was added 5 N-sodium hydroxide solution (0. 94m l), and stirred at room temperature for 4 hours. 5N- by adding an aqueous solution of sodium hydroxide (2 m 1) and methanol (5 m l), after stirring for a further 4 hours and allowed to stand overnight. And two layers separated by adding ether, the aqueous layer two 1 N-hydrochloric acid was added, followed by extraction with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, after the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 1 0 g, mobile phase: black port Hol arm methanol // acetate = 20Z 1 . Z0 1) after concentration, by the child crystallized in E one ether, 4 one [1 0- {[2 - (hydroxymethyl § amino) one 1-methyl-2-O Kisoechiru] amino} one 1 0 Okiso one 1-decenyl] benzoic acid was obtained 40 Omg.

JH-NMR δ (DMSO-d 6) 12. 73 (b rs, 1 H), 10. 55 (s, 1 H), 8. 79 (br- s, 1H), 7. 85-7. 93 ( m, 2H), 7. 36- 7. 50 (m, 2H), 6. 35-6. 53 (m, 1. 5H), 5. 77 (td, 0. 5H, J = 7. 1Hz, 11 . 6H z), 4. 13- 4. 25 (m, 1 H), 2. 15-2. 37 (m, 2H), 2. 05-2. 12 (m, 2H), 1. 36-1 . 56 (m, 4H), 1. 17 (d, 3H, J = 6. 9Hz), 1. 0 4-1. 36 (m, 6H) example 64

4 - [10 {[2 - (hydroxyamino) one 1-methyl-_2- Okisoechiru 1 amino} - 1 0- benzoic acid

In an analogous manner to that described in Example 53, 4 one [1 0- {[2 - (hydroxy Shiamino) one 1-methyl-2-Okisoechiru] amino} one 1 0 Okiso one 1-de Seniru] benzoic acid ( 4 scratch [1 0- {[2- (hydroxymethyl amino) one 1-methyl-2-Okisoechiru] amino} one 1 0 Okisodeshiru] benzoic acid was obtained 1 91 mg of 200 meters g).

! H - NMR δ (DMSO- d 6) 12. 55 (b rs, 1 H), 10. 55 (s, 1 H), 8. 82 (b rs, 1H), 7. 93 (b rs, 1 H, J = 7. 9Hz), 7. 85 (d, 2H, J = 7. 9Hz), 7. 29 (d, 2H, J = 8. 3Hz), 4. 13-4. 24 (m, 1 H), 2. 63 (t, 2H, J = 7. 8Hz), 2. 08 (t, 2H, J = 7. 4Hz), 1. 38-1. 69 (m, 4H), 1. 16 ( d, 3H, J = 6. 9Hz), 0. 90-1. 38 (m, 1 OH) example 65

3- [1 0 {[2- (hydroxyamino) - A 1-methyl-- 2 Okisoechiru Ί amino} one 1 0 Okiso one 1 Deseniru] benzoate

In an analogous manner to that described in Example 52, 2- [{1 0- [3- (Main butoxy carbonyl) phenyl] one 9-Desenoiru} Amino] propanoic acid 3. 2 g 3- [1 0- the {[2- (hydroxymethyl § Mino) Single 1-methyl one 2-year old Kisoechiru] amino} one 1 0 Okiso _ 1-decenyl] benzoate was obtained 504 m g.

] H-NMR δ (DMSO-d 6) 10. 54 (s, 1 H), 8. 78 (s, 1 H), 7. 41- 7. 93 (m, 5H), 6. 34-6. 50 (m, 1. 6H), 5. 77 (td, 0. 4H, J = 7. 3Hz, 11. 2Hz), 4. 06-4. 24 (m, 1 H), 3. 86 (s, 3H), 2. 1 9-2. 34 (m, 2H), 2. 05-2. 17 (m, 2H), 1. 37-1. 49 (m, 4H) 1. 17 (d, 3H, J = 6. 9Hz), 1. 00-1. 37 (m, 6H) example 66

3 - [1 0 - {[2- _ (hydroxyamino) one 1-methyl-2-Okisoechiru] amino} 1 0 Okisodeshiru] benzoate

In an analogous manner to that described in Example 53, 3- [1 0- {[2- (hydroxymethyl Shiamino) one 1-methyl-2-Okisoechiru] amino} - 1 0 Okiso one 1-de Seniru] benzoate from (200 mg) 3- [1 0- {[2- (hydroxymethyl Amino) one 1-methyl-2-Okisoechiru] Amino) one 1 0 Okisodeshiru] depreciation Ikikosan methyl obtain 1 6 Omg.

One NMR δ (DMSO-d 6) 10. 54 (s, 1 H), 8. 78 (s, 1 H), 7. 93 (b rd, 1H, J = 7. 6Hz), 7. 76-7 . 78 (m, 2H), 7. 39-7. '48 (m, 2H), 4. 13-4. 24 (m, 1 H), 3. 85 (s, 3H), 2. 64 (t , 2H, J = 7. 8Hz), 2. 07 (t, 2H, J = 7. 4Hz), 1. 16 (d, 3H, J = 7. 3Hz), 1. 36-2. 67 (m, 4H), 0. 83-1. 36 (m, 1 OH) example 67

N- [2 - (hydroxyamino) one 1-methyl-2-Okisoechiru] - 10- (1 H- 1 one-indolyl) Dekanami de

In an analogous manner to that described in Example 52, 2- {[1 0- (1 H- 1 one-indolyl) Dekanoiru] amino} propanoic acid 704m g of N- [2 - (hydroxymethyl Amino) Single 1- methyl-2 Okisoechiru] -1 0 a (1 H- 1-indolyl) de force cyanamide to give 405 mg.

! H-NMR δ (DMSO- d 6) 10. 55 (s, 1 H), 8. 79 (s, 1 H), 7. 93 (d, 1H, J = 7. 9Hz), 7. 53 ( d, 1 H, J = 7. 9Hz), 7. 43 (d, 1 H, J = 7. 2Hz), 7. 34 (d, 1 H, J = 2. 9Hz), 7. 11 (t, 1 H, J = 7. 2H z), 6. 40 (dd, 1H, J = 2. 97Hz, 0. 66Hz), 4. 20-4. 12 (m, 3 H), 2. 07 (t, 2H, J = 7. 26Hz), 1. 74 (b rt, 2H), 1. 43 (br - t, 2H), 1. 20 (b rs, 1 OH), 1. 15 (d, 3H, J = prepared by analogous method to that described for 6. 9 Hz) the following compounds in example 1.

Example 68

^ -NMR δ (DMSO- d 6) 0. 83-1. 37 (m, 12 H), 1. 37-1. 75 (m, 8H), 2. 10 (t, 2H, J = 7. 1 H z), 2. 64 (t, 2 H, J = 7. 4Hz), 2. 7 4 (t, 2 H, J = 7. 3Hz), 3. 85 (s, 3H), 4. 12 ( m, 1H), 7. 23-7. 53 (m, 2H), 7. 53- 8. 10 (m, 3H), 8. 81 (b rs, 1 H), 10. 59 (b rs, 1H ) example 69

1 H-NMR δ (DMSO- d 6) 1. 14-1. 33 (m, 1 OH), 1. 33-1. 64 (m, 4H), 1. 64-1. 90 (m, 2H) , 2. 02-2. 25 (m, 4H), 2. 64 (t, 2 H, J = 7. 7Hz), 3. 83 (s, 3H), 4. 14 (m, 1 H), 7 . 32-7. 35 (m, 2H), 7. 86-7. 88 (m, 2H), 7. 96 (d, 1 H, J = 8. 4Hz), 8. 86 (b rs, 1H) , 10. 62 (s, 1 H) example 70

1 H-NMR δ (DMSO- d 6) 0. 92-1. 35 (m, 12H), 1. 35-1. 83 (m, 8H), 2. 09 (t, 2H, J = 7. 2Hz ), 2. 64 (t, 2H, J = 7. 7Hz), 2. 73 (t, 2H, J = 7. 3Hz), 3. 83 (s, 3H), 4, 12 (m, 1 H) , 7. 32- 7. 35 (m, 2H), 7. 86-7. 89 (m, 2H), 7. 96 (d, 1 H, J = 8. 3H z), 8. 82 (b rs , 1H) example 7 1

C0 2 Me C0 2 H 1 H -NMR δ (DMSO- d 6) 0. 95-1. 36 (m, 1 OH), 1. 36-1. 65 (m, 4H), 1. 65-1. 95 (m, 2H), 1. 95-2. 30 (m, 4H), 2. 64 (t, 2 H, J = 7. 6Hz), 3. 85 (s, 3H), 4. 16 (m , 1 H), 7. 39- 7. 49 (m, 2H), 7. 76-7. 78 (m, 2H), 7. 94 (d, 1 H, J = 7. 9Hz), 8. 83 (b rs, 1H), 10. 61 (br- s, 1 H), 12. 05 (br- s, 1H) example 72

1 H-NMR δ (DMSO- d 6) 1. 14-1. 40 (m, 12H), 1. 40-1. 70 (m, 8H), 2. 09 (t, 2H, J = 7. 5Hz ), 2. 49 (t, 2H, J = 7. 5Hz), 2.

72 (t, 2H, J = 7. 5Hz), 3. 71 (s, 3H), 4. 13 (m, 1 H), 6. 80- 6. 84 (m, 2H), 7. 07-7 . 09 (m, 2H), 7. 97 (d, 1 H, J = 8. 4H z), 8. 55 (br- s, 1 H) example 73

1 H-NMR δ (DMSO- d 6) 0. 90-1. 38 (m, 12H), 1. 38-1. 73 (m, 8H), 2. 10 (t, 2H, J = 6. 7Hz ), 2. 44 (t, 2H, J = 7. 5Hz), 2. 72 (t, 2H, J = 7. 3Hz), 4. 14 (m, 1 H), 6. 64-6. 66 ( m, 2H), 9 L mm

(Ηΐ 's- q)

98 '8' (2H6 '9 = f' HI 'Ρ) 96' L (ZH6 'ί =' HZ 'Ρ) S 8 Ί' (z Si H9 'L = £' ΗΖ 'P) 6 Z' L ' (HI '∞) ΐ' V '(^ HS' ί ^ ΐ 'HZ' ΐ)

'Ζ' (ΖΗ 'ί = £' ΗΖ 'Ό S 9' Ζ '(ΖΗ' = Γ 'ΗΖ Ί) 0 ΐ' Ζ '(Η8

'M) L 9 Ί-LZ ' ΐ '(HZ I ι g · ι- 00' ΐ (9 P-OSWQ) S Η ^ Ν-Η Τ

Οΐ

(Z HS "A = f ' Ηΐ' Ρ) ΟΖ" 8 '(Ηΐ L £ Ί' (HC

¾) Z '-90 Ί' (Ηΐ) Zl '(UZ' s) gg 'S' (ΖΗ9 Ά = Γ Ή τ ') 09' Ζ '(Η "2-Ζ6 · ΐ' (Η ^ '^) 26 · ΐ- S9 · ΐ '(Η

1χ) S9 · ΐ- 6S · ΐ '(ΗΟ ΐ' ^) 6S · ΐ over arm 0 · ΐ (9 Ρ- OSWI) § H MM-H t

L m

(Ζ ΗΙ '8 = Γ' ΗΤ 'Ρ) S6 Ί' (ΗΖ 96 · 9 one S6 '9

III

ZPS £ 0IL6drilDd

] H-NMR δ (DMSO- d 6) 1. 12-1. 38 (m, 12H), 1. 38-1. 66 (m, 8H), 2. 10 (t, 2H, J = 7. 3 H z), 2. 63 (t, 2H, J = 7. 6 H z), 2. 7 3 (t, 2H, J = 7. 4 H z), 4. 13 (m, 1 H), 7 . 32-7. 48 (m, 2H), 7. 70-7. 79 (m, 2H), 7. 90 (br_s, 3H), 7. 96 (d, 1 H, J = 8. 1 H z ), 8. 82 (s, 1H), 10. 66 (s, 1 H) example 77

H- NMR δ (DMSO- d 6) 1. 12-1. 36 (m, 1 OH), 1. 38-1. 64 (m, 4H), 1. 64-1. 92 (m, 2H), 2. 02-2. 30 (m, 4H), 4. 15 (m, 1 H), 7. 34-7. 48 (m, 2H), 7. 10-7. 78 (m, 2H), 7 . 95 (d, 1 H, J = 7. 7H z), 8. 83 (br- s, 1 H), 10. 62 (s, 1 H), 12. 45 (br- s, 2H) example 78

iH-NMR 8... ( DMSO - d 6) 1. 12-1 39 (m, 12H), 1. 39-1 62 (m, 8H), 2. 10 (t, 2H, J = 7 4 H z), 2. 59 (t, 2H, J = 7. 8 H z), 2. 6 9 (t, 2H, J = 7. 5 H z), 3. 80 (s, 2H), 4. 12 (m, 1 H), 7. 07- 7. 22 (m, 3H), 7. 34-7. 42 (m, 1 H), 7. 96 (d, 1 H, J = 8. 3H z) example 79

(4 R) - 5-hydroxy § Mino one 4 {[1 0-- (2- {[(Amino "Imino methyl) Amino methyl} phenyl) Dekanoiru] Amino) Single 5 Okisopenta phosphate

] H-NMR δ... (DMSO - d 6) 1. 01-1 62 (m, 1 H), 1. 65-1 85 (m, 2H), 1. 82-2 18 (m, 4H) , 2. 58 (t, 2H, J = 8. OH z), 3. 97 (m, 1H), 4. 27 (s, 2H) 7. 12-7. 32 (m, 4H), 8. 11 (br- s, 3H), 8. 53 (d, 1H), 8. 73 (b rs, 1 H), 9. 13 (br- s, 1 H), 10. 52 (b rs, 1H) The starting It was used as the material (4 R) - 5-[(Benjiruokishi) amino] -4- [1 0- (2- {[({[(Benjiruokishi) carbonyl] amino} {[(Ben Jiruokishi) carbonyl] imino} methyl ) amino] methyl} phenyl) Dekano I le] amino} - 5-Okisopentan acid benzyl was prepared as follows.

(A) 1 0 _ (2- Shianofueniru) one 9-decenoic acid t- butyl Bromide 2-Xia Roh benzyl triphenyl phosphonyl © beam (40. 97 g) and 1 0 0 ° C After vacuum under 1 hour in a dry, was suspended in THF (3 50m l), 60% - hydrogen Kana thorium ( 3. 6 g) was added and stirred for 1 8 h. 9 Okisononan acid t-Bed chill (1 7 g) after 5 hours of stirring by addition of a 1 N-hydrochloric acid was added under ice-cooling, and extracted with acetic acid Echiru. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue by silica force gel column chromatography (stationary phase: silica gel 60, 70-2 30 mesh, 1 kg, mobile phase: hexane / acetic acid Echiru = 1 purification by 0/1), 1 0- (2-Shianofueniru) one 9-decenoic acid t one-butyl obtain 20 g.

1 H-NMR δ (CDC 1 3) 1. 24-1. 65 (m, 1 OH), 1. 438 (s, 3. 3Η), 1. 443 (s, 5. 7Η), 2. 16- 2. 32 (m, 4Η), 5. 92 (dt, 0. 37H, J = 7. 4Hz, 11. 5Hz), 6. 43 (dt, 0. 63H, J = 6. 9Hz, 15. 7Hz) 6. 61 (d, 0. 37H, J = l 1. 5Hz), 6. 74 (d, 0. 63H, J = l 5. 7Hz), 7. 24-7. 67 (m, 4H)

(B) 10- - t-butyl [2 (aminomethyl) phenyl] decanoic acid

1 0 - (2 one Shianofue sulfonyl) Single 9 Desen acid t one butyl (1. 7 5 g) was dissolved in acetic acid (30m l), 10% -P dZC the (20 Omg) was added, under a hydrogen atmosphere , and the mixture was stirred for 8.5 hours. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, redissolved in acetic acid (20m 1), 1 0% - P dZC the (80 Om g) was added, under hydrogen atmosphere and stirred for 12 hours. The catalyst was removed by filtration, The solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate © beam aqueous solution was added, followed by extraction with acetic acid Echiru, the organic layer was washed with saturated brine and dried over anhydrous sulfate sodium. The desiccant was filtered off, due to distilling off the solvent under reduced pressure connexion, 1 0- [2- (aminomethyl) phenyl] t-decanoic acid butyl give 1. 7 3 g.

1 H -NMR δ (CDC 1) 1. 21-1. 41 (m, 1 OH), 1. 44 (s, 9 H), 1. 49-1. 64 (m, 4H), 2. 20 ( t, 2H, J = 7. 4Hz), 2. 63 (t, 2H, J = 8. 0Hz), 3. 88 (s, 2H), 7. 13-7. 23 (m, 3H), 7. 28- 7. 35 (m, 1H) (C) 1 0- (2- {[({[(Benjiruokishi) carbonyl] amino} {[(Baie Njiruokishi) carbonyl] imino} methyl) amino] methyl} phenyl) deca phosphate t one-butyl

1 0- [2- (aminomethyl) phenyl] decanoic acid t one-butyl (6. 53 g) was dissolved in a mixed solvent of THF (60 m l) and water (1. 2m l), [1 i (Benjiruo alkoxycarbonyl § amino) - 1 scratch (methylthio) methylidene] Karubami phosphate benzyl (1 4 g) was added, and 1. stirred for 5 hours at 60 ° C. The solvent was distilled off under reduced distillation, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 500 g, mobile phase: hexane Z acetate Echiru - 1 0/1) 1 purified by 0- (2- {[({[(Benjiruokishi) carbonylation le] amino} {[(Benjiruokishi) carbonyl] imino} methyl) amino] methylation} phenyl) were collected and decanoic acid t one-butyl 1. 3 g [1- (Benjiruo butoxycarbonyl § mino) a mixture of single- 1 (methylthio) methylidene] force Rubamin acid benzyl give 1 7. 3 g.

1 H -NMR δ (CDC 1 3 ) 1. 20-1. 40 (m, 1 OH), 1. 44 (s, 9 Η), 1. 47-1. 65 (m, 4H), 2. 19 (t, 2H, J = 7. 5Hz), 2. 61 (t, 2H, J = 7. 9Hz), 4. 62 (d, 2H, J = 5. 0Hz), 5. 14 (s, 2H) , 5. 15 (s, 2H), 7. 13-7. 44 (m, 1 H), 8. 39 (s, 1 H), 11. 78 (s, 1H)

(D) 1 0- (2-{[({[(Benjiruokishi) carbonyl] amino} {[(Baie Njiruokishi) carbonyl] imino} methyl) Amino] methyl} phenyl) dec phosphate

1 0- (2- {[({[(Benjiruokishi) carbonyl] amino} {[(Ben Jiruokishi) carbonyl] Imino) methyl) Amino] methyl} phenyl) decanoic acid t one-butyl (1. 27 g) 95% - dissolved in TF a solution (1 Om l), allowed to stand at room temperature for 30 minutes. The above-described 1 0- (2- {[({[(Benjiruoki Shi) carbonyl] amino} {[(Benjiruokishi) carbonyl] imino} methylation) Amino] methyl} phenyl) and decanoic acid t one-butyl [1 one (Benjiruoki aryloxycarbonyl § mino) Single 1- (methylthio) methylidene] force Rubamin acid benzyl Le mixture of (7. 3 g) of 95% - TF a dissolved in an aqueous solution (1 0 m l), allowed to stand at room temperature for 30 minutes did. These together, the solvent was distilled off under reduced pressure and the residue was purified by silica gel force column chromatography (stationary phase: silica gel 60, 70-230 mesh, 3 50 g, mobile phase: to Kisan'no acetate Echiru = 5/1 → black hole Holm . methanol Z acetate = 1 0 Bruno 1/0 I'm on the this 1) to give 1 0 - (2 - {[({[(Benjiruokishi) carbonyl] amino} {[(Benjiruokishi) Cal Boniru] imino the} methyl) Amino] methyl} phenyl) decanoic acid 1 1. give 1 g.

1 H-NMR δ (CDC 1 3) 1. 17-1. 40 (m, 1 OH), 1. 47-1. 68 (m, 4Η), 2. 32 (t, 2H, J = 7. 4Hz ), 2. 61 (t, 2H, J = 7. 8Hz), 4. 62 (d, 2H, J = 4. 6Hz), 5. 14 (s, 2H),, 5. 15 (s, 2H) , 7. 13- 7. 43 (m, 14H), 8. 42 (s, 1 H) (E) (4 R) - 5- [(Benjiruokishi) Amino] one 4 one {[1 0 - (2- {[({[(Benjiruokishi) carbonyl] amino} {[(Benjiruokishi) Cal Boniru] imino} methyl) amino] methyl} phenyl) Dekanoiru] amino) Single 5 Okisopentan benzyl

(4 R) - 5 - [(Benjiruokishi) Amino] -4- [(t- Bed

Yl) Amino] - 5-pentanoic acid benzyl (2. 2 1 g) was suspended in Asetoni Bok Lil (20 m l), was added methanesulfonic acid (3. 85 g) under ice-cooling, stirred for 1 hour did. Toryechiruamin (4. 04 g), HOB t (0. 8 1 g), 1 0 i (2- {[({[(Benjiruokishi) carbonyl] amino} {[(Benjiruo carboxymethyl) carbonyl] imino} methyl) Amino] methyl} phenyl) decanoic acid (3.

53 g), was added in DMF (20 m l) in this order, 3 0 minutes after stirred with WS C · HC 1 under ice-cooling, and allowed to stand overnight at room temperature. 1 N-hydrochloric acid was added, followed by extraction with acetic acid Echiru, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous sulfate magnesium © beam. The desiccant was filtered off, THF the residue by crystallization from a mixed solvent of hexane ether and to, (4 R) - 5 - [(Benjiruoki Shi) Amino] -4- {[1 0- (2 _ the {[({[(Benjiruokishi) carbonylation le] amino} {[(Benjiruokishi) carbonyl] imino} methyl) amino] methylation} phenyl) Dekanoiru] amino} one 5- Okisopentan benzyl 3.

6 were obtained g.

] H- NMR δ (CDC 1 3) 1. 13-1. 39 (m, 1 OH), 1. 45-1. 70 (m, 4H), 1. 92-2. 20 (m, 2H), 2. 09 (t, 2H, J = 7. 4Hz), 2. 2 7-2. 55 (m, 2H), 2. 60 (t, 2H, J = 7. 9Hz), 4. 28 (m, 1 H), 4. 6 1 (t, 2H, J = 2. 5Hz), 4. 88 (s, 2H), 5. 10 (d, 2U, J = l. 5H z), 5. 14 (s , 2H), 5. 1 5 (s, 2H), 6. 30 (d, 1 H, J = 7. 2Hz),

7. 14-7. 43 (m, 24H), 8. 39 (s, 1 H), 9. 23 (s, 1 H), 1 1. 77 (s, 1H) Example 8 0

-. NMR 8 (DMSO- d 6 ) 1. 10- 1. 62 (m, 20 H), 1. 70-1 79 (s, 1. 5 H), 2. 10 (t, 2 H, J = 7. 2 H z), 2. 55-2. 64 (m, 4 H), 4. 12 (m, 1 H), 4. 35 (s, 2 H) 7. 17-7. 30 (m, 4 H), 7. 95 (m, 1 H), 8. 30 (m, 1 H) example 8 1

iH-NMR δ (DMSO - d 6) 1. 23. (br - s, 1 OH), 1. 45 (m, 2H), 1. 56 (m, 2H), 2. 09-2 1 8 (m , 4H), 2. 65 (t, 2H, J = 7. 9Hz), 4. 14 (m, 1H), 7. 40 (d, 2H, J = 8. 4Hz), 7. 73 (d, 2H , J = 8. 4Hz), 7. 95 (d, 1H, J = 7. 8Hz) 8. 90 (br- s, 1 H), 10. 61 (s, 1H) example 82

] H-NMR δ (TFA- d) 1. 6 (b rs, 1 OH), 1. 61-1. 88 (m, 4 H), 2. 25-2. 50 (m, 2H), 2. 62 (t, 2H, J = 7. 3Hz), 2. 71-2. 92 (m, 4H), 4. 44 (d, 2H, J = 5. 5Hz), 4. 91 (t, 1 H, J = 8. OH z), 7. 35-7. 43 (m, 4H) example 83

J H-NMR δ.. ( DMSO - d 6) 1. 24 (b rs, 1 OH), 1. 29-1 3 (m, 1 H), 1. 3-1 63 (m, 3H), 1 . 63-1. 83 (m, 2H), 1. 91-2. 00 (m, 3H), 2. 09-2. 18 (m, 1 H), 2. 54 (t, 2H, J = 7 . 2Hz), 4. 0 5 (dd, 1H, J = 7. 52Hz, 13. 78Hz), 4. 28 (b rs, 2H), 7. 04 -7. 10 (m, 2H), 7. 16 (b rs, 1 H), 7. 19- 7. 25 (m, 1 H), 7. 67 (b rs, 1 H), 8. 23 (d, 1 H, J = 7. 7Hz), 8 . 77 (b rs, 1 H), 10. 17 (b rs, 2H), 10. 58 (br- s, 1 H) example 84

1 H-NMR δ. (DMSO - d 6) 1. 23- 1. 39 (m, 12H), 1. 39 (s, 9H), 1. 40-1 60 (m, 8H), 2. 10 ( t, 2H, J = 7. 2Hz), 2. 50-2. 56 (m, 2H), 2. 72 (t, 2H, J = 7. 5Hz), 4. 09 (d, 2H, J = 6 . 1Hz), 4. 08-4. 16 (m, 1 H), 7. 01-7. 04 (m, 3H), 7. 17-7. 22 (m, 1H), 7. 35 (t, 1H, J = 6. 2Hz), 7. 97 (d, 1 H, J = 8. 3Hz), 8. 54 (b rs, 3H) example 85

1 H-NMR δ (CDC 1 3) 0. 98- 1. 36 (m, 1 OH), 1. 36- 1. 65 (m, 4 H), 1. 65-1. 93 (m, 2H) , 2. 09 (t, 2H, J = 7. 3Hz), 2. 15-2. 22 (m, 2H), 2. 63 (t, 2H, J = 7. 6Hz), 4. 15 (m, 1 H), 7. 29 (b rd, 2H, J = 7. 92Hz), 7. 85 (d, 2H, J = 8. 2Hz), 7. 96 (d, 1H, J = 8. 2Hz), 10. 63 (b rs, 1 H) example 86

1 H-NMR δ (DMSO- d 6) 1. 25- 1. 8 (m, 2H), 1. 48-1. 61 (m, 2H), 1. 61-1. 95 (m, 4H), 2. 03 (t, 2H, J = 7. 7Hz), 2. 10 (t, 2H, J = 7. 5Hz), 2. 1 -2. 24 (m, 2H), 2. 57 (t, 2H , J = 7. 7Hz), 3. 05 (dd, 2H, J = 7. OHz, 12. 8Hz), 4. 14 (m, 1 H), 7. 10-7. 21 (m, 3H), 7. 21-7. 31 (m, 2H), 7. 77 (t, 1 H, J = 4. 6Hz), 8. 00 (d, 1H, J = 8. 3Hz), 10. 64 (br- s, 1 H) example 87

] H-NMR δ.. (DMSO - d 6) 1. 42- 1. 68 (m, 6H), 1. 68-1 92 (m, 2H), 2. 00-2 31 (m, 6H), 2. 57 (t, 2H, J = 6. 6Hz), 3. 00 (m, 2H), 4. 15 (m, 1 H), 7. 09- 7. 22 (m, 3H), 7. 22 - 7. 32 (m, 2H), 7. 79 (t, 1H, J = 5. 5Hz), 8. 01 (d, 1 H, J = 8. 3Hz), 10. 66 (s, 1H) carried example 88

1 H-NMR δ (DMSO- d 6) 1. 25-1. 40 (m, 2H), 1. 40-1. 56 (m, 2H), 1. 64-1. 92 (m, 4H), 1. 98- 2. 30 (m, 6H), 2. 55 (t, 2 H, J = 7. 5Hz), 3. 02 (m, 2H), 4. 15 (m, 1 H), 7. 12-7. 22 (m, 3H), 7. 22-7. 32 (m, 2H), 7. 77 (br- s, 1 H), 7. 98 (d, 1 H, J = 8. 3Hz ), 10. 64 (s, 1 H) example 89

. 1 H-NMR δ (DMSO - d 6) 1. 61-1 92 (m, 2H), 2. 14 (t, 2H, J:

7. 6Hz), 2. 32-2. 45 (m, 2H), 2. 80 (t, 2H, J = 7. 3Hz), 4. 17 (m, 1H), 7. 11-7. 31 ( m, 5H), 8. 03 (d, 1 H, J = 8. 3Hz),

8. 80 (s, 1H), 10. 62 (s, 1 H), 12. 06 (s, 1 H) Example 90

1 H-NMR δ.. ( DMSO - d 6) 1. 1 -1 35 (m, 2H), 1. 40-1 62 (m, 4H), 1. 63- 1. 92 (m, 2H), 2. 09- 2. 24 (m, 4H), 2. 55 (t, 2 H, J = 7. 59Hz), 4. 15 (m, 1 H), 7. 09-7. 22 (m, 3H ), 7. 22- 7. 30 (m, 2H), 7. 96 (d, 1 H, J = 7. 92Hz), 8. 98 (br s, 1 H), 10. 61 (b rs, 1H ) example 9 1

1 H-NMR δ (DMSO- d 6) 1. 27 (b rs, 4H), 1. 36-1. 68 (m, 4 H), 1. 68-1. 92 (m, 2H), 2. 10 (t, 2H, J = 6. 6Hz), 2. 21 (t, 2H, J = 6. 3Hz), 2. 56 (t, 2H, J = 7. 3Hz), 4. 15 (m, 1 H), 7. 10-7. 20 (m, 3H), 7. 20- 7. 32 (m, 2H), 7. 94 (d, 1 H, J = 7. 9Hz), 10. 61 (s , 1H) example 92

1 H-NMR δ (CD 3 OD) 1. 20-1. 45 (1 OH, m), 1. 50-1. 70 (4H, m), 1. 82-2. 13 (2H, m), 2. 22 (2H, t, J = 7. 4H z), 2. 34 (2H, t, J = 7. 6H z), 2. 59 (2H, t, J = 7. 8 H z), 4 . 23-4. 33 (1H, m), 7. 08-7. 18 (3H, m), 7. 18-7. 29 (2H, m) example 93

1 H-NMR δ (CDC 1 3) 1. 10-1. 41 (1 OH, m), 1. 35 (3H, d, J = 6. 9 H z), 1. 45-1. 68 (4H , m), 2. 20 (2H, t, J = 7. 5 H z), 2. 58 (2H, t, J = 7. 6H z), 4. 47 (1H, m), 6. 78 ( 1H, d, J = 7. 3 H z), 7. 10-7. 20 (3H, m), 7. 20-7. 30 (2 H, m) example 94

1 H-NMR δ (CD 3 OD) 1. 31 (1 OH, b r. S), 1. 45-1. 70 (4H, m) 2. 24 (2H, t, J = 7. 6 H z ), 2. 59 (2H, t, J = 7. 6 H z), 3. 71 (2H, d, J = 5. 9H z), 4. 35 (1H, t, J = 5. 8 H z ), 7. 07-7. 18 (3H, m), 7. 18-7. 27 (2H, m) example 95

1 H-NMR δ (DMSO- d 6) 1. 27 (b rs, 6H), 1. 39- 1. 63 (m, 4 H), 1. 64-1. 92 (m, 2H), 2. 04-2. 26 (m, 4H), 2. 56 (t, 2H, J = 7. 3Hz), 4. 15 (m, 1 H), 7. 11-7. 22 (m, 3H), 7 . 22-7. 3 0 (m, 2H), 7. 96 (d, 1 H, J = 8. 1Hz), 10. similar to 64 (s, 1H) method below described compound in example 2 It was prepared by the method. Example 96

] H- NMR 8 (DMSO-d 6 ) 1. 12-1. 34 (m, 10 H), 1. 36-1. 51 (m, 2 H), 1. 51-1. 64 (m, 2 H), 1. 64-1. 80 (m, 2 H), 1. 86-2. 01 (m, 2H), 2. 06 (t, 2H, J = 7. 4 H z), 2. 64 (t, 2 H, J = 7. 6 H z), 3. 83 (s, 3 H) 4. 05 (m, 1 H), 7. 33 (b r. d, 2 H, J = 7. 9 H z), 7. 87 (b r. d, 2 H, J = 8. 3 H z), 8. 57 (d, 1 H, J = 7. 3 H z) example 97

^ -NMR δ (D 2 0) 0. 50-1. 08 (m, 1 OH), 1. 08-1. 40 (m, 4H), 1. 74-1. 90 (m, 2H), 2 . 01-2. 12 (m, 4H), 2. 20 (t, 2H, J = 7. 3Hz), 3. 60 (s, 3H), 4. 02 (t, 1 H, J = 7. 3Hz ), 6. 97-7. 04 (m , 2H), 7. 49 (m, 2H) example 98 Z 9 · ΐ- 0 · ΐ '(Η 8 ¾ι) Ί-00 · ΐ (9 P-OSWQ ) S Η ^ Ν-Η,

ο ο ι mm si

(RZ 'm) g L' L ~ 9 'L' (Ά Ζ

'ui) Z' LZ I ' L' (2 H 2 '= f ¾ S') 0 I · '(z H ε' arm = Γ 'H 2') 8 S · Ζ '(H 6 ΐ' S- 00 · τ '(Η S 06' ΐ -89 'ΐ' (Η ^ 9

• ΐ- 9ε · ι '(Η ο ΐ' ^) g ε * τ -ο ΐ Ί (ο ζ α + 9 ρ- os) s ¾ uniform Οΐ

66 m

(Ζ Η S 'arm = f

'Η ΐ' Ρ) £ 9 · 8 '(Η ΐ) 0' LZ Z 'L (H £ i \' LI O · L '(H i

'∞) 0 (HZ' s ) ε L '' (z H 6 '= f' HZ '^) 83' Z '(z H 6' Z, = f

'HS' ^) 90 '(H ^) 00 · 2- 8' ΐ '(HZ) 08 Ί -Ζ 9' ΐ '(H

'm) 8 "ΐ -68" ΐ' (HO I '∞) 6 £ · ΐ Ichi 00' ΐ (9 Ρ- OSWCI) Q ΙΑΙΝ-

rfS £ 0 / .6df / X3d 4H), 1. 64-1. 83 (m, 2 H), 1. 64-1. 83 (m, 2 H), 1. 92 (t, 2 H,

J = 7. 7H z), 2. 01-2. 18 (m, 2 H), 2. 60 (sH. T, 2 H), 3. 98 (m,

1 H), 4. 31 (s, 2 H), 7. 17- 7. 34 (m, 4 H), 8. 13 (t, 3 H, J = 2. 0 H z) Example 1 0 1

N- {5- amino-1 [(hydroxy § amino) carbonyl] pentyl} - 1 0 one [2 _ _ (aminomethyl) phenyl] Dekan'ami de dihydrochloride

The compound of Example 78 (26 1 mg) was suspended in water, 1 N-hydrochloric acid (1. 24m

And dissolved by adding 1). After dilution by adding water, lyophilized be by N- {5- amino-1 one [(hydroxyamino) carbonyl] pentyl} - 1 0- [2 i (aminomethyl) phenyl] Dekan'ami de dihydrochloride 233. It was obtained 7 mg. 1 H-NMR δ (DM S O- d 6) 1. 05-1. 40 (m, 12H), 1. 40-1. 67 (m, 8H), 2. 08-2. 15 (m, 2H ), 2. 64 (t, 2H, J = 7. 7Hz), 2. 72 (b rm, 2H), 3. 93-4. 07 (m, 2H), 4. 12 (m, 1 H), 7. 18- 7. 34 (m, 3H), 7. 39- 7. 47 (m, 1 H), 7. 78-8. 12 (m, 4H), 8. 41 (b rs, 3H), 8. 83 (s, 1 H), was prepared by methods analogous to those described in 10. 67 (s, 1 H) the following compounds example 52.

Example 102

1 H-NMR δ (CDC 1 3) 0. 98-1. 57 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 91-2. 16 (m, 3H ), 2. 16-2. 30 (m, 1 H), 4. 0 5-4. 27 (m, 1H), 5. 82 (dt, 0. 5H, J = 11. 6Hz, 6. 9Hz) , 6. 37 (dt, 0. 5H, Jl 5. 6Hz, 6. 9Hz), 6. 59-6. 70 (m, 1 H), 7. 25-7. 40 (m, 3H), 7. 82-8. 04 (m, 2H), 8. 78 (s, 1 H), 10. 54 (s, 1H) example 1 03

1 H-NMR δ (DMS O- d 6) 1. 06-1. 58 (m, 1 OH), 1. 16 (d, 3H, J = 7. 0Hz), 2. 00- 2. 38 (m , H), 4. 18 (m, 1 H), 5. 77- 5. 94 (m, 0. 5H), 6. 48-6. 61 (m, 1. 5H), 7. 52-8. 26 (m, 4 H), 8. 79 (br- s, 1 H), 10. 56 (s, 1 H) example 104

O click N

1 H-NMR δ (DMSO- d 6) 1. 00-1. 60 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 2. 00-2. 17 (m, 2H), 2. 17-2. 40 (m, 2H), 4. 18 (m, 1H), 5. 81-5. 96 (m, 0. 44H), 6. 47- 6. 69 (m, 1. 56H), 7. 54 (d, 0. 88H, J-8. 9Hz), 7. 65 (d, 1. 12H, J = 8. 9Hz), 7. 92 (br- d, 0. 44H , J = 8. 3Hz), 7. 93 (br - d, 0. 56 H, J = 7. 9Hz), 8. 16 (d, 1. 12H, J = 8. 9Hz), 8. 21 (d , 0. 88 H, J = 8. 6Hz), 8. 79 (br- s, 1 H) example 1 05

1 H-NMR 8 (DMSO- d 6) 0. 95- 1. 57 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 87-2. 28 (m, 4H), 3. 80 (s, 1. 2H), 3. 8 7 (s, 1. 8H), 4. 19 (m, 1 H), 5. 67 (m, 0. 4H), 6. 21 (m, 0. 6 H), 6. 77 (d, 0. 4H, J = l 1. 9Hz), 7. 00 (d, 0. 6H, J = l 5. 5H z), 7. 28- 7. 85 (m, 4H), 7. 93 (m, 1 H), 8. 79 (s, 1 H), 10. 55 (s, 1H) example 1 06

1 H-NMR δ.. ( DMSO - d 6) 1. 00-1 41 (m, 6H), 1. 20 (d, 3H, J = 7. 3Hz), 1. 41-1 61 (m, H ), 2. 00-2. 20 (m, 2H), 2. 2 0-2. 41 (m, 2H), 4. 11-4. 31 (m, 1 H), 5. 88 (dt, 0 . 5H, J = 11. 6Hz, 7. 3Hz), 6. 45-6. 64 (m, 1. 5H), 7. 59- 8. 22 (m, 5H), 8. 81 (s, 1H) , 10. 58 (s, 1 H ) the following c exemplary compounds were prepared by analogous method to that described in example 3 example 1 0 Ί

1 H-NMR δ (DMS Ο- d 6) 0. 83- 1. 38 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 38- 1. 62 (m , 4H), 2. 08 (t, 2H, J = 7. 4H z), 2. 39 (t, 2H, J = 7. 6Hz), 4. 19 (m, 1 H), 6. 43-6 . 49 (m, 1H), 6. 57-6. 59 (m, 1 H), 6. 83-6. 88 (m, 2H), 7. 92 (d, 1 H, J = 7. 6Hz) , 8. 78 (s, 1 H), 10. 52 (s, 1 H) example 1 08

] H - NMR δ (DMS O- d 6) 0. 80- 1. 36 (m, 1 OH), 1. 20 (d, 3H, J = 6. 9Hz), 1. 36- 1. 67 (m , 4H), 1. 95- 2. 22 (m, 2H), 2. 58 (t, 2H, J = 7. 1 Hz), 4. 22 (m, 1 H), 7. 10- 7. 21 (m, 2 H), 7. 68-7. 74 (m, 2H), 8. 42 (b rs, 1 H) example 1 09

1 H-NMR δ (DMS O- d 6) 0. 90- 1. 37 (m, 1 OH), 1. 20 (d, 3H, J = 7. 3Hz), 1. 37- 1. 63 (m , 4H), 1. 91-2. 20 (m, 2H), 2. 86 (t, 2H, J = 7. 8Hz), 4. 23 (m, 1 H), 6. 93- 7. 14 ( m, 3 H), 7. 43-7. 46 (m, 1 H), 8. 62 (br- s, 1 H) example 1 1 o

1 H-NMR δ. (DMSO - d 6) 0. 90-1 38 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 38- 1. 63 (m, 4H), 2. 08 (t, 2H, J = 7. 3H z), 2. 86 (t, 2H, J = 7. 3Hz), 3. 82 (s, 3H), 4. 18 (m, 1 H), 7. 26-7. 31 (m, 2H), 7. 44-7. 50 (m, 1 H), 7. 73-7. 76 (m, 1H), 8. 12 (d, 1H , J = 7. 9Hz), 8. 79 (s, 1 H), 10. 44 (s, 1 H) example 1 1 1

1 H-NMR δ. (DMSO - d 6) 0. 98- 1. 34 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 34-1 61 (m, 4H), 2. 07 (t, 2H, J = 7. 4H z), 2. 37 (t, 2H, J = 7. 4Hz), 4. 18 (m, 1 H), 4. 86 (b rs , 2 H), 6. 47 (d, 2H, J = 8. 2Hz), 6. 81 (d, 2H, J = 8. 6), 7. 92 (b rd, 1H, J = 7. 9Hz) , 8. 78 (br_s, 1 H) example 1 1 2

1 H-NMR 8 (DMSO- d 6) 1. 00-1. 57 (m, 1 H), 1. 15 (d, 3H, J = 7. 0Hz), 2. 07 (t, 2H, J = 7. 5Hz), 2. 41 (t, 2H, J = 7. 5Hz), 4. 17 (m, 1 H), 6. 28-6. 46 (m, 3H), 6. 92 (t, 1 H, J = 7. 6Hz), 7. 95 (d, 1 H, J = 7. 7Hz), 8. 79 (s, 1 H), 10. 56 (s, 1H) example 1 1 3

N- E (IRS) 2 (hydroxymethyl § amino) Single 1 one methyl _ 2 Okisoechi le] 1 0 (2-two Torofueniru) Dekan'ami de

Compound described in Example 1 02 (200 meters g) was dissolved in ethanol (2. 5m 1), p- toluenesulfonyl hydrazine (1 1 8m g, 0. 64 mm ol) and trimethoxy borane (68. 8 mg and heated to reflux for 0. 66 mm ol) was added 5 hours. It was added portionwise 1 N-sodium hydroxide aqueous solution (0. 8 m 1) to 7 times during this period. After cooling to room temperature, 1 N-hydrochloric acid was added, saturated sodium Hydrogen aqueous sodium extracted organic layer with acetic Echiru, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and performing the above steps again by crystallization in ether, N- [(1 RS) - 2 - (hydroxymethyl § amino) - 1- methyl-2 Okisoechiru] an 1 0- (2-two Torofueniru) Dekan'ami de afford 67 mg.

1 H-NMR δ (DMSO- d 6) 0. 90-1. 37 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 37- 1. 64 (m, 4H), 2. 08 (t, 2H, J = 7. 3H z), 2. 79 (t, 2H, J = 7. 8Hz), 4. 24 (m, 1 H), 7. 41-7. 50 (m, 2H), 7. 60-7. 66 (m, 1 H), 7. 88 (d, 1 H, J = 8. 3Hz), 7. 87-7. 90 (m, 1H), 9. 04 (s, 1 H), by 10. 55 (s, 1 H) the following compounds example 1 1 3 a similar manner were prepared.

Example 1 14

1 H-NMR 8. (DMSO - d 6) 1. 07-1 37 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 37- 1. 53 (m, 2H), 1. 53-1. 70 (m, 2H), 2. 07 (t, 2H, J = 7. 4Hz), 2. 71 (t, 2H, J = 7. 6Hz), 4. 18 ( m, 1H), 7. 48 (d, 2H, J = 8. 9Hz), 7. 92 (d, 1 H, J = 7. 9Hz), 8. 1 (d, 2H, J = 8. 9Hz) , 8. 78 (s, 1 H) example 1 1 5

1 H-NMR δ (DMSO- d 6) 0. 96-1. 69 (m, 14H), 1. 15 (d, 3H, J = 7. 0Hz), 2. 07 (t, 2H, J = 7 . 3Hz), 2. 72 (t, 2H, J = 7. 7Hz), 4. 18 (m, 1 H), 7. 44-7. 71 (m, 3H), 7. 93 (d, 1 H , J = 7. 9Hz), 8. 30 (s, 1H), 10. 55 (s, 1 H) example 1 1 6 N [(IRS) - 2- (hydroxy § amino) Single 1 one methyl one 2 - Okisoechi Le] one 1 0- (2-Aminofue sulfonyl) 9

Compound of Example 1 02 (0. 2 g) in water (1 1 ml), acetone (55m l), IN- aqueous sodium hydroxide (7. Om l) and Hydro sulfite sodium U beam (92. 3 mg) It was heated to reflux for 0.5 hours. The solvent was distilled off under reduced pressure, and separated into two layers by adding 1 N monohydrochloride and ether. And neutralize by adding bicarbonate Natoriumu the aqueous layer was extracted with acetic acid Echiru, and dried over anhydrous sulfate Maguneshiu beam and the organic layer was washed with saturated brine. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue silica gel Tous layer chromatography ((stationary phase: silica gel 60 F 254: mobile phase: click port opening Holm methano Ichiru = 1 0/1) in by purifying N-[(1 RS) - 2- (hydroxy § amino) Single 1 Mechiru one 2-Okisoechiru] - 1 0- (2-§ Minofueniru) Single 9 Desen'ami de give 63m g.

1 H-NMR δ (DM S O- d 6) 1. 10-1. 54 (m, 1 OH), 1. 17 (d, 3H, J = 6. 9Hz), 2. 04-2. 22 ( m, 4H), 4. 19 (m, 1 H), 4. 75 (s, 1. 1H), 4. 91 (s, 0. 9H), 5. 63 (dt, 0. 53H, J = l 1. 2Hz, 7. 3 Hz), 5. 99 (m, 0. 47H), 6. 24-6. 28 (m, 0. 53H), 6. 46- 7. 17 (m, 4. 47H) , 7. 91 (m, 1 H), 8. 78 (s, 1 H), by 10. 55 (s, 1 H) the following compounds example 1 1 6 a similar manner were prepared.

Example 1 1 7

1 H-NMR δ (DMS O- d 6) 1. 00- 1. 58 (m, 1 OH), 1. 16 (d, 3H, J = 6. 9Hz), 1. 94-2. 33 (m , 4H), 4. 18 (m, 1 H), 5. 81 5. 98 (m, 0. 58H), 6. 04-6. 37 (m, 1. 2H), 6. 48 (d, 1 . 16 H, J = 8. 6Hz), 6. 53 (d, 0. 84H, J = 8. 6Hz), 6. 96 (d, 0. 84 H, J = 8. 3Hz), 7. 03 ( d, 1. 16H, J = 8. 3Hz), 7. 93 (d, 1 H, J = 8. 3Hz), 8. 79 (br- s, 1 H) example 1 1 8

1 H-NMR δ (CD 3 OD) 1. 20-1. 67 (m, 1 OH), 1. 31 (d, 3H, J = 7. 2Hz), 2. 10-2. 36 (m, 4H ), 4. 27 (q, 1 H, J = 7. 1Hz), 5. 51-5. 63 (m, 0. 46H), 6. 09-6. 34 (m, 1. 54H), 6. 51-6. 76 (m, 3H), 6. 95-7. 09 (m, 1 H) example 1 1 9

(4 R) one 4 - [1 0- _ (3 Shianofueniru) Dekanoiru] Amino) - A 5-

(Hydroxy § Mino) Single 5- Okisopentan acid

Example 32 by analogous methods to (4 R) -4- {[1 0- (3- Shianofue sulfonyl) Dekanoiru] amino} one 5- (hydroxymethyl § Mino) Single 5 Okisopentan acid was prepared.1 H-NMR δ (DMS O- d 6) 0. 96- 1. 97 (m, 16H), 1. 97-2. 36 (m, 4H), 2. 62 (t, 2H, J = 7. 4Hz), 4. 09- 4. 27 (m, 1 H), 7. 37-7. 72 (m, H), 7. 94 (d, 1 H, J = 8. 3Hz) example 1 20

N_ [2- (hydroxy § Mino) Single 1-methyl one 2- Okisoechiru] one 1 0_ (4-menu Tokishifueniru) Dekan'ami de

1 0- (4- main Tokishifueniru) one decanoic acid (0. 97 g) was dissolved in methylene chloride (1 0 m l), DMF (300 ^ 1) was added, the addition of chloride Okizariru (0. 37m 1) 2 . was stirred at 75 h at room temperature. After drying under vacuum the solvent was evaporated under reduced pressure to prepare a Asetonitoriru solution of Asetonitoriru (7. 5 m l) was dissolved in an acid chloride.

The DL chromatography § oxiranylmethyl hydroxamic acid (0. 3 6 g) Asetonitorisore (7. 5 m 1) the suspended allowed diisopropyl E chill § Min (1. 2m l) was added, 0 ° C with trimethylsilyl chloride (1. 0m l) was added dropwise. After 2.5 hours of stirring at room temperature, it was added dropwise Asetonitoriru solution of the acid chloride under ice-cooling. After stirring at room temperature for 1 h, acetic Echiru and 5% - two layers separated by adding hydrogen sulfate Kariumu solution, The organic layer was washed with saturated brine, in washed and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure, by crystallizing in hexane mixed solvent to an ether residue, N-[2- (hydroxy § amino) _ 1-methyl-2- Okisoechiru] - 10- (4-methoxyphenyl) Dekan'ami de

It was obtained 732 mg.

1 H-NMR δ (DMS 0- d 6) 0. 99- 1. 35 (m, 1 OH), 1. 17 (d, 3H, J = 7. 3Hz), 1. 35- 1. 60 (m , 4H), 2. 08 (t, 2H, J = 7. 4H z), 2. 46-2. 53 (m, 2H), 3. 72 (s, 3H), 4. 14-4. 24 ( m, 1 H), 6. 80-6. 82 (m, 2H), 7. 06-7. 08 (m, 2H), 7. 89 (b rd, 1H), 8. 77 (s, 1H) , 10. 54 (s, 1 H) example 1 2 1

(4 R) - 4 one [(1 0 4 eleven [Amino (Imino) methyl] Hue sulfonyl} Dekanoi Le) Amino] - 5- (hydroxymethyl § Mino) Secondary 5- Okisopentan acid

H click N

Example 1 by analogous methods (4 R) - 4- [(1 0- {4- [Amino (I) methyl] Fueeru) Dekanoiru) Amino] one 5- Okiso one 5- (benzyl Okishiamino) pentanoic acid benzyl by catalytic reduction of (6 1 8m g) (4 R) - 4- [(1 0- {4 one [amino (imino) methyl] Hue sulfonyl} Dekanoi Le) amino] one 5- (hydroxymethyl § Mino) to give an 5 Okisopentan acid 330 mg.

1 H-NMR δ (TFA- d ) 1. 40 (b rs, 1 OH), 1. 74 (br- s, 4 H), 2. 18-2. 45 (m, 2H), 2. 51- 2. 56 (m, 2H), 2. 69-2. 74 (m, 2H), 2. 78-2. 84 (m, 2H), 4. 81 (m, 1 H), 7. 50 (d , 2H, J = 8 44Hz), 7. 73 (d, 2H, J = 8. 44Hz) used as starting material (4 R) - 4 one [(1 0- {4- [Amino (Imino). menu chill] Hue sulfonyl} Dekanoiru) amino] - 5- Okiso one 5- (Benjiruokishia amino) benzyl pentanoate was prepared as follows.

(A) (4 R) - 5 - [(Benjiruokishi) Amino] one 4 one {[1 0- (4-Xia Nofueniru) Dekanoiru] amino} one 5- Okisopentan benzyl

In Example 1 (B) by an analogous method (4R) - 5-[(Benjiruokishi) Amino] _4 one {[1 0- (4-Shianofueniru) Dekanoiru] amino} - 5 - the Okisopentan benzyl was prepared.

1 H-NMR δ (CDC 1 3) 1. 25 (br - s, 1 0 H), 1. 43- 1. 68 (m, 4 H), 1. 86- 2. 06 (m, 2H), 2. 11 (t, 2H, J = 7. 6H z), 2. 23-2. 45 (m, 2H), 2. 64 (t, 2H, J = 7. 3Hz), 4. 35 (m, 1H), 4. 87 (s, 2H), 5. 10 (s, 2H), 6. 45 (d, 1 H, J = 7. 8Hz), 7. 25 (d, 2H, J = 8. 4Hz ), 7. 33 (br -. s, 1 OH), 7. 55 (d, 2H, J = 8 4Hz), 9. 63 (s, 1 H)

(B) (4 R) - 4 - ({1 0- [4 (§ amino carbothioyl) phenyl] dec Noiru} Amino) Single 5- [(base Amino - 5 Okisopentan benzyl

(4 R) - 5 - [(Benjiruokishi) Amino] one 4- {[1 0- (4-Shiano phenyl) Dekanoiru] amino} - 5-Okisopentan benzyl (1. 5 g) in pyridine (7. 5 g ) and it was dissolved in a mixed solvent of Toryechiruamin (3. 7 g), and stirred for 4 hours while blowing hydrogen sulfide at room temperature. It was stirred at room temperature for 3 hours while blowing nitrogen slurry was allowed to stand overnight and sealed. 1 N-hydrochloric out extracted with acetic acid Echiru added, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue by silica gel column chromatography (stationary phase: silica gel 60, 2 3 0-400 mesh, 1 50 g, mobile phase: black port Holm Z methanol = 50 by Rukoto be purified in 1), (4 R) - 4- ({1 0- [4 - (§ amino carbothioyl) off Eniru] Dekanoiru} amino) Single 5- [(Benjiruokishi) amino] - 5- the O key Sopentan benzyl 1. give 47 g.

1 H-NMR 8 (CDC 1 3) 1. 10-1. 35 (m, 10H), 1. 35-1. 67 (m, 4H), 1. 92-2. 20 (m, 4H), 2 . 27-2. 42 (m, 2H), 2. 59 (t, 2H, J = 7. 6Hz), 4. 43 (m, 1 H), 4. 85 (s, 2H), 5. 07 ( s, 2H), 6. 80 (br -.. s, 1H), 7. 16 (d, 2H, J = 8 3Hz), 7. 18-7 40 (m, 1 OH), 7. 62 (br - s, 1 H), 7. 80 (d, 2H, J = 8 3Hz), 8. 22 (br -. s, 1H), 10. 00 (b rs, 1 H)

(C) (4 R) - 5 - [(Benjiruokishi) Amino] one 4 one [(1 0 - {4- [I Mino (methylthio) methyl] Hue sulfonyl} Dekanoiru) Amino] _ 5 Okisopen Tan benzyl

(4 R) Single 4- ({1 0- [4 - (§ amino carbothioyl) phenyl] Dekano I le} Amino) Single 5- [(Benjiruokishi) Amino] one 5-Okisopentan benzyl (1. 47 g ) was dissolved in Aseton (1 5 m 1), was added dropwise methyl iodide (463 mg) was stirred for 2 hours at 55 ° C. The residue solvent was distilled off under reduced pressure silica gel force column chromatography (stationary phase: silica gel 60, 2 3 0 400 mesh, 1 00 g, mobile phase: Black port Holm / methanol = 50Z 1) Purification child and by, (4 R) - 5-O Kisopentan acid benzyl - 5 - [(Benjiruokishi) Amino] one 4 one [(1 0- {4- [Imino (methylthio) methyl] Hue sulfonyl} Dekanoiru) Amino] 1. obtained 39 g.

1 H-NMR δ (CDC 1 3) 1. 22 (b rs, 1 OH), 1. 43 (m, 2H), 1. 64 (m, 2H), 2. 05-2. 17 (m, 4H ), 2. 43 (t, 2H, J = 7. 3Hz), 2. 69 (t, 2H, J = 6. 9Hz), 3. 06 (s, 3H), 4. 77 (dd, 1 H, J = 7. 3Hz, 14. 9Hz), 4. 94 (s, 2H), 5. 10 (s, 2H), 7. 02 (d, 1 H, J = 7. 9Hz), 7. 25-7 . 42 (m, 12H), 7. 88 (d, 2H, J = 8. 3Hz), 10. 63 (s, 1H)

(D) (4 R) - 4 one [(1 0- {4 one [Amino (Imino) methyl] Hue sulfonyl} de Kanoiru) Amino] - 5- (base Mino) one 5-Okisopentan benzyl

(4 R) one 5- [(Benjiruokishi) Amino] one 4 one [(1 0- {4 one [Imi Roh (methylthio) methyl] Hue sulfonyl} Dekanoiru) Amino] - 5-Okisopenta phosphate benzyl (1. 38 g) and acetic acid Anmoniumu the (3. 96 g) was dissolved in methanol (25 m 1), and stirred for 6 hours at 55 ° C. Water was added and the precipitate was collected by filtration, washed with water, followed by drying under vacuum, (4 R) - 4 - [(1 0 - {4 - [Amino (Imino) methyl] Hue sulfonyl} Dekanoiru) Amino] - 5- (Benjiruo Kishiamino) an 5 Okisopentan benzyl give 700 meters g.

1 H-NMR δ (DMSO- d 6) 1. 25 (b rs, 1 OH), 1. 45-1. 65 (m, 4H), 1. 86-2. 01 (m, 2H), 2. 15 (t, 2H, J = 7. 5Hz), 2. 3 5 (t, 2H, J = 7. 5Hz), 2. 66 (t, 2H, J = 7. 5Hz), 3. 23 (b rs , 3H), 4. 27 (m, 1 H), 4. 82 (s, 2H), 5. 08 (s, 2H), 7. 16- 7. 40 (m, 12H), 7. 72 (d , 2H, J = 8. 3Hz), 7. 81 (d, 1 H, J = 8. 6H z) example 1 22

(2 S) _N- hydroxy one 3 [(3-phenylene Amino] 2

{[(3-Futaruimi de) Puropanoiru] amino} _ Puropanami de

(2 S)-N-Benjiruokishi one 3- [(3-phenylpropyl prop Noi Le) amino - 2 - {[(3 one Futaruimi de) Puropanoiru] amino} Puropanami de the (2 O Omg) methanol (5 m l) , black hole Holm (5 m l), acetic acid (5 m l), was dissolved in a mixed solvent of water (0. 5 m 1), 1 0% - palladium Z carbon (1 00 mg) was added, 1 under an atmosphere of hydrogen 0 hours and the mixture was stirred. The catalyst was removed by filtration, it was removed by reduced 圧留 the solvent. By crystallizing by adding water to the residue, to obtain the desired compound 1 35 mg.

1 H-NMR δ (DM S O- d 6) 10. 67 (1 H, br- s), 8. 85 (1H, br - s), 8. 12 (1H, d, J = 8Hz), 7 . 83 (5H, m), 7. 20 (5H, m), 4. 23 (1 H, td, J = 8, 6Hz), 3. 77 (2H, t, J = 7. 5Hz), 3. 10-3. 35 (2H, m), 2. 77 (2H, t, J = 7. 7Hz), 2. 50 (2H, m), 2. 32 (2H, t, J = 7. 7H z) 2 S)-N-Benjiruokishi 3- [(3-Fuenirupu Ropanoiru) amino] one 2- {[(3-Futaruimi de) Puropanoiru] amino} Puropanami de used as starting material was prepared as follows.

(A) (2 S) - 2 _ t- butoxycarbonylamino chromatography 3- (3-Fuenirupuropa Noiru) Aminopuropion acid

Vist Riffle O b acetonate Kisho de benzene (1 4 g) and DMF (30m l) - dissolved in water (30 m l), under ice-cooling (S) -N- t- butoxycarbonyl two Ruasu aspartic (5 g) added and stirred for 1 5 minutes at room temperature. Further added dropwise pyridine (3. 5 m 1), and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, pressure to give a water to the residue, and washed with ether. The aqueous layer until the 5 Om 1 was concentrated under reduced pressure.

Under ice-cooling thereto, 3-phenylpropyl propionyl chloride (3. 77m l) and potassium carbonate (4. 57 g) was added and stirred for 12 hours at room temperature. Add the chloride 3 _ Fuenirupu port Pioniru (2. 82m l) and potassium carbonate (2. 1 g), After stirring for a further 1 2 hour, the reaction mixture was washed with ether. The aqueous layer with 1 N hydrochloric acid and p H 2, and extracted with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous sulfate Magne Shiumu. The desiccant was filtered and concentrated under reduced pressure. The residue was purified by silica gel column Roma Togurafi one (silica force Gel 1 00 g, solvent: black port Holm one methanol (1 0 0: 1 → 50: 1 → 1 0: 1)) the desired product was purified by 5. 26 g It was obtained.

1 H-NMR δ (DMS 0- d 6) 12. 58 (1H, b rs), 7. 95 (1H, t, J = 5. 5Hz), 7. 10-7. 30 (5H, m), 6. 94 (1H, d, J = 8Hz), 4. 01 (1 H, m), 3. 38 (1H, m), 3. 26 (1H, m), 2. 77 (2H, t, J = 8Hz), 2. 34 (2H, J = 8Hz), 1. 37 (9H, s)

(B) N-base one 2-(t-butoxycarbonyl) amino-3- (3 phenylene Aminopuropanami de

(2 S) one 2-t-butoxycarbonyl § Mino one 3- (3- Fuenino

Dissolved I le) Aminopuropion acid (663 mg) in DMF (3m l), one 5 ° C at black port isobutyl (0. 383m l), the then N- methylmorpholine (0. 28 1 ml) was added It was stirred for 5 minutes at one 5 ° C Te. Then, it was added 0-benzyl hydroxy Ruamin hydrochloride (409 mg) and N- methylmorpholine (0. 325 ml). After stirring one 5 ° C 1 0 minutes, and stirred for 1 7 hours at room temperature. The reaction mixture was diluted with water and extracted with acetic acid Echiru. The organic layer with saturated aqueous sodium bicarbonate solution, 1 0% Kuen acid aqueous solution was washed successively with saturated brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, collected by filtration with ether crystals obtained was concentrated under reduced pressure to give the desired compound 768m g.

1 H-NMR δ (CDC 1 3) 9. 67 (1H, b rs), 7. 10-7. 40 (1 OH, m), 6. 59 (1H, m), 5. 85 (1H, m ), 4. 84 (2H, s), 4. 13 (1H, m), 3. 58 (1H, m), 3. 45 (1H, m), 2. 89 (2H, m), 2. 45 (2H, t, J = 7. 5Hz), 1.

1 (9H, s)

(C) (2 S)-N-Benjiruokishi - 3- [(3-phenylpropyl prop Noi Le) amino] -2- {[(3-Futaruimi de) Puropanoiru] amino} Puropanami de

Ν- Benjiruokishi - 2-(t-butoxycarbonyl) Amino - 3 dissolved (3 full E sulfonyl prop Noi) amino propanaminium de a (200 mg) in Asetonitorinore (2 ml), under ice-cooling to methanesulfonic acid (0 . and stirred for 30 minutes at room temperature by adding 1 47m l). Thereto was added under ice cooling DM F (3m l) and Toryechiruamin the (0. 255m l), HOB t (67mg), WS C / HC 1 (95m g), N- (2- carboxy E chill) Futaruimi de (1 09mg), and stirred for 1 at room temperature for 4 hours bets Riechiruamin (0. 064m l) successively added. WS C · HC 1 (30mg), triethylamine (0. 03m l) After stirring for further 2 hours by adding, after the reaction mixture was concentrated under reduced pressure, water was added and acetic acid Echiru. The precipitated crystals were collected by filtration, it was extracted mother liquor with acetic acid Echiru. The organic layer was wash with brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and concentrated under reduced pressure, the residue was recrystallized from acetic acid E Chiru ether, combined with the previously obtained crystals. The yield 2 14m g.

1 H-NMR δ (CDC 1 3) 9. 90 (1Η, b rs), 7. 80 (2Η, m), 7. 70 (2Η, m), 7. 10-7. 45 (11Η, m) , 6. 41 (1 Η, m), 4. 89, 4. 90 (2Η, s), 4. 30 (1Η, m), 3. 95 (2Η, t, J = 6. 8Hz), 3. 70 (1H, m), 3. 46 (1H, m), 2. 91 (2H, m), 2. was prepared by 50 (4H, m) the following compounds analogous to example 1 22 method.

Example 1 23

1 H-NMR δ (DMSO - d 6) 10. 67 (1H, br- s), 8. 86 (1H, b r- s), 7. 98 (. 1H, d, J = 8 4Hz), 7 . 87 (1H, t, J = 5. 9Hz), 7. 10-7. 30 (1 OH, m), 4. 26 (1 H, dt, J-7. 8, 6. 7Hz), 3. 10-3. 32 (2H, m), 2. 77 (4H, t, J = 7. 8Hz), 2. 36 (4H, m) example 1 24

1 H-NMR δ (DMSO- d 6) 10. 82 (1H, b rs), 8. 98 (1H, br - s), 8. 00 (. 1H, t, J = 5 9Hz), 7. 85 (4H, m), 7. 72 (1H, d, J = 9. 0 Hz), 7. 10-7. 30 (5H, m), 3. 94 (2H, m), 3. 79 (1H, dt, J = 8. 8, 6. 9Hz), 3. 0-3. 5 (4H, m), 2. 77 (2H, t, J = 7. 5Hz), 2. 35 (2H, t, J = 7. 5 Hz) example 1 25

1 H-NMR δ (DMS O- d 6) 10. 67 (1H, br- s), 8. 85 (1H, br- s), 8. 13 (1H, d, J-8Hz), 7. 83 (5H, m), 7. 06 (4H, m), 4. 24 (1 H, td, J = 8Hz, 6Hz), 3. 76 (2H, dd, 7Hz), 3. 10-3. 50 ( 2H, m), 2. 72 (2H, m), 2. 5 (4H, m), 2. 30 (2H, m), 1. 54 (2H, tq, J = 7Hz), 0. 85 (3H , t, J = 7Hz) example 1 26

1 H-NMR δ (DMS O- d 6) 2. 30-2. 42 (4H, m), 2. 74-2. 79 (2H, m), 3. 18-3. 34 (2H, m) , 3. 44-3. 46 (2H, m), 4. 26 (1H, m), 7. 15-7. 17 (3H, m), 7. 22-7. 28 (2H, m), 7 . 39-7. 46 (3 H, m), 7. 80-7. 82 (2H, d, J = 6. 26Hz), 7. 89 (1H, m), 8. 07 (1H, d, J = 7. 24Hz), 8. 48 (1H, s), 8. 89 (1H, s), 10. 69 (1 H, s) example 1 27

1 H-NMR δ (DMS Ο- d 6) 10. 69 (0. 3Η, s), 10. 62 (0. 7Η, s), 8. 29 (0. 7H, t, J = 5. 7Hz) , 8. 22 (0. 3H, t, J = 5. 7Hz), 7. 65-8. 07 (2H, m), 7. 10-7. 30 (5H, m), 4. 18-4. 40 (2H, m), 3. 25-3. 80 (5H, m), 3. 20 (1 H, m), 2. 77 (2H, t, J = 7. 5 Hz), 2. 34 ( 2H, t, J = 7. 5Hz), 1. 60-2. 20 (7H, m) example 1 28

1 H-NMR δ (DMS O- d 6) 10. 65 (1 H, b rs), 8. 92 (1 H, b rs), 8. 77 (1H, t, J = 5Hz), 8. 12 (1H, d, J = 8. 0Hz), 7. 87 (3H, m), 7. 40-7. 60 (3H, m), 7. 10-7. 28 (5H, m), 4. 27 (1H, dt, J = 6Hz), 3. 88 (2H, m), 3. 0-3. 3 (2H, m), 2. 72 (2H, t, J = 8Hz), 2. 32 (2H , t, J = 8Hz) example 1 29

1 H-NMR δ (DMS O- d 6) 10. 65 (1 H, br- s), 8. 82 (1 H, b rs), 8. 13 (1H, d, J = 8. 2Hz), 7. 82 (IH, t, J = 5. 8Hz), 7. 06-7. 25 (1 OH, m), 4. 19 (1 H, dt, J = 8Hz, 7Hz), 3. 38 (2H , s), 3. 19 (2H, t, J = 6. 5Hz), 2. 69 (2H, t, J = 8. 7Hz), 2. 25 (2H, t, J = 8. 7Hz) example 1 30

1 H-NMR δ (DMS O- d 6) 10. 61 (1 H, b rs), 8. 84 (1 H, b rs), 7. 70-7. 98 (6H, m), 7. 10 -7. 30 (5H, m), 4. 22 (1H, dt, J = 6. 1Hz, 7. 8Hz), 3. 56 (2H, t, J = 6. 8Hz), 3. 1-3. 4 (2 H, m), 2. 75 (2H, t, J = 8. 4Hz), 2. 33 (2H, J = 8. 4Hz), 2. 14 (2H, J = 8. 4Hz), 1 . 78 (2H, m) example 1 3 1

1 H-NMR δ (DMSO- d 6) 10. 64 (1H, b rs), 8. 02 (1H, d, J = 8. 3Hz), 7. 84 (1H, t, J = 5. 8Hz) , 7. 76 (2H, m), 7. 50-7. 70 (4H, m), 7. 10-7. 30 (5H, m), 4. 20 (1 H, dt, J = 6Hz, 8H z), 3. 28 (1H, m), 3. 15 (1H, m), 2. 90 (2H, m), 2. 75 (2H, t, J = 8. 4Hz), 2. 30 (4H , m) example 1 32

(2 S) - N-hydroxy-3- (3-phenylene Amino one 2- (3 phenylpropyl) Aminopuropanami de 'Torifuruoro acetate

Example 1 22 by analogous methods (2 S) -Ν- Benjiruokishi 3- (3 - phenylpropyl prop Noi Le) Amino one 2- (3-phenylpropyl) from Aminopuropa cyanamide (2 S) -Ν- hydroxy-3- (3 _ phenylalanine prop Noi Le) Ami no 2- (3-phenylpropyl) Aminopuropanami de 'Torifuruoro acetate was prepared.

1 H-NMR δ (DMS O- d 6) 11. 22 (1H, br- s), 9. 47 (1H, b rs), 9. 08 (2H, b rs), 8. 24 (1 H, t, J = 5. 7Hz), 7. 10-7. 35 (1 OH, m), 3. 40-3. 70 (2H, m), 3. 20-3. 50 (1 H, m), 2. 8 0 (4H, m), 2. 61 (2H, t, J = 7. 9Hz), 2. 39 (2H, t, J = 7. 9Hz), 1. 88 (2H, m)

Is a precursor (2 S)-N-Benjiruokishi one 3- (3-phenylpropyl prop Noi Le) amino-2_ (3 _ phenylpropyl) Aminopuropanami de was prepared as follows.

(2 S) - N-Benjiruokishi 2- Amino one 3- (3-Fuenirupuropano I le) Aminopuropanami de hydrochloride (1 0 Omg) lend and methanol (2m 1), under ice-cooling 3-phenyl added propanal (36 mg) and Shiano sodium borohydride (2 Omg), and stirred for 1 8 h at room temperature. It was added to Shiano sodium borohydride (1 0 mg) after 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered and concentrated under reduced pressure to give the desired product as an oil. The yield 1 23 mg

1 H-NMR δ (CDC 13 ) 7. 08-7. 40 (16Η, m), 6. 30 (1H, t, J = 6Hz), 4. 83 (2H, m), 3. 55 (1 H , m), 3. 35 (1 H, m), 3. 06 (1H, t, J = 5Hz), 2. 90 (2H, m), 2. 50 (6H, m), 1. 64 (2H , m) example 1 33

By a method similar to Example 1 32, the following compounds were prepared.

1 H-NMR δ (DMSO- d 6) 1. 46-1. 69 (4H, m), 2. 36-2. 41 (2 H, m), 2. 76-2. 91 (4H, m) , 3. 22-3. 64 (5H, m), 7. 16-7. 18 (3H, m), 7. 24-7. 29 (2H, m), 7. 82-7. 89 (4H, m), 8. 20 (1H, m), 9. 44 (1H, s), 11. 22 (1H, s) example 1 34

(2 S) one 2- {[(benzyl O butoxycarbonyl) Amino] Etanoiru} Amino - N- hydroxy-3_ (3-phenylpropyl prop Noi Le) Aminopuropanami de

(2 S) - 2 - dissolved in {2- [(benzyl O butoxycarbonyl) Amino] Etanoiru} amino-3- (3-phenylpropyl prop Noi Le) Aminopuropan acid (1 9 1 mg) and DMF (1 m 1) one 5 ° C under a black hole formic acid isobutyl (0. 083 m 1), and N- methylmorpholine (0. 07 1 ml) was stirred for 5 minutes one 5 added. Then one 5 ° C under a 0- t one-heptyl-butyldimethylsilyl hydroxyl § Min a (76 mg) was added, for 15 minutes in one 5 ° C, followed by stirring at room temperature for 20 hours. After stirring for 30 minutes by adding 1 N hydrochloric acid (3m l) the reaction mixture was diluted with water, issued extracted with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off and purified residue obtained by concentration under reduced pressure was by HPLC (column: YMC one OD S (SH- 363 - 5) 3 cmx 25 cm; solvent: (A solution) 0. 1% TFA / H 2 0 (B solution) 0. 1% TF AZCH 3 CN ; gradient: (B%: 0 → 2 0% (30 min) → 40% (1 50 min); flow rate: 7 m 1 Bruno min; detection:. UV 220 nm yield 49. 7 mg (26. 3%).

1 H-NMR δ (DMS O- d 6) 10. 67 (1 H, s), 8. 90 (1H, bs), 7. 99 (1H, d, J = 8Hz), 7. 87 (1 H , t, J = 6Hz), 7. 44 (1 H, t, J = 6Hz), 7. 10-7. 35 (1 OH, m), 5. 01 (2H, s), 4. 27 (1H , m), 3. 63 (2H, t, J = 6Hz), 3. 10-3. 35 (2H, m), 2. 76 (2H, m), 2. 34 (2H, m) as the starting material using (2 S) - 2- {2- [(benzyl O butoxycarbonyl) Amino] Etanoiru} amino-3- (3 _ phenylalanine prop Noi Le) Aminoburopa phosphate was prepared as follows.

(A) (2 S) - 3- Amino _ 2-benzyl O alkoxycarbonyl § amino propane Sana Lil hydrochloride

(S) - 2 one base Nji Ruo butoxycarbonylamino - 3- t-butoxycarbonyl Aminopuropion dissolved acid (3 g) in DMF (1 0 m l), potassium carbonate © beam under ice-cooling (2.0 1 and stirred for 24 hours at room temperature, mixed g) and bromide Ariru (1. 06 m 1). The reaction mixture was diluted with water and extracted with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

The drying agent was filtered off, the residue obtained by concentration under reduced pressure, the mixture was stirred for 30 minutes at room temperature by addition of 4N hydrochloric acid Z Jiokisan (20 ml). The reaction mixture was concentrated under reduced pressure to obtain the desired product as an oil-like material. Yield 2. 6 1 g (89. 4%).

(B) (2 S) one 2-benzyl O alkoxycarbonylamino chromatography 3- (3-Fuenirupuro Panoiru) Aminopuropan acid Ariru

(2 S) - 3- Amino one 2-base Nji Ruo alkoxycarbonyl § amino propanoic acid § Li Le hydrochloride dissolved in (0. 86 g) and DMF (6m l), diisopropyl under ice cooling Echiruamin (1 ml) and it was stirred for 20 hours at room temperature, mixed chloride 3-phenylpropyl propionyl the (0. 44m l). The reaction mixture was diluted with water and extracted with acetic acid Echiru. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the residue obtained was concentrated under reduced pressure and purified by silica gel column chromatography (silica gel 50 g; solvent: hexane - acetic Echiru (2: 1 → 1: 1)). The yield 1. 03 g (92. 0%).

1 H-NMR 8 (CDC 1 3) 7. 01-7. 40 (1 OH, m), 5. 86 (3H, m), 5. 32 (1H, d, J = 17Hz), 5. 26 ( 1H, d, J = 10Hz), 5. 10 (2H, S), 4. 62 (2H, m), 4. 38 (1H, dt, J = 5, 7Hz), 3. 64 (2H, t, J = 5. 7Hz), 2. 91 (2H, t, J = 8Hz), 2. 44 (2H, t, J = 8Hz) (C) (2 S) - 2- Amino one 3- (3-off enyl prop Noi Le) Aminopuropan acid Ariru ■ hydrobromide

(2 S) one 2-benzyl O alkoxycarbonyl § amino - 3- (3-Fuenirupuropa Noiru) Aminopuropan acid Ariru (1. 03 g) under ice cooling, 25% hydrobromic Suisonosu acid (1 0 m l) dissolved was stirred at room temperature for 2 hours. The reaction mixture while handling ether was collected by filtration and the resulting precipitate. The yield 959mg (quantitative).

1 H-NMR δ (DM S 0- d 6) 8. 37 (3H, m), 8. 17 (1H, t, J = 6 Hz), 7. 10-7. 30 (5H, m), 5 . 92 (1H, t dd, J = 5. 5, 17, 1 OH z), 5. 37 (1H, t dd, J = 1. 6, 1. 5, 17Hz), 5. 27 (1H, t dd, J = 1. 5, 1. 5, 10Hz), 4. 65 (2H, m), 4. 13 (1H, m), 3. 51 (2H, m), 2. 79 (2H, t, J = 8Hz), 2. 40 (2H, t, J = 8Hz)

(D) (2 S) - 2 - {2 - [(benzyl O butoxycarbonyl) Amino] Etanoi Le} amino-3- (3-phenylpropyl prop Noi Le) Aminopuropan acid Ariru

(2 S) - 2-Amino dissolved one 3- (3-phenylpropyl prop Noi Le) Aminopuropan acid Ariru 'hydrobromide (200 mg) in DMF (2m l), under ice-cooling, N- benzyl O butoxycarbonyl glycine (1 29mg), HOB t (83mg), WSC- HC 1 added (1 1 8 mg) and Toryechiruamin (0 · 087 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with acetic acid Echiru. The organic layer 1 0% Kuen acid solution, saturated aqueous sodium bicarbonate solution, successively washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the residue obtained by concentration under reduced pressure was purified by silica gel force column chromatography (silica gel 25 g; Solvent: Black port Holm one methanol (1 00: 1 → 50: 1 → 20: 1 )). Yield 2 38m g (90. 8%).

1 H-NMR δ (CDC 1 3) 7. 10-7. 40 (1 OH, m), 7. 04 (1H, d, J = 6. 5Hz), 5. 89 (2H, m), 5. 37 (1 H, tdd, J = 1. 6, 1. 5, 17 Hz), 5. 35 (1H, m), 5. 27 (1H, tdd, J = 1. 5, 1. 5, 10Hz) , 5. 12 (2H, S), 4. 60 (3H, m), 3. 83 (2H, d, J = 5. 7Hz), 3. 65 (2H, m), 2. 92 (2H, t , J = 8Hz), 2. 47 (2H, t, J = 8Hz)

(E) (2 S) - 2 - {2 - [(benzyl O butoxycarbonyl) Amino] Etanoi Honoré} amino-3- (3-phenylpropyl prop Noi Le) Aminopuropan acid

(2 S) 2- dissolved {2- [(benzyl O butoxycarbonyl) Amino] Etanoiru} amino-3 (3-phenylpropyl prop Noi Le) Aminopuropan acid Ariru a (200 mg) in Jiokisan (4m l), tetrakis triphenyl was stirred for 5 minutes at room temperature, mixed phosphine para Jiumu (27 mg) and morpholine (0. 1 1 2m l). The reaction mixture was concentrated under reduced pressure, and washed with ether by dissolving the residue in water. The aqueous layer with 1 N hydrochloric acid and p H 2, and extracted with acetic acid Echiru. The organic layer was wash with brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered and concentrated under reduced pressure to give the desired product as an oil. Yield 1 9 l mg (quantitative). The following compounds were prepared by methods analogous to Example 1 34

Example 1 35

1 H-NMR δ (DMSO- d 6) 10. 63 (1H, b rs), 8. 84 (1H, b rs), 8. 33 (1H, t, J = 5. 7Hz), 7. 47 ( 1H, d, J = 8Hz), 7. 20 -7. 35 (1 OH, m), 5. 00 (2H, s), 4. 23 (2H, d, J = 5. 7Hz), 3. 85 (1H, td, J = 8. 6Hz, 6Hz), 2. 16 (2H, m), 1. 80 (2H, m) example 1 36

1 H-NMR δ (DMSO- d 6) 10. 59 (1H, b rs), 8. 84 (1 H, b rs), 7. 80 (1H, t, J = 5. 5Hz), 7. 43 (1H, d, J = 8. 3Hz), 7. 12-7. 35 (1 OH, m), 5. 00 (2H, s), 3. 81 (1H, td, J = 8. 5Hz, 6 . 4Hz), 2. 98 (2H, m), 2. 78 (2H, t, J = 7. 7Hz), 2. 32 (2H, t, J = 7. 7Hz), 1. 43 (4H, m ) example 1 37

1 H-NMR δ (DMS O- d 6) 10. 60 (1H, s), 8. 84 (IHb rs), 8. 03 (1H, t, J = 5. 3Hz), 7. 44 (1 H , d, J = 8Hz), 7. 10-7. 40 (1 OH, m), 4. 99 (2H, s), 3. 82 (1 H, td, J = 8Hz, 6Hz), 3. 40 (2H, s), 2. 99 (2H, td, J = 6. 5Hz, 6Hz), 1. 45 (4H, m) example 1 38

1 H-NMR δ (DMS O- d 6) 10. 62 (1H, b rs), 8. 83 (1H, b rs), 8. 03 (1H, t, J = 5. 3Hz), 7. 52 (1H, d, J = 8Hz), 7. 10- 7. 40 (1 OH, m), 5. 00 (2H, s), 3. 87 (1H, td, J = 8Hz, 6Hz) 3. 37 (2H, s), 3. 02 (2H, m), 1. 68 (2H, m) example 1 39

1 H-NMR δ (DMS O- d 6) 2. 27-2. 69 (4H, m), 3. 11-3. 24 (2H, m), 4. 23 (1H, m), 4. 94 (2H, s), 7. 09-7. 31 (11 H, m), 7. 84 (1H, m), 8. 75 (1H, s), 10. 60 (1H, s) example 1 40

1 H-NMR δ (DMS O- d 6) 10. 72 (1H, b), 8. 85 (1H, brs), 7. 93 (1H, t, J = 6Hz), 7. 1-7. 4 (11 H, m), 5. 03 (2H, s) 4. 02 (1H, dt, J = 8Hz), 3. 20 (2H, ra), 2. 80 (2H, t, J = 8Hz) 2 . 35 (2H, t, J = 8Hz) example 14 1

1 H-NMR δ (DMS Ο- d 6) 10. 70 (1 Η, b), 8. 86 (1 Η, brs), 7. 93 (IH, t, J = 6Hz), 7. 1-7 . 4 (11 Η, m), 5. 01 (2Η, s) 4. 00 (1Η, dt, J = 8Hz), 3. 20 (2Η, m), 2. 77 (2H, t, J = 8Hz ) 2. 34 (2H, t, J = 8Hz) example 142

1 H-NMR δ (DMSO - d 6) 10. 69 (1 H, b rs), 8. 85 (1 H, b rs), 7. 87 (. IH, t, J = 5 5Hz), 7. 1-7. 4 (11 H, m), 4. 98 (2

H, s), 3. 98 (IH, dt, J = 8Hz), 2. 81 (2H, m), 2. 56 (2H, m), 2. 06 (2H, t, J = 7Hz), 1 . 48 (4H, m) example 143

1 H-NMR δ (DMSO- d 6) 10. 68 (1H, br- s), 8. 83 (1H, b rs), 7. 82 (1H, t, J = 6Hz), 7. 1-7 . 4 (11 H, m), 4. 99 (2H, s), 3. 98 (1H, dt, J = 8Hz, 6. 5Hz), 3. 25 (2H, m), 2. 50 (2H, m), 2. 02 (2H, t, J = 7Hz), 1. 52 (2H, m), 1. 43 (2H, m), 1. 23 (6H, m) example 144

1 H-NMR δ (DMSO - d 6) 10. 61 (1H, br- s), 8. 87 (1H, b rs), 7. 80 (. 1H, t, J = 5 5Hz), 7. 51 (1H, d, J = 8. 0Hz), 7. 10-7. 40 (1 OH, m), 5. 00 (2H, s), 3. 84 (1H, td, J = 8. 3Hz, 6Hz ), 3. 01 (2H, m), 2. 79 (2H, t, J = 7. 7Hz), 2. 33 (2H, t, J = 7. 7Hz), 1. 65 (2H, m) carried example 145

1 H-NMR δ (DMSO- d 6) 10. 62 (1H, b rs), 8. 83 (1 H, b rs), 7. 89 (IH, t, J = 5. 5Hz), 7. 45 (IH, d, J = 8Hz), 7. 1 0-7. 40 (1 OH, m), 5. 00 (2H, s), 3. 83 (IH, m), 3. 22 (2H, m ), 2. 67 (2H, t, J = 7. 5Hz), 2. 06 (2H, m), 1. 77 (2H, m) example 146

1 H-NMR δ (DMSO- d 6) 10. 65 (IH, b rs), 8. 85 (1 H, b rs), 8. 01 (IH, d, J = 8Hz), 7. 86 (1 H, t, J = 6Hz), 7. 10- 7. 40 (1 IH, m), 4. 98 (2H, s), 4. 24 (1 H, dt, J = 6Hz, 8H z), 3 . 20-3. 50 (4H, m), 2. 77 (2H, t, J = 7. 7Hz), 2. 31 (4H, m) example 147

By a method similar to Example 1 to obtain the following compound.

1 H-NMR δ (DMSO- d 6) 1. 64- 1. 95 (m, 2H), 2. 18 (m, 2 H), 3. 45 (s, 2H), 4. 14 (m, 1 H), 7. 15-7. 33 (m, 5H), 8. 3 0 (d, 2H, J = 8. 3Hz), 10. 69 (s, 1 H) example 148

(4 R) - 5- (hydroxymethyl § Mino) Single 4 one {[1 0- (4-hydroxy-phenylene Le) Dekanoiru] amino} - 5-Okisopentan acid sodium salt

By methods analogous to those described in Example 2 (4 R) - 5-(hydroxy amino) Single 4 one {[1 0- (4-hydroxyphenyl) Dekanoiru] amino} - 5 - Okisopentan acid (4 . 0 g) from (4 R) - 5- (hydroxymethyl § Mino) Single 4 one {[1 0- (4-hydroxyphenyl) Dekanoiru] amino) 4. 0 g to give an 5 Okisopenta phosphate sodium salt It was.

1 H-NMR δ (DMSO- d 6) 1. 21 (b rs, 1 OH), 1. 33-1. 55 (m, 4H), 1. 62-1. 82 (m, 2H), 1. 96 (t, 2H, J = 6. 5Hz), 2. 0 6 (t, 2H, J = 6. 8Hz), 2. 43 (t, 2H, J = 7. 6Hz), 4. 05 (m, 1 H), 6. 06 (d, 2H, J = 8. 1Hz), 6. 93 (d, 2H, J = 8. 1Hz), 8. 4 2 (b rs, 1H), 10. 05 (b rs, 2H) example 149 (4 R) - 4 {1 0- [3- (aminomethyl) phenyl] Dekanoiru} § Roh] one 5- (hydroxymethyl § Mino) Single 5 Okisopentan acid sodium salt

Example by methods analogous to those described in 2 (4 R)-4-[{1 0- [3 - (aminomethyl) phenyl] Dekanoiru} Amino] one 5- (hydroxymethyl § Mino) Single 5- Okisopentan acid (2. 7 g) from (4R)-4-[{1 0- [3- (amino Nomechiru) phenyl] Dekanoiru} amino] one 5- (hydroxymethyl § Mino) an 5 Okisopentan acid sodium salt 2.3 It was obtained g.

H-NMR δ (CD OD) 1. 30 (b rs, 1 OH), 1. 50-1 58.. (: M, 4H), 1, 88-2 02 (m, 2H), 2. 12- 2. 32 (m, H), 2. 59 (t, 2 H, J = 7. 5Hz), 3. 76 (s, 2H), 4. 18 (dd, 1 H, J = 6. 2Hz, 8 . 3 Hz), 7. 00-7. 28 (m, 4H) example 1 50

(2 RS) - N 1 - hydroxy-2- [(3- {[Imino (Fuenechiruamino) methylation] amino} Puropanoiru) Amino] Puropanami de

By methods analogous to those described in the first section of the embodiment 1, benzyl Ν- {[(Benjiruokishi) carbonyl] - 8-methyl - 6, 9 Jiokiso 1 2 off Eniru - 1 1 one Okisa - 2, 7, 1 0-tri § the dodecane Imi Doyle) Single Nyu- (3-phenylpropyl) force Rubameto (1 33 mg) from (2 RS) -N] over human Dorokishi one 2- [(3- {[imino (Fuenechiruamino ) methyl] Amino) pro Panoiru) Amino] Puropanami de was obtained 77 mg.

1 H-NMR 8 (CD 3 〇_D) 1. 35 (d, 3H, J = 7. 2Hz), 1. 79-1. 98 (m, 4H), 2. 29-2. 35 (m, 2H ), 2. 68 (t, 2H, J = 8. 1Hz), 3. 15-3. 25 (m, 4H), 4. 27 (q, 1 H, J = 7. 2Hz), 7. 13- 7. 29 (m, 5H) benzyl was used as starting material N-{[(Benjiruokishi) carbonyl] one 8-methyl one 6, 9 Jiokiso one 1 2 phenyl one 1 1- Okisa one 2, 7, 1 0 - tri § the dodecane Imi Doyle} - N-(3- phenylpropyl) force Rubameto was prepared as follows.

(A) N-base Nzoiru N '- (3- phenylpropyl) Chiourea

3- phenylpropyl amine (1 5 g) and 1, was dissolved in 1,2-dichloroethane (1 50 m 1), was added dropwise a benzo I Louis Seo thio Xia sulfonate (27. 2 g), and stirred at room temperature for 4 hours. The residue was purified by silica gel column chromatography - (stationary phase: silica gel 60, 70-230 mesh, 1 kg, mobile phase: to hexa N'no acetate Echiru = 6Z 1) purified by, N- Benzoiru _Ν '- (3-phenylpropyl) Chiourea 3 1. give 4 g.

1 H-NMR δ (CDC 1 3) 1. 99- 2. 10 (m, 2H), 2. 73 (t, 2H, J = 7. 5Hz), 3. 68- 3. 75 (m, 2H) , 7. 16- 7. 24 (m, 3H), 7. 2 5- 7. 32 (m, 2H), 7. 45-7. 52 (m, 2H), 7. 60 (m, 1 H) , 7. 79 -7. 85 (m, 2H), 9. 12 (s, 1 H), 10. 80 (s, 1 H)

(B) N- (3- phenylpropyl) Chiourea

N- Benzoiru N '- (3- phenylpropyl) Chiourea the (3 1. 4 g) was dissolved in a mixed solvent of methanol (50 m l) and THF (1 00m l), carbonate force potassium (34. 3 g) It was added, the mixture was heated under reflux for 2 hours. Removed by filtration potassium carbonate, the solvent was distilled off under reduced pressure, added with water, extracted with acetic acid Echiru. The organic layer was saturated sodium hydrogen Natoriumu solution was washed with saturated brine and dried over anhydrous sulfate Maguneshiumu. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 400 g, mobile phase: to Kisan'no acetate Echiru = 1 1) to give We by, N-(3- phenylpropyl) Chiourea were obtained 1 9. 2 g.

1 H-NMR δ (CDC 1 3) 1. 89- 1. 99 (m, 2H), 2. 69 (t, 2H, J = 7. 7Hz), 3. 11 (b rs, 2H), 5. 84 (br- s, 2H), 6. 49.. (br - s, 1H), 7. 15-7 24 (m, 3H), 7. 24-7 32 (m, 2H)

(C) 1 i (3- {[imino (methylsulfanyl) methyl] amino} propyl) benzene

N- (3 _ phenylpropyl) Chiourea (1 9. 2 g) was dissolved in acetone (250 m 1), was added carbonate Kariumu (1 7. 8 g). This methyl iodide (1. 0 g) in was added dropwise under ice water cooling, after stirring for 3 hours and warm to room temperature and allowed to stand at between 2 days at room temperature. Removed by filtration potassium carbonate, The solvent was evaporated under reduced pressure, by recrystallization from hexane mixed solvent to the chloroform the residue, 1 i (3- {[imino (methylsulfanyl) methyl] amino} propyl) benzene to give 1 5. 1 g.

1 H-NMR δ (CDC 1 3) 1. 85-1. 95 (m, 2H), 2. 31 (s, 3H),

2. 68 (t, 2H, J = 8. 1Hz), 3. 32 (t, 2H, J = 6. 8Hz), 7. 15- 7. 22 (m, 3H), 7. 23-7. 32 (m, 2H)

(D) Benzyl N-[{[(Benjiruokishi) carbonyl] imino} (methylstyrene Rufaniru) methyl] - N-(3- phenylpropyl) force Rubameto

1 - (3- {[imino (methylsulfanyl) methyl] amino} propyl) benzene (1 3. 3 g) and sodium bicarbonate (53. 8 g) in methylene chloride (1 50 m l) and water (1 50 m It was added to the l). It warmed to room temperature after which was added to the mixture under ice water cooling with downy chloride Njiruokishi carbonyl (65. 5 g), and stirred for 1 5 hours. Water was added and extracted with black port Holm, the organic layer 1 N-hydrochloric acid, saturated aqueous sodium bicarbonate, washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-2 30 mesh, 1. 5 kg, mobile phase: hexane / acetic acid Echiru = 4 to It was purified by Roh 1). The resulting pressurized been example to 1 8. 5 g and sodium hydrogen carbonate crude product (6. 89 g) in methylene chloride (50 m 1) and water (1 00m 1). It warmed to room temperature after which was added to the base chloride under ice water cooling Nji Ruo alkoxycarbonyl (8. 3 9 g), and stirred for 1 5 hours. Water was added and extracted with black port Holm, the organic layer 1 N-hydrochloric acid, saturated aqueous sodium bicarbonate, washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, silica force gel column chromatography scratch residue (stationary phase: silica force Gel 60, 200 -4 00 mesh, 700 g, mobile phase: hexane Z acetate Echiru = 6 Roh 1) benzyl N- purified by [{[(Benjiruokishi) carbonyl] imino} (methylsulfanyl) methyl] - was obtained N- (3- phenylpropyl) force Rubameto 1 0. 2 g.

1 H-NMR 8 (CDC 1 3) 1. 90-2. 00 (m, 2H), 2. 36 (s, 3H), 2. 59 (t, 2H, J = 7. 7Hz), 3. 62 (t, 2H, J = 7. 7Hz), 5. 05 (s, 2H), 5. 07 (s, 2H), 7. 12-7. 42 (m, 15H)

(E) Benzyl N-{[(Benjiruokishi) carbonyl] - 8-methyl _ 6, 9 Jiokiso one 1 2 phenylene Lou 1 1 one Okisa one 2, 7, 1 0-Toriazadodekan Imi Doyle) - N-(3 - phenylpropyl) force Rubameto

N- dissolved [{[(Benjiruokishi) carbonyl] imino} (methylsulfanyl) methyl]-N-(3- phenylpropyl) force Rubameto a (1. 43 g) in Aseto nitriles (30 m l), in which 4 one amino-were prepared by methods analogous to those described in Section 2 of example 1 N- {(1 RS) - 2 - [(Benjiruoki Shi) Amino] one 1-methyl-2-Okisoechiru} Butan'ami de hydrochloride ( 0. 9 5 g) and Toriechiruamin the (0. 3 1 g) was added and stirred for 5 hours at 50 ° C. 1 N-hydrochloric acid was added thereto, followed by extraction with acetic acid Echiru, the organic layer was washed with saturated sodium hydrogen Natoriumu solution and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off The solvent was distilled off under reduced pressure, the residue silica gel preparative thin layer chromatography (stationary phase: shea Rikageru 60 F 2 54: mobile phase: black port Holm // methanol = 20/1) benzyl by purifying N-{[(Benjiruokishi) carbonyl] - 8-methyltransferase - 6, 9-Jiokiso - 1 2-phenylene Lou 1 1 one Okisa one 2, 7, 1 0-tri Azadodekan'imi Doyle} -N - (3-phenylpropyl) force Rubameto was obtained 1 3 3 mg.

1 H-NMR 8 (CDC 1 3) 1. 23 (d, 3H, J = 7. OHz), 1. 60-1. 95 (m, 4H), 2. 56 (t, 2H, J = 7. 5Hz), 3. 05-3. 33 (m, 2H), 3. 55- 3. 75 (m, 2H), 4. 27 (m, 2H), 4. 84 (s, 2H), 5. 10 (s, 2H), 5. 12 (s, 2H), 6. 69 (s, 1 H), 6. 95-7. 50 (m, 21 H), 9. 81 (s, 1H) example 1 5 1

(4 R) - 5-(hydroxy § Mino) Single 5 _ Okiso _4 one - ({2 - [- (8-phenylene Ruokuchiru) Okishi Ί Asechiru} _ Amino) pentanoic acid

By methods analogous to those described in the first section of Example 1, (4 R) - 5- [(Baie Njiruokishi) Amino] - 5- Okiso one 4 one ({2 - [(8-Fueniruokuchi Le) Okishi ] Asechiru} amino) pentanoic acid base Njiru (0. 8 2 g) from (4 R) - 5- (hydroxymethyl § Mino) over 5 Okiso one 4- ({2 - [(8-phenyl Okuchiru) Okishi] Asechiru the} Amino) pentanoic acid was obtained 0. 53 g.

1 H-NMR 8... (DMSO - d 6) 1. 19-1 38 (m, 8H), 1. 4-1 6 4 (m, 4H), 1. 70-1 96 (m, 2H) , 2. 19 (t, 2H, J = 7. 4Hz), 2. 56 (t, 2H, J = 7. 7Hz), 3. 43 (t, 2H, J = 6. 6Hz), 3. 85 ( s, 2 H), 4. 24 (m, 1H), 7. 07-7. 21 (m, 3H), 7. 21- 7. 30 (m, 2 H), 7. 59 (b rs, 1 H), 8. 93 (s, 1 H), it was used as a 10. 74 (s, 1 H) the starting material (4 R) - 5- [(Benjiruokishi) Amino] - 5- O Kiso 4- ({2 - [(8-Fueniruokuchiru) Okishi] Asechiru} Amino) pentane benzyl was prepared as follows.

(A) 2- [(8- Fueniruokuchiru) Okishi] acetate t one-butyl

8 - 1-phenylene Ruokutano Ichiru a (5 g) was dissolved in toluene (70m l), sulfate hydrogen tetra n- Petit Ruan monitor © beam (0. 82 g), 50% - sodium hydroxide aqueous solution (50 m It added l) and bromoacetate t one-butyl (7. 09 g), and stirred for 1.5 hours. 1 N-hydrochloric acid was added to weakly acidic and extracted with acetic acid Echiru, the organic layer 5% - aqueous potassium hydrogensulfate solution, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 200 g, mobile phase: to Kisan'no acetate Echiru = 20/1) give by, 2- [(8-Fueniruokuchiru) Okishi] acetate t one butyl 6. give 56 g.

1 H-NMR δ (CDC 1 3) 1. 17-1. 46 (m, 8H), 1. 48 (s, 9H), 1. 52-1. 70 (m, 4H), 2. 59 (t , 2H, J = 7. 3Hz), 3. 50 (t, 2H, J = 6. 6Hz), 3. 94 (s, 2H), 7. 08-7. 22 (m, 3H), 7. 22 -7. 3 6 (m, 2H) (B) 2- [(8- Fueniruokuchiru) Okishi] acetic acid

2 - [(8-Fueniruokuchiru) Okishi] acetate t one-butyl (6. 56 g) in 95% - Torifuruoro acetic acid water (5 Om 1) was added, and allowed to stand for 30 minutes. By adding toluene and the solvent was evaporated under reduced pressure, followed by drying under reduced pressure to give 2- [(8-phenylene Ruokuchiru) Okishi] acetic acid quantitatively.

1 H-NMR δ (CDC 1 3) 1. 21-1. 44 (m, 8H), 1. 50-1. 71 (m, 4H), 2. 60 (t, 2H, J = 7. 7Hz) , 3. 55 (t, 2H, J = 6. 7Hz), 4. 11 (s, 2H), 7. 10-7. 21 (m, 3H), 7. 21-7. 33 (m, 2H)

(C) (4 R) - 5- [(Benjiruokishi) Amino] _ 5 Okiso _4 i ({2 [(8-Fueniruokuchiru) Okishi] Asechiru} Amino) base pentanoic acid Njiru

By methods analogous to those described in Section II of Example 1 (4 R) - 5- [(Ben Jiruokishi) Amino] one 4-[(t one butoxycarbonyl) Amino] - 5-O key Sopentan benzyl When 2- from [(8 Fueniruokuchiru) Okishi] acetic acid (4 R) - 5- [(Benjiruokishi) Amino] one 5- Okiso one 4- ({2 - [(8-Fueniruokuchiru) Okishi] Asechiru} Amino) pentane It was obtained benzyl. 1 H-NMR δ (CDC 1 3) 1. 16-1. 42 (m, 8H), 1. 46-1. 72 (m, 4H), 1. 92-2. 23 (m, 2H), 2 . 27-2. 54 (m, 2H), 2. 60 (t, 2H, J = 7. 7Hz), 3. 45 (t, 2H, J = 6. 3Hz), 3. 79 (d, 1 H , J- 1 5. 6Hz), 3. 87 (d, 1 H, J = l 5. 6Hz), 4. 34 (m, 1 H), 4. 89 (s, 2H), 5. 09 (s , 2H), 7. 1 1 (d, 1 H, J = 8. 4Hz), 7. 12-7. 21 (m, 3H), 7. 22-7. 42 (m, 12H) 9. 29 ( s, 1 H) example 1 52

(4 R) - 5- (hydroxymethyl § Mino) Single 5- Okiso one 4- {[6 - (3-phenyl Purobokishi) to Kisanoiru] amino} pentanoic acid

By methods analogous to those described in the first section of Example 1 (4 R) - 5- [(Ben Jiruokishi) Amino] - 5- Okiso one 4 one {[6- (3-phenylpropyl Provo carboxymethyl) to Kisanoiru] amino} base pentanoic acid from Njiru (4 R) - 5 - to give a (hydroxy § Mino) Single 5- Okiso one 4 one {[6- (3-phenylpropyl propoxy) to Kisanoiru] amino} pentanoic acid.

1 H-NMR δ (DMS 0- d 6) 1. 27-1. 36 (m, 2H), 1. 44-1. 5 2 (m, 4H), 1. 72-1. 83 (m, 4H ), 2. 02-2. 16 (m, 4H), 2. 61 (t, 2H, J = 7. 8Hz), 3. 31 (t, 4H, J = 5. 9Hz), 4. 13 (m , 1 H), 7. 14-7 30 (m, 5H), 8. 00 (d, 1 H, was used as a J = 8. 6 Hz) starting material (4 R) -. 5- [(Baie Amino] - 5 -. O Kiso one 4 one {[6- (3-phenylpropyl Provo carboxymethyl) to amino} base penta phosphate Njiru were prepared as follows (a) 1 {(E) one 3- [2 - (base Etokishi] one 1- Purobe two Le} benzene

Cinnamyl bromide (1 9. 7 g) was dissolved in toluene (1 00m l), was added to ethylene glycol monomethyl base Nji ether (1 5. 2 g), was dissolved by adding toluene (1 80 ml) . 50% - was stirred at room temperature for 1 hour by the addition of aqueous sodium hydroxide (200 meters l) and sulfuric acid hydrogen tetra n- Petit Ruan monitor © beam (3. 4 g). The aqueous layer was extracted with toluene, washed 1 N-hydrochloric acid and the combined organic layer, saturated sodium hydrogen carbonate solution, and water. The solvent was removed in vacuo and the residue silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 50 0 g, mobile phase: to Kisan'no acetate Echiru == 1 0 Roh 1) purified by, 1 - {(E) one 3- [2- (Benjiruokishi) ethoxy] - 1 one-propenyl} the benzene to give 23. 5 g.

1 H-NMR δ (CDC 1 3) 3. 64-3. 71 (m, 4H), 4. 21 (dd, 2H, J = 1. 5Hz, 6. 1Hz), 4. 59 (s, 2H) , 6. 31 (d, 1 H, J = 6. 1Hz, 15. 9Hz), 6. 61 (d, 1 H, J = l 5. 9Hz), 7. 20-7. 42 (m, 1 OH )

(B) 2 - (3- phenylpropyl propoxy) Single 1- ethanol 1- {(E) - 3- [2- (Benjiruokishi) ethoxy] one 1 one-propenyl} benzene (23. 5 g) and THF (1 00m l), methanol (1 00m l) Contact and 4N- chloride was dissolved in hydrogen one Jiokisan solution (20m 1), 1 0% - was added P d / C (wet) (2 g) was 5. stirred for 5 hours under hydrogen atmosphere. The catalyst was removed by filtration, after neutralization of the filtrate with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. Acetic acid Echiru added to the residue, washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, the residue was purified by silica gel column chromatography (stationary phase: silica gel 6 0, 7 0 2 3 0 mesh, 3 0 0 g, mobile phase: hexane Bruno acetate Echiru = 3 1 to eluent) it allows 2- (3 - Fuenirupuropoki sheet) an 1 one ethanol 6. give 8 g.

1 H-NMR δ (CDC 1 3) 1. 88- 1. 97 (m, 2H), 2. 02 (t, 2H, J = 6. 1 Hz), 2. 70 (t, 2H, J = 7 . 6Hz), 3. 49 (t, 2H, J = 6. 4H z), 3. 7 1 -3. 76 (m, 2H), 7. 1 5- 7. 26 (m, 3H), 7. 26-7. 38 (m, 2H)

(C) 6 - (3- phenylpropyl Provo carboxymethyl) hexanoic acid Echiru Dichloride Okisariru the (1. 4 4 ml) was dissolved in methylene chloride (6 0 ml), was added DM S 0 in one 5 0-1 6 0 ° C (2. 6 g). 2- (3 - Fuenirupuropoki sheet) - 1- ethanol (2. 7 g) in methylene (1 0 ml) chloride solution an 5 0 - 6 was added at 0 ° C, after stirring for 15 minutes, Toryechiruamin (7 . 6 g) was added with stirring rather violently to. The reactor was warmed up to room temperature, and extracted by adding 1 N-hydrochloric acid with acetic acid Echiru, organic layer with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous sulfate Ma Guneshiumu. The desiccant was filtered off, the filtrate was evaporated under reduced pressure. The residue was dissolved in THF (1 5 ml), it was used in the following reaction.

Sodium hydride (1. 2 g) was suspended in TH F (6 0 ml), THF (1 0 ml) solution dropwise under a under ice water cooling 4 one Hosuhonokuroton acid Toryechiru (7. 5 g) then, the mixture was stirred for 1 hour. After stirring for 2 hours and warmed to room temperature, it was added dropwise T HF solution of the reaction product was stirred at room temperature for 3 hours. Saturated chloride Anmoniumu aqueous solution was added, followed by extraction with acetic acid Echiru, the organic layer was washed with saturated brine and Drying over anhydrous magnesium sulfate. The desiccant was filtered off, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 400 g, mobile phase: hexane Bruno acetate Echiru = 20/1 → 5/1) was purified by. The crude product was dissolved in methanol (2 0m l), 1 0% - P d Bruno C a (wet) (0. 2 5 g) was added, and stirred for 3 hours under hydrogen atmosphere. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in methanol (20m l), 1 0% - P dZC (we t) (0. 2 5 g) pressure to give a hydrogen atmosphere in and the mixture was stirred for 7 hours. The catalyst was removed by filtration, by evaporation of the solvent under reduced pressure, 6- (3-phenylpropyl propoxy) hexanoic acid Echiru give 1. 5 g.

1 H-NMR δ (CDC 1 3) 1. 25 (t, 3H, 3 = 1. 2Hz), 1. 33-1. 47 (m, 2H), 1. 35-1. 71 (m, 4H) , 1. 84-1. 96 (m, 2H), 2. 3 1 (t, 2H, J = 7. 5Hz), 2. 69 (t, 2H, J = 7. 7Hz), 3. 40 (t , 2H, J = 6. 4Hz), 3. 41 (t, 2H, J = 6. 4Hz), 4. 12 (q, 2H, J = 7. 2H z), 7. 13-7. 23 (m , 3H), 7. 23-7. 33 (m, 2H)

(D) 6 - (3- phenylpropyl propoxy) hexanoic acid

6- (3-phenylpropyl Provo carboxymethyl) hexanoic acid Echiru (1. 5 g) was dissolved in methanol (1 5 m l), 2N-aqueous sodium hydroxide (1 0. 5 m l) was added, 7 at room temperature and the mixture was stirred time. 1 N-hydrochloric acid was added, followed by extraction with acetic acid Echiru, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, by distilling off the solvent under reduced pressure, the hexanoic acid 6- (3-phenylpropyl Provo carboxymethyl) to give 1. 3 g.1 H-NMR δ (CDC 1 3) 1. 36- 1. 47 (m, 2H), 1. 56-1. 72 (m, 4H), 1. 84-1. 95 (m, 2H), 2 . 36 (t, 2H, J = 7. 4Hz), 2. 6 8 (t, 2H, J = 7. 6Hz), 3. 410 (t, 2H, J = 6. 5 Hz), 3. 414 ( t, 2H, J = 6. 5 Hz), 7. 13-7. 23 (m, 3H), 7. 23-7. 32 (m, 2H)

(E) (4R) one 5 - [(base Amino] one 5-Okiso one 4 one {[6 (3-phenylpropyl propoxy) to amino} base pentanoic acid Njiru

By methods analogous to those described in Section II of Example 1 6- (3-Fuenirupuro epoxy) to the hexanoic acid (4 R) - 5 - [(Benjiruokishi) Amino] - 5- O Kiso 4- {[ 6 - (3-phenylpropyl propoxy) to Kisanoiru] amino} penta phosphate benzyl.

1 H-NMR δ (CDC 1 3) 1. 28- 1. 40 (m, 2H), 1. 52-1. 68 (m, 4H), 1. 83-2. 10 (m, 4H), 2 . 14 (t, 2H, J = 7. 8Hz), 2. 2 6- 2. 59 (m, 2H), 2. 67 (t, 2H, J = 7. 7Hz), 3. 36- 3. 42 (m, 4H), 4. 28 (m, 1 H), 4. 88 (s, 2H), 5. 10 (s, 2H), 6. 32 (d, 1H), 7. 15- 7. 43 (m, 15H), 9. 30 (s, 1 H) example 1 53

6- [4- (2-Shianoechiru) phenyl, -N- [(1 RS) - 2 Kisan'ami de and the (hydro Kishiamino) one 1-methyl-2-Okisoechiru 6-

[4 -_ (3 Aminopuropiru) Hue sulfonyl] - N- Kisan'ami Dotorifuruoro acetate to [_ (1 RS) - 2 - - (hydroxy Amino) 1-methyl __2- Okisoechiru]

By methods analogous to those described in the first section of Example 1, (EZ) - N- {(1 RS) - 2 - [(Benjiruokishi) Amino] _ 1 Mechiru one 2-Okisoechiru} - 6- {4 - [(EZ) - 2 _ Shiano one 1- Echiru] Hue sulfonyl} - 5-hexene amine de the crude product from (1. 57 g), thin layer chromatography (stationary phase: Merck , silica gel 60, 1. 0 mm thick, mobile phase: purified by black port Holm methanol one le 5 1), 6- [4- (2-Shianoechiru) phenylene Sole]-N-[(1 RS ) - 2- (yield hydroxy § mino) 3 3 mg of Kisan'ami de to single 1-methyl-2-Okiso Echiru. The The crude product HPLC (column: YMC- OD S (R- 3 5 5- 2 0) 5 cm φ x 2 5 cm; solvent: (A solution) 0. 1% TF A / H 2 0 ( solution B) 0. 1% TF AZCH 3 CN ; gradient: (B%: 0 → 2 5% (1 80 min); flow rate: 1 5 m l min; detection: purified by UV 220 nm) 6- [4 i (3 Aminopuropiru) phenyl]-N-[(1 RS) - 2- (hydroxy § Mino) Single 1-methyl one 2- Okisoechiru] to the key San'ami Dotorifuruoro acetate to give 1 45 m g.

1 H-NMR δ (DMS O- d 6)

6- [4 one (2- Shianoechiru) phenyl] - N_ [(1 RS) - 2- (hydro Kishiamino) one 1-methyl-2-Okisoechiru] Kisan'ami de to

1. 15 (d, 3H, J = 7. 0Hz), 1. 18-1. 34 (m, 2Η), 1. 41-1. 62 (m, 4Η), 2. 08 (t, 2H, J = 7. 2Hz), 2. 54 (t, 2H, J = 7. 4Hz), 2. 70-2. 88 (m, 4H), 4. 18 (m, 1 H), 7. 08-7. 19 (m, 4H), 7. 94 (d, 1H), 8. 80 (s, 1 H), 10. 55 (s, 1 H)

6 - [4 - (3-Aminopuropiru) phenyl] - N-[(1 RS) - 2 - (hydrate Rokishiamino) one 1-methyl-2-Okisoechiru] Kisan'ami Dotorifuruoro acetate to

1. 18 (d, 3H, J = 7. 0Hz), 1. 22-1. 34 (m, 2H), 1. 44-1. 6 2 (m, Η), 1. 76-1. 92 ( m, 2H), 2. 10 (t, 2H, J = 7. 4Hz), 2. 53 (t, 2H), 2. 61 (t, 2H, J = 7. 5Hz), 2. 70-2. 86 (m, 2 H), 4. 20 (m, 1H), 7. 00- 7. 18 (m, 4H), 7. 77 (br- s, 3H), 7. 93 (m, 1H), 8. 80 (br- s, 1 H), was used as a 10. 58 (s, 1 H) starting material (EZ) - N- {(IRS) - 2- [(Benjiruoki Shi) Amino] one 1-methyl one 2-Okisoechiru} one 6- {4- [(EZ) one 2-Shiano - 1 Echiru] Hue sulfonyl} - Kisen'ami de to 5 were prepared as follows.

(A) (2 RS) - 2- (5- to Kisenoiruamino) propanoate

To 5 hexene acid (25 g) was dissolved in THF (650m l), N- Mechirumoru holin the (24. lml) were added and cooled to a 1 0-1 20 ° C. Black hole formic acid isobutyl the (28. 4m l) and stirred slowly retriever dropped 1 5 minutes at the same temperature. (2 RS) one 2-Aminopuropan methyl hydrochloride (30. 6 g) was added, dropwise N- Mechirumo Ruhorin (24. lml), 30 minutes at the same temperature, and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with acetic acid Echiru. The organic layer IN- hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous sulfate magnesium © beam. The desiccant was filtered off, by distilling off the solvent under reduced pressure, to obtain 43. 6 g of (2 RS) -2- (5- to Kisenoiruamino) propanoate.1 H-NMR 5 (CDC 13 ) 1. 40 (d, 3H, J = 7. 2Hz), 1. 64-1. 80 (m, 2H), 2. 04-2. 14 (m, 2H), 2. 22 (t, 2H, J = 7. 3Hz), 3. 75 (s, 3H), 4. 61 (m, 1 H), 4. 97-5. 07 (m, 2H), 5. 72 -5. 85 (m, 1H), 6. 02 (b rd, 1 H)

(B) (2 RS) 2 - (to 5 Kisenoiruamino) propanoic acid

(2 RS) - 2- (5- to Kisenoiruamino) methylpropanoic acid (43. 6 g) was dissolved in methanol (1 00m l), under ice-cooling 5 N-hydroxide Natoriumu aqueous solution (88m l) was added It was stirred at room temperature for 3 hours Te. Water was added, washed with ether, the 1 N-hydrochloric acid was added to the aqueous layer was extracted with acetic acid Echiru. The organic layer was washed with water, saturated saline after rinsing, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off by the solvent removed by distillation under reduced pressure, (2 RS) - 2-a (5 to Kisenoiruamino) propanoic acid 40. give 2 g.

1 H-NMR δ (CDC 1 3) 1. 5 (d, 3H, J = 7. 2Hz), 1. 66-1. 84 (m, 2H), 2. 03-2. 15 (m, 2H) , 2. 26 (t, 2H, J = 7. 6Hz), 4. 59 (m, 1H), 4. 92-5. 12 (m, 2H), 5. 78 (m, 1 H), 6. 36 (b rd, 1H)

(C) (2 RS) -2- (to 5 Kisenoiruamino) propanoic acid t _ butyl

(2 RS) - 2- (5- to Kisenoiruamino) propanoic acid was dissolved in (40. 2 g) of di chloromethane (400 meters l), concentrated sulfuric acid (2. 9m l) was added, Korihiyakai Sobuten ( 1 00 g) was allowed to Paburingu. After 1 晚 standing at room temperature, saturated sodium hydrogen carbonate aqueous solution was added, the solvent was extracted under vacuum distilled off acetic Echiru. The organic layer was washed with saturated Japanese brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, by distilling off the solvent under reduced pressure, (2 RS) - 2 - (5- to Kisenoiruami Roh) propanoic acid t- butyl obtain 20 g.

1 H-NMR δ (CDC 1 3) 1. 36 (d, 3H, J = 7. 2Hz), 1. 47 (s, 9H), 1. 68-1. 80 (m, 2H), 2. 06 -2. 13 (m, 2H), 2. 21 (t, 2 H, J = 7. 3Hz), 4. 48 (m, 1 H), 4. 97- 5. 07 (m, 2H), 5 . 78 (m, 1H), 6. 03 (b rd, 1 H)

(D) (2 RS) - 2- propanoic acid t _ butyl {amino [(EZ) - 6 - - (4- Buromofueniru) xenon Noiru to 5]}

(2 RS) - 2 - (5 _ to Kisemeiruamino) propanoic acid t- butyl (20 g) was dissolved in methanol (250 meters l), Sudan ΙΠ a (25 mg) was added, an 7 8 ° C under an ozone 6 was time Paburingu. Triphenyl phosphinite down the (2 1. 7 g) was added, the temperature was raised to slowly litho room temperature, allowed to stand for 1 晚. By distilling off the solvent under reduced pressure, the crude product was obtained 54. 8 g. After 4-bromobenzyl bromide triflate et Niruhosuhoniumu (42. 4 5 g) and 1 00 ° C under vacuum for one hour drying, was suspended in THF (250m l), 60% - Sodium hydride (3. 3 g) and the mixture was stirred for 4 hours. The above crude product after THF (l O Om l) solution was added 7 hours stirring (54. 8 g), and allowed to stand for one 晚. The 1 N-hydrochloric acid was added under ice-cooling, and extracted with acetic acid Echiru. The organic layer with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous sulfate Ma Guneshiumu. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue silica force gel column chromatography (stationary phase: silica gel 60, 70- 230 mesh, LKG, mobile phase: to Kisan'no acetate Echiru = 2/1) in Te cowpea in purifying, (2 RS) - 2- {[(EZ) one 6- (4 one Buromofueniru) one 5- to xenon I le] amino} propanoic acid t one-butyl 1 1. 6 g Obtained.

1 H-NMR δ (CDC 1 3) 1. 26- 1. 42 (m, 3H), 1. 46 (s, 4. 5 Η), 1. 47 (s, 4. 5H), 1. 75- 1. 88 (m, 2H), 2. 18-2. 36 (m, 4H), 4. 39-4. 52 (m, 1 H), 5. 66 (dt, 0. 5H, J = 7. 3, 11. 7H z), 5. 90-6. 10 (m, 1 H), 6. 17 (dt, 0. 5H, J = 6. 8, 15. 8H z), 6. 31-6. 39 (m, 2H), 7. 08- 7. 26 (m, 2H), 7. 36- 7. 48 (m, 2H)

(E) (2 RS) - 2 - [((EZ) - 6- {4 - [(EZ) - 2- Shiano 1 Eteniru] Hue sulfonyl} - Kisenoiru to 5) Amino] propanoic acid t one-butyl

(2 RS) - 2- {[(EZ) - 6- (4- Buromofueniru) one 5- to Kisenoi Le] amino} dissolved propanoic acid t- butyl (1 1. 3 g) in DMF (ll Om l) and sodium acetate (2. 6 g), acrylonitrile (1 8. 8m l), acetic acid palladium (6 5 mg), was added a tree 0- tolylphosphine (0. 34 g), 20 in 1 1 0 ° C time and the mixture was stirred. Middle sodium acetate, palladium acetate, tri - 0 - tolylphosphine the same amount was added three times. The 1 N-hydrochloric acid and acetic acid E chill was added under ice-cooling, the insoluble material was removed by Celite and. The organic layer with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 7 0 2 3 0 mesh, 1 kg, mobile phase: hexane Z acetate Echiru = 2 Bruno purification by 1), (2 RS) - 2- [((EZ) - 6 one {4 one [(EZ) - 2-Shiano one 1- Eteniru] Hue sulfonyl} Kisenoi Le to single 5-) Amino] propanoic acid t one-butyl 6. give 32 g.

1 H-NMR δ (CDC 1 3) 1. 23-1. 38 (m, 3H), 1. 46-1. 48 (m, 9H), 1. 78-1. 91 (m, 2H), 2 . 18- 2. 42 (m, 4H), 4. 38-4. 53 (m, 1H), 5. 41, 5. 73, 5. 85, 6. 24-6. 48, 7. 09, 7 . 77 (m, 4H, Orefin property H), 5. 96-6. 10 (m, 1 H), 7. 26-7. 44 (m, 4H)

(F) (2 RS) one 2- [((EZ) - 6 - {4- [(EZ) - 2- Shiano 1 Eteniru] Hue sulfonyl} - 5- to Kisenoiru) Amino] propanoic acid

(2 RS) - 2- [((EZ) - 6- {4 one [(EZ) one 2- Shiano one 1 Ete sulfonyl] Hue sulfonyl} - 5- to Kisenoiru) Amino] propanoic acid t one-butyl (2 . 53 g) 95% - was dissolved in aqueous TFA (2 Om 1), and allowed to stand at room temperature for 30 minutes. By distilling off the solvent under reduced pressure, (2 RS) - 2- [((EZ) - 6- {4- [(EZ) - 2- Shiano 1 Eteniru] Hue sulfonyl} - Kisenoiru to 5) amino the] propanoic acid 2 was obtained 14 g.

1 H-NMR δ (CDC 1 .) 1. 33-1. 45 (m, 3H), 1. 76-1. 90 (m, 2H), 2. 22-2. 45 (m, H), 4 . 55 (m, 1 H), 5. 40, 5. 71, 5. 84, 6. 10- 6. 50, 7. 10, 7. 76 (m, To ta 15H, Orefin of H + § Mi de H), 7. 26-7. 43 (m, 4H)

(G) (EZ) _N- {(IRS) - 2- [(Benjiruokishi) Amino] - 1- main Chiru 2 Okisoechiru} - 6 - {4- [(EZ) one 2- Shiano - 1- Echiru] Hue nil} - Kisen'ami de to 5

(2 RS) one 2-[((EZ) one 6- {4 - [(EZ) - 2- Shiano one 1-E Te sulfonyl] Hue sulfonyl} one 5- to Kisenoiru) Amino] propanoic acid (2. the 68 g) was dissolved in TH F (20m l), added N- methylmorpholine (0. 76m l), - and cooled to 1 0~- 20 ° C. Black hole formic acid isobutyl the (0. 89m l) and stirred slowly retriever dropped 1 5 minutes at the same temperature. O-benzyl hydroxylamine hydrochloride (1.1) was added, dropwise N- methylmorpholine (0. 76m l), 30 minutes at the same temperature, and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with acetic acid Echiru. The organic layer 1 N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, reduced solvent 圧留 Sanochi, the residue was purified by silica gel column chromatography (stationary phase: silica gel 6 0, 70-230 mesh, 200 g, mobile phase: black port Holm Z methanol = 2 0 / purification by 1), (EZ) - N- {(1 RS) - 2 - [(Ben Jiruokishi) Amino] - 1-methyl-2-Okisoechiru} one 6- {4- [(EZ) - 2- Shiano _ 1 Echiru] Hue sulfonyl} - to 5- Kisen'ami de 1. give 57 g.

1 H-NMR δ (CDC 1 3) 1. 20-1. 40 (m, To ta 13H), 1. 70- 1. 90 (m, 2H), 2. 05-2. 40 (m, 4H) , 4. 29 (m, 1 H), 4. 80-5. 00 (m, 2H), 5. 40, 5. 71, 5. 84, 6. 28, 6. 42, 7. 09, 7. 75 (m, Tot al 4 H, old olefin '14H), 5. 97 (m, 1 H), 7. 20-7. 48 (m, 9H), 9. 12 (m, 1 H) example 1 54

N- [2- (hydroxy § Mino) Single 1-methyl one 2- Okisoechiru] -9 (2-phenylalanine E chill amino) Nonanami de

Was synthesized from 0_ trimethyl silyl hydroxyl § Min and method similar in 2- {9 i (2-phenylene Ruechiru N- base Nji Ruo butoxycarbonylamino) Nonanoiruamino} propanoic acid described in Example 52 N- [2- (hydroxymethyl § amino) - 1 _ methyl - 2 Okisoechiru] - 9- (2-phenylene Ruechiru N- benzyl O alkoxycarbonyl § mino) Nonanami de (442 mg) was dissolved in methanol (20 m l) , 1 0% palladium carbon (200 mg) was added and stirred for 3 hours under a hydrogen atmosphere at normal temperature and normal pressure. The catalyst was removed by filtration, The solvent was distilled off under reduced pressure, the residue was suspended in diisopropyl port Pirue one ether, and dried under reduced pressure after removing the supernatant by decantation one Deployment N- [2- (hydroxy § amino) Single 1 one methyl one 2- Okisoechiru] - 9 - to give 34 1 mg of (2-phenylalanine E chill § mino) Nonanami de.

1 H-NMR δ (DMSO- d 6) 1. 00-1. 34 (m, 8H), 1. 15 (d, 3 H, J = 7. 3Hz), 1. 34- 1. 57 (m, 4H), 2. 08 (t, 2H, J = 7. 4H z), 2. 63 (t, 2H, J = 7. 3Hz), 2. 68-2. 91 (m, 4H), 4. 17 . (m, 1H), 7. 12-7 37 (m, 5H), 7. 95 (b rd, 1 H, J = 7. 6Hz) used as starting material 2- {9 - (2-Fueniruechiru one N- Benjiruokishi carbonyl § mino) Nonanoiruamino} propanoic acid was prepared as follows. (A) 9- (2- phenylpropyl E chill § amino) nonanoic acid t one-butyl

2-phenylpropyl E chill § Min a (7. 26 g) was dissolved in methanol (20 m l), it was added 4N- hydrochloric Jiokisan solution (5 m l). Methanol (1 0 m l) solution of 9-Okisononan acid t- butyl at room temperature (2. 2 8 g), Shiano water sodium borohydride is subsequently (6 2 8 m g) was added and stirred for 3 days. The reaction mixture was added a black hole Holm and ice water was extracted and subjected to liquid separation to, and twice extracted and subjected to liquid separation by further black port Holm aqueous layer. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue by silica gel column chromatography (stationary phase: silica gel 60, 70-2 30 mesh, 1 20 g, mobile phase: black port Holm methanol) Purification it allows 9- (2-phenylene Ruechiruamino) t-butyl nonanoic acid 2. give 05 g of.

1 H -. NMR δ (CDC 1 3) 1. 1 -1 64 (m, 12H), 1. 44 (s, 9 H), 2. 19 (t, 2H, J = 7. 4Hz), 2. 60 (t, 2H, J = 7. 3Hz), 2. 7 4-2. 93 (m, 4H), 7. 13- 7. 37 (m, 5H)

(B) 9 - (2- Fueniruechiru one N- benzyl O alkoxycarbonyl § amino) nonanoic acid t one-butyl

Black hole formate base Njiru (1.2 3 1 g) dry black port Holm (2 5 m l) solution was ice-cooled, and 9 i (2-phenylpropyl E chill § amino) nonanoic acid t one-butyl (1.7 1 the dried click port opening Holm (1 0 m l) solution of drying chloroform (2 5 m l) solution and Toryechiruamin (1. 04 g) was successively added dropwise in g), and stirred for 1 hour. Ice water was added, extracted - were separated, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, was distilled off under reduced pressure Solvent, the residue was purified by silica gel column chromatography (stationary phase: silica gel 60, 70-2 30 mesh, 6 5 g, mobile phase: to Kisan'no acetate Echiru) give by the 9 i (2 Fueniruechiru -N- base Nji Ruo propoxycarbonyl Niruamino) nonanoic acid t one-butyl 2 to give 34 g.

1 H-NMR δ (CDC 1 3) 1. 10-1. 63 (m, 12H), 1. 44 (s, 9 H), 2. 19 (t, 2H, J = 7. 6Hz), 2. 71-2. 94 (m, 2H), 3. 06- 3. 26 (m, 2H), 3. 35- 3. 52 (m, 2H), 5. 11 (b rs, 1 H), 5. 1 (b rs, 1H), 7. 02-7. 47 (m, 1 OH)

(C) 9 - (2- phenylene Ruechiru N- benzyl O alkoxycarbonyl § mino) nonane

9 - (2-Fueniruechiru - N- benzyl O butoxycarbonylamino) nonanoic acid t one butyl (2. 34 g) was dissolved under ice-cooling Torifuruoro acetate (5 m 1), the temperature was gradually raised to room temperature, 30 minutes and the mixture was stirred. By concentration under reduced pressure, the 9- (2 _ full Eniruechiru -N- base Nji Ruo alkoxycarbonyl § amino) nonanoic acid 2. give 24 g. This compound was used in the next reaction without further purification.

(D) 2 - {9 - (2- phenylene Ruechiru N- benzyl O alkoxycarbonyl § mino) Nonanoiruamino} propanoic acid t- butyl

And a method described in Example 52 in a similar manner 9- (2-phenylene Ruechiru N- Baie Nji Ruo alkoxycarbonyl § amino) nonanoic acid and (823 mg) 2-Aminopuropan acid t- butyl (3 1 9 mg) 2- {9 - (2-Fueniruechiru - N- benzyl O alkoxycarbonyl § mino) Nonanoiruamino} propanoic acid t one-butyl give 0. 89 g.

1 H-NMR δ (CDC 1 3) 1. 07-1. 71 (m, 12H), 1. 36 (d, 3H, J = 7. 3Hz), 1. 46 (s, 9H), 2. 18 (t, 2H, J = 7. 6Hz), 2. 72 - 2. 95 (m, 2H), 3. 05- 3. 27 (m, 2H), 3. 35- 3. 52 (m, 2H) , 4. 47 (m, 1 H), 5. 10 (b rs, 1H), 5. 14 (br- s, 1H), 6. 02 (b rs, 1H), 7. 03-7. 47 ( m, 1 OH)

(E) 2- {9 - (2- phenylene Ruechiru N- benzyl O alkoxycarbonyl § mino) Nonanoiruamino} propanoic acid

Of this example (C) 2 in a manner similar to that described in step {9 i (2-phenylene Ruechiru N- benzyl O alkoxycarbonyl § mino) Nonanoiruamino} propanoic acid t- butyl (0. 89 g) from 2- {9 - (2-phenylene Ruechiru N- benzyl O alkoxycarbonyl § mino) Nonanoiruamino} propanoic acid was obtained 0. 82 g. Example 1 55

N - [2 - (hydroxymethyl § Mino) Single 1-methyl one 2- Okisoechiru] -4 one (5 - phenylpropyl Rua mino) Butanami de

Example 52 the method and in a similar manner 2- {4 one described in (5 phenylene

-N- benzyl O alkoxycarbonyl § mino) Butanoiruamino} was synthesized from propanoic acid and 0- t over butyldimethylsilyl hydroxyl § Min N- [2- (hydroxymethyl Shiamino) one 1-methyl-2-Okisoechiru] one 4 one (5 phenylene Rupenchiru - N- benzyl O alkoxycarbonyl § mino) using Butanami de a (366 mg), in a manner similar to that described in example 1 54 N- [2 - (hydroxymethyl § amino) Single 1 over methylation one 2-Okisoechiru] one 4 one (5 phenylene Rupenchiruamino) Butanami de afford 2 48 mg.

1 H-NMR δ (DM S O- d 6) 1. 10-1. 70 (m, 8H), 1. 17 (d, 3 H, J = 7. 3Hz), 2. 14 (t, 2H, J = 7. 3Hz), 2. 43-2. ​​61 (m, 6 H), 4. 19 (m, 1H), 7. 11-7. 31 (m, 5H), 8. 00 (br- d , 1 H, J = 7. 9Hz) 2- was used as the starting material {4- (5-phenylalanine pliers Lou N- Benjiruoki aryloxycarbonyl § mino) Butanoiruamino} propanoic acid was prepared as follows. (A) 4- (5- phenylene Rupenchiru - N- benzyl O alkoxycarbonyl § mino) pigs phosphate

1 - (5-phenylene Rupenchiru) pyrrolidin - 2-one (2. 3 1 g) and construed dissolved sodium hydroxide (600 mg) in Echirendariko Ichiru (6 m l) and water (2m l), heated 22 hours and reflux. After cooling to room temperature, it was added to the reaction solution 5N- sodium hydroxide aqueous solution (2m l). Further added oxygenate chill ether and water, extracted - the separated aqueous layer was cooled with ice. To this was added Jechirue one ether (50 m l), with vigorous stirring black port formate base Njiru (1. 7 1 g) Jefferies chill ether (1 2m of

1) solution was added dropwise. After stirring for 2 hours at ice-cooling 5 N-aqueous sodium hydroxide (2m l) was added, further Jechirue one ether and water were added, extraction 'liquid separation was. Again GETS chill ether was added to the aqueous layer, the extraction and liquid separation aqueous layer was cooled with ice. This was adjusted to acidic with concentrated hydrochloric acid and extracted with acetic acid Echiru. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure 4 one (5 phenylene Rupenchiru - N- base Nji Ruo butoxycarbonylamino) butanoic acid 84

1 to obtain mg.

1 H-NMR δ (CDC 1 3) 1. 17-1. 40 (m, 2H), 1. 4-1. 72 (m, 4Η), 1. 74-1. 94 (m, 2Η), 2 . 23-2. 44 (m, 2H), 2. 48- 2. 67 (m, 2H), 3. 12-3. 37 (m, 4Η), 5. 12 (s, 2Η), 7. 10 -7. 4 0 (m, 1 OH)

(B) 2- {4- (5- phenylalanine pliers Lou N- base Nji Ruo alkoxycarbonyl amino) Butanoiruamino} propanoic acid t one-butyl

Example 52 4 one by a method analogous to that described in (5 phenylene Rupenchiru _N_ benzyl O alkoxycarbonyl § mino) 2- {4 butanoic acid (825 mg) - (5 - phenylene Rupenchiru one N- Benjiruo alkoxycarbonyl § mino) Butanoiruamino} to give 922 mg of the flop port pan acid t- butyl.

1 H-NMR δ (CDC 1 3) 1. 17-1. 71 (m, 9H), 1. 6 (s, 9Η), 1. 76-1. 92 (m, 2Η), 2. 06- 2 . 25 (m, 2H), 2. 48-2. 65 (m, 2H), 3. 13-3. 43 (m, 4H), 4. 35- 4. 51 (m, 1 H), 5. 12 (s, 2 H), 7. 09-7. 39 (m, 1 OH)

(C) 2 - {4 - (5- phenylalanine pliers Lou N- benzyl O alkoxycarbonyl amino) Butanoiruamino) propanoic acid

Example 1 54 (C) an analogous manner to that described in section 2 {4 one (5 Hue Nirupenchiru N- benzyl O butoxycarbonylamino) Butanoiruamino} propane acid t 2 from a butyl (9 14 mg) - the {4- (5-phenylalanine pliers Lou N- Baie Nji Ruo alkoxycarbonyl § mino) Butanoiruamino} propanoic acid was obtained 8 1 Omg. Example 1 56

N- [2- (hydroxyamino) _ 1-methyl-2-Okisoechiru, - 9 - (N one Fueniruamino) Nonanami de

In an analogous manner to that described in Example 52 2- {9- (N- t- Butokishikaru Boniru one N- Fueniruamino) Nonanoiruamino} was synthesized from propanoic acid and 0- t one Puchiruji methyl silyl hydroxyl § Min N- [ 2- (hydroxy § Mino) _ 1-methyl - 2-Okisoechiru] - 9 was dissolved scratch (N- t-butoxycarbonyl two Lou N- Fueniruamino) Nonanami de (8 1 Omg) in Asetonitoriru (1 5 m l), Asetonitoriru under ice-cooling methanesulfonic acid (1 53 mg) and (3m l) was added dropwise. After stirring for 1 hour then warmed to room temperature, or by the addition of acetic acid Echiru and ice water et the reaction solution was neutralized with saturated aqueous sodium bicarbonate. It was extracted two more times and the aqueous layer at extraction and liquid separation after acetic Echiru. The organic layers were brine washed, dried over anhydrous magnesium sulfate, removing the desiccant by filtration, the solvent was distilled off under reduced pressure, residue was purified by silica gel thin-layer black Mato chromatography (mobile phase: chloroform methanol Ichiru two 1 5 / by the purified child in 1), N-a [2- (hydroxymethyl § amino) one 1-methyl-2-Okisoechi le] one 9 one (N- Fueniruamino) Nonanami de give 8 Omg.

1 H-NMR δ (CD .OD) 1. 25-1. 67 (m, 12H), 1. 32 (d, 3H, J = 7. 3Hz), 2. 21 (t, 2H, J = 7. 6Hz), 3. 06 (t, 2H, J = 7. 1 Hz), 4. 28 (q, 1H, J = 7. OHz), 6. 56- 6. 68 (m, 3H), 7. 05 - 7. 15 (m, 2H) 2- {9- (N- t one butoxycarbonyl two Lou N- phenylene Ruamino) Nonanoiruamino} propanoic acid used as starting material was prepared as follows.

(A) 9- (N- t- butoxycarbonyl two Lou N- Fueniruamino) Echiru nonanoic acid

N-t-butoxycarbonyl two Ruanirin (734 mg) and 9-® one Dononan Sane chill the (1. 1 86 g) was dissolved in dry tetrahydrofuran (8m l), under ice-cooling 6 0% sodium hydride (1 52m g) was added. Further drying N, N-Jimechiruho ​​Rumuami added de the (8m l), and reacted overnight at the same temperature. The reaction was quenched by the addition of dilute After ice water Jechirue ether. And extracted 'fraction was further added acetic acid Echiru. The organic layer was washed with water washing (4 times), brine washed, dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography grayed Rafi one (stationary phase: silica gel 6 0, 7 0 2 3 0 mesh, 7 0 g, mobile phase: hexane / acetic acid Echiru purification by), 9 one (N- t -. the Butokishikaru Boniru N- Fueniruamino) Echiru nonanoic acid 1 3 0 were obtained g.

1 H -NMR 8 (CDC 1 3 ) 0. 97- 1. 68 (m, 1 5H), 1. 42 (s, 9 H), 2. 27 (t, 2H, J = 7. 6Hz), 3 . 60 (t, 2H, J = 7. 4Hz), 4. 1 2 (q, 2H, J = 7. 2Hz), 7. 1 3- 7. 38 (m, 5H)

(B) 9 - (N- t one butoxycarbonyl one N- Fueniruamino) nonanoic acid

9 one (N-t-butoxycarbonyl - N- Fueniruamino) nonanoic acid Echiru the (1. 3 0 g) was dissolved in 9 9.5% ethanol (3 0 ml), 1 N sodium hydroxide aqueous solution at room temperature ( 3. 5 ml) was added dropwise. After reacting at the same temperature overnight, the solvent was distilled off under reduced pressure. The residue was dissolved in black port Holm, by adjusting the p H 3-4 and extracted-liquid separation from using Kuen acid aqueous solution, black hole Holm layer brine washed, dried over anhydrous sulfate Maguneshiu beam. The desiccant was filtered off, the solvent was distilled off under reduced pressure 9 one (N _ t-butoxy Shikarubo two Lou N- Fueniruamino) nonanoic acid was obtained 1. 1 7 8 g.

1 H-NMR 8 (CDC 1 3) 1. 1 2- 1. 68 (m, 1 2H), 1. 2 (s, 9 H), 2. 33 (t, 2H, J = 7. 6Hz), 3. 60 (t, 2H, J = 7. 6Hz), 7. 1 3-7. 23 (m, 3H), 7. 28- 7. 47 (m, 2H)

(C) 2- {9 - (N- t - butoxycarbonyl two Lou N- Fueniruamino) Nonanoi Ruamino} propanoate

Example 1 (B) 9-in a manner similar to that described in section (N- t one Butokishika Ruboniru N- Fueniruamino) nonanoic acid (1. 1 6 g) and DL- Araninmechiru ester hydrochloride (509 mg) from 2- {9 one (N-t one butoxycarbonyl - N- Fueniruamino) Nonanoiruamino} methyl propanoate 1. give 30 g.

(D) 2 - {9 one (N- t-butoxycarbonyl two Lou N- Fueniruamino) Nonanoi arylamino} propanoic acid

From - {(N- t one-but Kishikarubo two Lou N- Fueniruamino) Nonanoiruamino 9} propanoate (1. 26 g) 2- {of this embodiment (B) in a manner similar to that described in paragraph 2 9 - (N- t-butoxycarbonyl two Lou N- Fueniruamino) the Bruno Nanoiruamino} propanoic acid 1. give 274 g. Example 1 57

N - [2 two (hydroxymethyl § Mino) one 1-methyl-2-Okisoechiru] - 9 one (N - Kishiruamino cyclohexylene) Nonanami de

N synthesized from methods and in a similar manner 2-{9-(N- cycloheteroalkyl Kishiru N- base Nji Ruo butoxycarbonylamino) Nonanoiruamino} 0_ propanoic acid t- heptyl butyldimethylsilyl hydroxyl § Min described in Example 52 - to - [2 (hydroxymethyl amino) _ 1 one methyl one 2- Okisoechiru] one 9 one (N- cyclohexyl one N- benzyl O butoxycarbonylamino) Nonanami de (1 67 mg) in methanol (1 0 ml) dissolved, 1 0% palladium / carbon (80 mg) was added, followed by stirring for 3 hours and 20 minutes under a hydrogen atmosphere at normal temperature and normal pressure. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and repulped purified filtration and washing after vacuum drying the residue at Jie isopropyl ether N- [2 - (hydroxymethyl § amino) _ 1-methyl-2- Okisoechiru] - 9- (N- cyclo to Kishiruamino) Nonanami de were obtained 97 mg.

1 H-NMR δ (CD 3 OD) 1. 01- 2. 03 (m, 22H), 1. 35 (d, 3Η, J = 7. 3Hz), 2. 23 (t, 2 H, J = 7 . 6Hz), 2. 48-2. 64 (m, 1 H), 2. 68 (t, 2H, J = 7. 6Hz), 4. 35 (q, 1 H, J = 7. 1Hz) starting material was prepared in 2-{9-(N- cyclohexyl one N- Benjiruokishi carbonyl § mino) Nonanoiruamino} propanoic acid method analogous to that described in (a) ~ (E) of example 1 54 was used as a . Example 1 58

(2 S) one N- hydroxy one 3- {[3 - (4-propyl-phenylalanine) Puropanoi le] amino} one 2- {[(3-Futaruimi de) Puropanoiru] amino} Puropana ^ de

(2 S)-N-Benjiruokishi 3- {[3- (4-propyl-phenylalanine) _ 2 - propenyl Noiru] amino} - 2- {[(3-Futaruimi de) Puropanoiru] amino} Puropanami de (1 2. 96 g) in methanol (1 50 m l), tetrahydro-furan (1 5 Om 1), was dissolved in acetic acid (1 5 Om 1), 1 0% - palladium / carbon containing U 3 g) was added, a hydrogen atmosphere and the mixture was stirred for 6 hours under. The catalyst filtered in. Except, the Solvent was evaporated under reduced pressure. The residue HP LC (column: YMC- OD S (R- 3 5 5 - 2

0) 5. 0 cmX 50 cm; solvent: (A solution) 0. 1% TFA / H 2 0 (B solution) 0. 1% TF A / CH 3 CN; Gradient: (B%: 20 → 40 % (60 minutes) - 5

5% (1 80 min); flow rate: 1 4m 1 Z min; detection: the desired compound 2. give 1 2 g in a child purified by UV 22 0 nm).

1 H-NMR 8 (DM S 0- d 6) 0. 85 (t, 3H, J = 7Hz), 1. 53 (m, 2H), 2. 30 (m, 2H), 2. 49 (m, H), 2. 72 (m, 2H), 3. 42-3. 15 (m, 2H), 3. 76 (dd, 2H, J = 7Hz), 4. 23 (m, 1 H), 7. 06 (s, 4H), 7. 82 (m, 5H), 8. 1 1 (d, 1 H, J = 8. 22Hz), 8. 86 (s, 1 H), 10. 67 (s, 1H ) was used as the starting material (2 S) - N-Benjiruokishi 3- {[3 - (4-flops port Pirufueniru) one 2-propenyl Noiru] amino} - 2- {[(3-Futaruimi de) Puropanoiru] amino } Puropanami de was prepared as follows.

(2 S) Single N- Benjiruokishi 3- {[3 - (4 one propyl phenylpropyl) Single 2- profile Bae Noiru] amino} one 2- [(benzyl O butoxycarbonyl) Amino] Puropana Mi de,

(2 S) one N- Benjiruokishi - 2- [(benzyl O butoxycarbonyl) Amino - construed dissolved 3- Aminopuropanami de hydrochloride (1 5. 1 9 g) in DMF (1 00m l), Toryechiruamin (4. 2 5 g), (E) - 3 - (4 one Puropirufue two Le) - 2-propenoic acid (7. 99 g), HO B t / H 2 0 (6, 43 g), WS C / HC 1 ( 8. 05 g) overnight by the addition of the mixture was stirred. The solvent was distilled off under reduced pressure, diluted with acetic acid E Ji Le, the organic layer 0. 5N hydrochloric acid, saturated aqueous sodium bicarbonate solution, washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off The solvent was distilled off under reduced pressure, by repulping purified Toruen the residue to obtain the desired product 22. 0 g.

] H- NMR δ (DMSO - d 6 ) 0. 87 (t, 3H, J = 7. 32Hz), 1. 57 (dd, 2H, J = 7. 5, 15. 0Hz), 2. 55 (t , 2H, J = 7Hz), 3. 41 one 3. 35 (m, 2H), 4. 04 (m, 1 H), 4. 76 (s, 2H), 5. 02 (s, 2H), 6 . 59 (d, 1H, J = l 5. 75Hz), 7. 51-7. 11 (m, 16H), 8. 20 (m, 1H), 11. 40 (br one s, 1 H)

(2 S)-N-Benjiruokishi - 3 _ {[3- (4-propyl-phenylalanine) Single 2- profile Bae Noiru] Amino) Single 2- Aminopuropanami de hydrobromide OBzl

(2 S) _N- Benjiruokishi 3- {[3- (4 one propyl phenylpropyl) one 2 - propenyl Noiru] amino} one 2- [(benzyl O butoxycarbonyl) Amino] Pro Panami de (22. 0 g) It was dissolved in 25% hydrogen bromide // acetic acid solution for 3 hours stirred at room temperature. The reaction solvent was distilled off under reduced pressure, by the repulped purified child residue is Jeffrey chill ether to obtain the desired product 1 3. 52 g.

1 H-NMR δ (DMSO- d 6) 0. 81 (t, 3H, J = 7Hz), 1. 51 (dd, 2H, J = 7. 37, 14. 82Hz), 2. 46 (m, 2H ), 3. 41 (m, 1 H), 3. 5 4 (m, 1H), 3. 66 (m, 1 H), 4. 77 (dd, 2H, J = l 1. 16, 21. 06H z), 6. 57 (d, 1H, J = l 5. 75Hz), 7. 43-7. 10 (m, 1 OH), 8. 3 6 (m, 3H), 11. 72 (br- s , 1H) (2 S) -N- Benjiruokishi - 3- {[3- (4 one-propyl-phenylalanine) - 2- profile Bae Noiru] amino) one 2- {[(3-Futaruimi de) Puropanoiru] amino} Puropanami de

(2 S) one N- Benjiruokishi 3- {[3- (4-propyl-phenylalanine) - 2 one propenyl Noiru] amino} one 2- Aminopuropanami de hydrobromide (3. 0 1 g) and DMF (20 m was dissolved in l), Bok triethylamine (0. 69 g), N- ( 2- mosquito Robo hexyl E chill) Futaruimi de (1. 50 g), HOB t / H 2 0 (1. 05 g), WSC / HC 1 overnight by the addition of (1. 3 1 g) and the mixture was stirred. The solvent was distilled off under reduced pressure, diluted with acetic acid Echiru, the organic layer 0. 5N hydrochloric acid, saturated aqueous sodium bicarbonate solution, washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, by repulping purified toluene the residue to obtain the desired compound 2. 60 g.

1 H-NMR δ (DMSO- d 6) 0. 87 (t, 3H, J = 7Hz), 1. 57 (dd, 2H, J = 7, 15Hz), 2. 52 (m, 4H), 3. 34 (m, 2H), 3. 79 (t, 2H, J = 7Hz), 4. 25 (m, 1 H), 4. 75 (dd, 2H, J = 11, 14Hz), 6. 57 (d , 1H, J = l 5. 75Hz), 7. 46- 7. 13 (m, 9H), 7. 86-7. 78 (m, 4H), 8. 09 (m, 1 H), 8. 29 (d, 1 H, J = 7. 86Hz), 11. 35 (s, 1 H)

CONHOH 1 H-NMR δ (DMS O- d 6) 0. 82 (t, 3H, J = 7Hz), 1. 52 (m, 2H), 2. 50-2. 47 (m, 4H), 3. 38- 3. 20 (m, 2H), 3. 70 (m, 2 H), 4. 25 (m, 1H), 6. 50 (d, 1 H, J = l 5. 90Hz), 7. 16 (d, 2H, J = 8. 07Hz), 7. 30 (d, 1 H, J = l 5. 75Hz), 7. 39 (d, 2H, J = 8. 25Hz), 7. 79-7. 73 (m, 4H), 8. 00 (m, 1 H), 8. 21 (m, 1 H), 8. 82 (s, 1H), 10. 64 (s, 1 H) example 1 59

1 H-NMR δ (DMS O- d 6) 0. 80 (t, 3H, J = 7Hz), 1. 47 (dd, 2H, J = 7. 32, 14. 82Hz), 2. 26 (m, 2H), 2. 44-2. 36 (m, 4 H), 2. 68 (m, 2H), 3. 39- 3. 07 (m, 2H), 3. 62 (t, 2H, J = 7H z), 4. 17 (m, 1H), 6. 37 (s, 2H), 6. 88 (m, 2H), 7. 01 (s, 4 H), 7. 34 (t, 1H, J = 7Hz), 7. 75 (m, 1 H), 8. 05 (d, 1 H, J = 8. 43Hz), 8. 80 (s, 1H), 10. 61 (s, 1 H) example 1 60

1 H-NMR δ (DMSO- d 6) 0. 80 (t, 3H, J = 7Hz), 1. 47 (dd, 2H, J = 7, 15Hz), 2. 26 (m, 2H), 2. 44-2. 34 (m, 4H), 2. 68 (m, 2H), 3. 13 (m, 1 H), 3. 31 (m, 1 H), 3. 62 (t, 2H, J = 7. 5H z), 4. 17 (m, 1H), 6. 39 (b rs, 2H), 6. 71 (JR, 1 H), 6. 84 (d, 1H, J = 1. 65Hz), 7. 01 (s, H), 7. 39 (d, 1 H, J = 8. 25Hz), 7. 75 (m, 1H), 8. 04 (d, 1 H, J = 8. 07Hz), 8. 81 (br - s, 1 H), 10. 61 (s, 1H) example 1 6 1

1 H-NMR δ (DMSO - d 6) 0. 80 (t, 3H, J = 7. 32Hz), 1. 53 (m, 2H), 2. 31 (m, 2H), 2. 44 (m, 4H), 2. 73 (m, 2H), 3. 34 - 3. 16 (m, 2H), 3. 70 (t, 2H, J = 7Hz), 4. 23 (m, 1 H), 7. 06 (s, 4H), 7. 20 (m, 2H), 7. 56 (t, 1 H, J = 7. 68Hz), 7. 80 (m, 1H), 8. 12 (d, 1H, J = 8. 25Hz), 10. 67 (s, 1 H) example 1 62

1 H-NMR 8 (DMSO- d 6) 0. 80 (t, 3H, J = 7Hz), 1. 47 (m, 2H), 2. 25 (m, 2H), 2. 43 (m, 4H) , 2. 67 (m, 2H), 3. 12 (m, 1H), 3. 31 (m, 1H), 3. 66 (t, 2H, J = 7. 32Hz), 4. 17 (m, 1 H), 7. 06-7. 01 (m, 6H), 7. 60 (d, 1 H, J = 8. 04Hz), 7. 74 (m, 1H), 8. 05 (d, 1 H, J = 8. 07Hz), 8. 80 (s, 1 H), 10. 61 (s, 1H), 10. 88 (b rs, 1 H) example 1 63

1 H-NMR δ (DMS Ο- d 6) 0. 80 (t, 3Η, J = 7. 32Hz), 1. 47 (dd, 2H, J = 7, 15Hz), 2. 24 (m, 2H) , 2. 44-2. 39 (m, 7H), 2.

67 (m, 2H), 3. 12 (m, 1 H), 3. 33 (m, 1 H), 3. 69 (t, 2H, J = 7 Hz), 4. 17 (dd, 1H, J = 8, 13Hz), 7. 01 (s, 4H), 7. 54 (d, 1 H, J = 7. 71Hz), 7. 61 (s, 1 H), 7. 66 (d, 1 H, J = 7. 5Hz), 7.

74 (m, 1H), 8. 05 (d, 1 H, J = 8. 43Hz), 8. 81 (s, 1 H), 10. 6 2 (s, 1H) Example 1 64

1 H-NMR δ (DMSO- d 6) 0. 93 (t, 3H, J = 7. 14Hz), 1. 40

- 1. 35 (m, 4H), 1. 75- 1. 57 (m, 6H), 2. 42 (m, 2H), 2. 52

(M, 4H), 2. 81 (m, 2H), 2. 95 (br-s, 2H), 3. 24 (m, 1 H), 3.

41 (m, 1H), 3. 63 (t, 2H, J = 7. 14Hz), 4. 29 (m, 1 H), 7. 17

(S, 4H), 7. 86 (m, 1 H), 8. 16 (d, 1 H, J = 7. 86Hz), 8. 93 (brs, 1H), 10. 72 (s, 1H) carried example 1 65

1 H-NMR δ (DMS O- d 6) 0. 79 (t, 3H, J = 7Hz) 1. 47 (dd, 2H, J = 7, 15Hz), 2. 25 (m, 2H), 2. 44 (m, 2H), 2. 59 (m, 2 H), 2. 67 (m, 2H), 3. 1 1 (m, 1 H), 3. 32 (m, 1 H), 3. 86 (m, 2 H), 4. 21 (m, 1H), 7. 00 (s, 4H), 7. 77 (m, 1H), 8. 05-7. 9 0 (m, 3H), 8. 14 (d, 1 H, J = 8. 04Hz), 8. 23 (d, 1 H, J = 7. 5H z), 8. 81 (s, 1H), 10. 63 (s, 1 H) carried example 1 66

1 H-NMR 8 (DMS O- d 6) 0. 85 (t, 3H, J = 7Hz), 1. 52 (dd, 2H, J = 7, 15Hz), 2. 30 (m, 2H), 2 . 56- 2. 44 (m, 4H), 2. 72 (m, 2H), 3. 52-3. 15 (m, 2H), 3. 71 (m, 2H), 4. 22 (m, 1 H),

7. 06 (s, 4H), 7. 18 (m, 2H), 7. 56 (m, 1 H), 7. 79 (m, 1 H),

8. 09 (d, 1 H, J = 7. 68Hz), 8. 85 (b rs, 1 H), 10. 66 (s, 1 H) Example 1 67

1 H-NMR δ (DMS O- d 6) 0. 80 (t, 3H, J = 7Hz), 1. 48 (dd, 2H, J = 7, 15Hz), 2. 24 (m, 2H), 2 . 40 (m, 4H), 2. 67 (m, 2 H), 3. 39-3. 10 (m, 2H), 3. 73 (t, 2H, J = 7Hz), 4. 17 (m, 1 H), 7. 00 (s, 4H), 7. 59 (m, 1 H), 7. 68 (dd, 1 H, J = 2. 19, 7. 32Hz), 7. 75 (m, 1 H), 7. 85 (dd, 1 H, J = 4. 5, 8. 2Hz), 8. 0 6 (d, 1H, J = 8. 04Hz), 8. 80 (s, 1 H), 10 . 61 (s, 1 H) example 1 68

1 H-NMR δ (DMS O- d 6) 0. 80 (t, 3H, J = 7. 32Hz), 1. 48 (m, 2H), 2. 45 (m, 2H), 2. 44 (m , 4H), 2. 67 (m, 2H), 3. 10 (m, 1H), 3. 30 (m, 1 H), 3. 71 (t, 2H, J = 7Hz), 4. 17 (m , 1 H), 7. 02 (d, 4H, J = 8. 43Hz), 7. 77 (m, 5H), 8. 06 (d, 1 H, J = 8. 04Hz), 8. 80 (s , 1H), 10. 61 (s, 1 H) example 1 69

1 H-NMR δ. (DMSO - d 6) 0. 93 (t, 3H, J = 7Hz), 1. 41-1 33 (m, 4H), 1. 76- 1. 55 (m, 6H), 2. 42 (m, 2H), 2. 56 (m, 4 H), 2. 81 (m, 2H), 2. 95 (b rs, 2H), 3. 25 (m, 1 H), 3. 42 (m, 1H), 3. 63 (t, 2H, J = 7Hz), 4. 29 (m, 1 H), 7. 14 (s, 4H), 7. 80 (m, 1H), 8. 15 (d, 1 H, J = 8. 04Hz), 8. 92 (s, 1 H), 10. 72 (s, 1H) example 1 70

(2 S) _N- hydroxy-3 {gamma 3 - (4 one propyl phenylpropyl) Single 2- Purobe Noiru] amino} - 2 {[(3-Futaruimi de) Puropanoiru] amino} prop-cyanamide

(2 S) - Nyu- Benjiruokishi - 3 _ {[3- (4-propyl-phenylalanine) one 2 - propenyl Noiru] amino} one 2- {[(3-Futaruimi de) Puropanoiru] amino} Puropanami de ( the 1 0 1. 8 mg) was dissolved in dichloromethane (1 0m l), 1M boron tribromide in dichloromethane solution (530 mu 1) is added, and overnight stirred at room temperature. After completion of the reaction, by adding water and extracted with black port Holm, and the organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure and the residue was purified by HPLC (Column: N acalai T esque -CO SMO SIL (5 C 1 8 - AR) 2. 8 cmX 25 cm; solvent: (A solution) 0. 1% TFA, H 2 0 (B solution) 0. 1% TF A / CH 3 CN; gradient: (B%: 20 → 40 % (60 min) → 55% (1 80 min); flow rate: . 7m 1 min; detection: UV220 nm) desired product purified by to give 30. Omg 1 H-NMR δ ( DMSO - d 6) 0. 82 (t, 3H, J = 7Hz), 1. 52 (m, 2H), 2. 50-2. 47 (m, 4H), 3. 38- 3. 20 (m, 2H), 3. 70 (m, 2 H), 4. 25 (m, 1H) , 6. 50 (d, 1 H, J = l 5. 90Hz), 7. 16 (d, 2H, J = 8. 07Hz), 7. 30 (d, 1 H, J = 15. 75Hz), 7 . 39 (d, 2H, J = 8. 25Hz), 7. 79-7. 73 (m, 4H), 8. 00 (m, 1 H), 8. 21 (m, 1 H), 8. 82 (s, 1H), 10. 64 (s, 1 H)

Used as starting material (2 S) - N-Benjiruokishi 3- {[3- (4-flops port Pirufueniru) one 2-propenyl Noiru] amino} - 2- {[(3-Futaruimi de) Puropanoiru] amino} Puropanami de was prepared in a way described in Section II of example 1 5 8. The following compounds were prepared by a method similar to Example 1 70.

Example 1 7 1

1 H-NMR δ. (DMSO - d 6) 0. 80 (t, 3H, J = 7Hz), 1. 47 (m, 2H), 2. 24 (m, 2H), 2. 44-2 40 ( m, 4H), 2. 66 (t, 2H, J = 7 Hz), 3. 37- 3. 10 (m, 2H), 3. 71 (t, 2H, J = 7Hz), 4. 19 (m , 1H), 7. 01 (s, 4H), 7. 76 (m, 1 H), 7. 79 (m, 1 H), 8. 09-8. 07 (m, 2H), 8. 20 ( d, 1 H, J = 8. 04Hz), 8. 80 (s, 1 H), 10. 6 2 (s, 1H) example 1 Ί 2

1 H-NMR 8 (DMSO- d 6) 0. 80 (t, 3H, J = 7Hz), 1. 47 (dd, 2H, J = 7, 15Hz), 2. 23 (m, 2H), 2. 39 (m, 4H), 2. 65 (m, 2 H), 3. 35-3. 10 (m, 2H), 3. 76 (m, 2H), 4. 17 (dd, 1 H, J = 8, 14Hz), 7. 00 (s, 4H), 7. 74 (m, 1 H), 8. 08- 8. 02 (m, 2H), 8. 41 (d, 1 bets I, J = 1 . 83Hz), 8. 53 (dd, 1 H, J = 1. 4, 8Hz), 8. 79 (s, 1H), 10. 61 (s, 1 H) example 1 73

1 H-NMR δ (DMSO- d 6) 0. 80 (dd, 3H, J = 6, 7Hz), 1. 48 (m, 2H), 2. 24 (m, 2H), 2. 43 (m, 4H), 2. 67 (m, 2H), 3. 10 (m, 1H), 3. 32 (m, 1 H), 3. 75 (t, 2H, J = 7Hz), 4. 18 (m, 1 H), 7. 01 (d, 4H, J = l. 29Hz), 7. 74-7. 67 (m, 2H), 8. 07 (d, 1 H, J = 7. 86Hz), 8. 20 (d, 1 H, J = 7. 53Hz), 8. 80 (b rs, 1 H), 8. 88 (d, 1H, J = 4. 95Hz), 10. 62 (s, 1 H) formula pharmacological action of one of the hydroxamic acid derivative or a pharmaceutically acceptable salt thereof can be confirmed as follows. Test Example 1

Inhibitory activity against MMP- 3

MM P _ 3 are known human MM P- 3 gene nucleotide sequence (Nature, 348, 699- 704 (1990)) based on, genetic engineering was prepared 4- Aminofue sulfonyl mercuric acetate the presence of 1 mM used was activated by holding 1 6 hours at 37 ° C.

Measurement of inhibitory activity against human MMP- 3 is, CGKnight et al's method (FEBS Lett., 296 (3), 263-266 (1992)) was carried out in accordance with.

That is, the thickness Si buffer fluorometric 96-well microplate in 45 β 1 - (0. 1M Tris-HCl, 0. 1M NaCl, 0. 0 1M calcium chloride, 0.05% Brij one 35, [rho Eta = 7 . 5) placed, added dimethylcarbamoyl Rusuruhokishido solution of 5 1 of the test compound, 2 5 mu 1-activated human Myumyuro- 3 and 1 mM of (7-menu Tokishikumarin - 4-I le) Asechiru L- prolyl one L bite Ishirugu Rishiru L- mouth Ishiru L one [N- (2, 4 over-di-nitrophenyl) _L_ 2, 3 over di § amino propionylamino] _ L one Araniru L one arginine amino-de (MCA) (peptide studies substrate solution in dimethyl sulfoxide solution was diluted with mediation Si buffer scratch 80 in addition 25 beta 1 of Tokoro, Ltd.) was measured with a fluorescence plate reader one fluorescent (e X. 320 nm, the em. 405 nm). After reacting and held 2 hours at 37 ° C, and measuring the fluorescence in a fluorescence plate reader and foremost, to measure the enzymatic activity remaining. Test Example 2

Inhibitory activity against MMP- 1

MMP- 1 were used active type I Collagenase one peptidase commercially available (Yagai made one Cosmo Bio).

Inhibitory activity against MMP- 1 is Nagai et al report (inflammation, 4 (2), 123-130 (1984)) Oh Rui CGKnight's method (FEBS Lett., 296 (3), 263-266 (1992) ) line in accordance with ivy.

That is, 1 0 dimethylsulfoxide solution of mu 1 of test compound is added to the enzyme solution 90 1, to which 1 00 mu 1 of FI TC labeled collagen solution (0. 1 M- tri scan hydrochloride, 0. 4 .mu. chloride eq 0. 0 1 M- acetate solution - sodium, 1 0 mm- calcium chloride, 0.04% - sodium azide, p H = 7. buffer solution 5 and 0. 1% - FI TC labeled collagen mixed to prepare) was added, 3 5 ° 4 hours ink Interview base and one Bok in C, 1 0 was gently stirred with mu 1 of 80 mm- o-phenanthroline solution, 500 mu 1 70% - Etano one Roux 30% - 0.1 by addition of 1 7M tris one 0. 67 .mu. calcium chloride aqueous solution was vigorously shaken, 3000 r centrifuged for 1 0 minutes pm, re the supernatant and the 500 1, fluorescence (e x. 495 nm, em. 52 0 nm) by measuring to measure the residual enzyme activity.

Alternatively, the thickness Si buffer 60 mu 1 of a 96-well microplate Ichito for fluorescence measurement - (0. 1M Tris-HCl, 0. 1 M sodium chloride, 0. 0 1 M calcium chloride, 0.05% Brij one 35, ρ Η = 7. 5) placed, dimethylol Rusuruhokishido solution of the test compound of 5 mu 1 addition, 1 0 mu 1 of enzyme solution and 1 mM of (7-main Tokishikumari down - 4-I le) Asechiru - L- prolyl - L- leucyl - Gurishiru L bite Issy Le one L- [N- (2, 4- dinitrophenyl) one L- 2, 3- Jiaminopuropio sulfonyl] one L- Araniru L one arginine amino-de (MCA) (peptide dimethyl sulfoxide solution based electrolyte solution 80 is diluted to a thickness Si buffer scratch added 25 mu 1 of Research Laboratory), fluorescent in a fluorescent plate reader one (e X. 320 nm, the e m. 405 nm) It was measured. After reacting and held for 24 hours at 37 ° C, and measuring the fluorescence with a fluorescent Plate reader one was assaying the residual activities. Test Example 3

Inhibitory activity against MMP- 1 3

MMP- 1 3 known human MMP - 1 3 gene nucleotide sequence (.. J. Biol Chem, 269 (24), 16766-16773 (1994)) based on genetic engineering (human chondrocyte cDNA library to scratch the material, primer 5 '- AATAAGCTTCCACCATGCATCCAGGGGTCCTGGC-3', amplified by PCR using a 5 '-CCGCTCGAGTTACCCCAAATGCTCTTCAGG-3', was inserted into the vector one pcDNAI, introduced into Afurikami Dorizaru kidney-derived COS- 1 cells, the culture supernatant prepared recovered), 4 Aminofueniru mercuric acetate the presence of I mM, used was activated by holding 2 hours at 37 ° C.

Measurement of inhibitory activity against human MMP- 1 3 is, CG Knight et al method (FEBS Lett., 296 (3), 263-266 (1992)) was carried out in accordance with.

That is, the thickness Si buffer 4 5 1 9 6-well microplate for fluorescence measurement - (0. 1 M Tris-HCl, 0. 1 M sodium chloride, 0.0 1 M calcium chloride, 0.0 5% Brij one 3 5, ρ Η = 7. 5) placed, dimethylol Rusuruhokishido was added and 5 mu 1 of the test compound, 2 5 mu 1 of activated already human ΜΜΡ- 1 3 and of 1 mM (7- main Tokishikumarin 4_ I le) Asechiru one L one-prolyl one L- mouth Isil - grayed Rishiru L- leucyl - L- [N- (2, 4- dinitrophenyl)-L-2, 3 over di § amino-propionyl] - L- Araniru one L - arginine Ami de (MCA) substrate solution was 80 2 5 mu 1 by adding diluted dimethyl sulfoxide solution (peptide Laboratory Ltd.) with a thickness Si buffer one, a fluorescence plate reader one fluorescent (e X. 3 20 nm, were measured em. 40 5 nm). After reaction and held for 12 hours at 37 ° C, and measuring the fluorescence in a fluorescence plate reader and foremost, to measure the enzymatic activity remaining.

The measurement results of the enzyme inhibitory activity expressed as follows.

RXBN (R 1) -A-CO -NHOH

1

MMP-3 MP-1 Example

10 (- (C) 6 - 0.24> 100

13 (- (CH 2) "0.085> 100

B - CO NR 1 - A- CO- = - D- G 1 u MMP-3 MMP-1 actual删X Kenkatsu I "raw醺活property

H

C one N- (CH 2) 7 -

20 II 0.94 3.5 o

88

87

86

OMe

33 0.24> 100

One (CH 2) 6 people CH 2 - 0,

43, (CH 2 2) of 8-0.31 3.31

R = phenyl; B = - CONR 1 - A- CO- = - DG 1 u Table 3

MMP-3 MMP-1 anonymous - 13 Example R - NR A- CO- inhibitory activity inhibitory activity inhibitory activity

ICso / ^ M ICso / μ ICso / M

79 (CH 2) D-Glu 0.004 2.3 0.004

80 - (CH 2) 9 - D-Lys 0.013 5.9 0.013

45 - (CH 2) 9 - D-Glu 0.05 18 0.062

60 (CH 2) 8 - DL -Ala 0.11 45 0.10

78 (CH 2) 9 - D -Lys 0.05 26 0.12

81 NC- - (C¾) 9 - D-Glu 0.025 32 0.14 (CH 2) 9 - D-Glu 0.043> 100 0.65

12 O- - (CH 2) 10- D-Glu 0.066> 100 0.49 Me0 2 C,

71 - (CH 2); D -Glu 0.017 36 1.2

B = - CO Table 4 real 删

122

124

127

125

Example

Five

jヽ- (C¾) 2 - D- Glu 24

89 - (C¾) 2 - L -Glu 130

90 \ _J - (CH 2) 5 - L-Glu 330

B = _CO negation P-3 Example RX NR 1 - A - CO inhibitory activity

IC 50 M

"ヽ

53 (CH 2) g- DL- Ala 0.093

B = - CO _6 (¾0) - = X: ^ Nyeotsu =>!

00ΐ <u-ιο-α LZ

001 rather than εζ · ο 9Z 00K 09 Ό usv - a Z

001 rather than οζ · ο z

001 rather than εο · ΐ zz 001 rather zz ε9 · ο 9ΐ · 0 IZ

9L N ε'ο 61

001 rather than εκτο I

OO-V- ^ N

¾ ^ 皋 ¾

I- d 丽 ε- d wicked person

9 \ Z negation P- 3 negation P - 1 inhibitory activity inhibitory activity Example NR 1 - A- CO

The field H

28 0.20> 100

D-Glu

29 D-Ala 0.17> 100 17 D-Hci 0.032> 100

30 D-Lys 0.20> 100 31 D-Arg 0.21> 100

32 D - Met 0.13> 100 18 D-Cit 0.062> 100 153 D-Thr 0.19> 100

159 D-Tyr 0.44> 100

161 D-homoGlu 0.078> 100

R = phenyl; X = - (CH 2) Test Example 4

Pharmacological studies in cartilage degeneration animal models

This study, Am. J.Pathol., 135 (6), and referring to the method described in 1001-1014 (1989), was carried out using an animal by changing the rats from mice.

Using a 1 0-week-old CD (SD) IGS rats were administered 80 ^ 1 single 1% collagenase (C 1 ostrid um derived) in both hind knee function in the section under ether anesthesia. It was started administration of the test compound as 8 animals per group after 1 week. Comparative Example 1 and the test of Gobutsu is dissolved in phosphate buffered saline (PH == 7. 4), 0. l gZ l O Ο μ ΐ Roh knee, 0. 1 MGZ 1 00 mu 1 knee one day put on three times a week, was administered in a three-week joint. The control group after a Collagenase one zero was administered intraarticularly was similarly administered phosphate buffered saline (ρ Η 7. 4). Both tibia was collected on the day following the final administration day, and fixed with 1 0% phosphate buffered formalin solution. Ethanol, dehydrated in xylene, after Barafu in embedded, sliced ​​to a thickness of 6 Myupaiiota, subjected Safranin 0 Fast Green staining. With lowering of dyeability Safranin 0 as an indicator of degeneration of cartilage matrix, 3-stage score § with the blind for each site of the tibial articular cartilage was divided into 6 portions (Score 0: normal, Score 1: mild denaturation score 2: been moderate denaturation) a. The average value of the scores of both knees in each group 8 rats, the score value of the control group as a 100%, and the cartilage degeneration inhibition rate of each compound was calculated by the following equation.

Inhibition rate (%) = 1 i (score value of the average score value Roh control group dose group) X 1 00 As a result, the compounds of the compounds and Example 1 49 Example 148, respectively, 2 to 4%, 48% It indicates cartilage degeneration suppression rate, the present invention compound was found to have a pharmacological work on cartilage degeneration. BACKGROUND OF THE

The present invention, there is provided a novel compound useful as a matrix meta port protease Ichize inhibitor, and a novel matrix meth port protease Ichize inhibitor. Sequence Listing

SEQ ID NO: 1

The length of the sequence: 3 4

The type of the array: Nucleic Acids

The number of chain: single-stranded

Topology: linear

Sequence type: other nucleic acid synthetic DNA

Hypothemycin Tikal array: No

Features of the array

Method to determine the features: E

Array

AATAAGCTTC CACCATGCAT CCAGGGGTCC TGGC SEQ ID NO: 2

The length of the sequence: 3 0

The type of the array: Nucleic Acids

The number of chain: single-stranded

Topology: linear

Sequence type: other nucleic acid synthetic DNA

Hypothemycin Tikal array: No

Features of the array

Method to determine the features: E

Array

CCGCTCGAGT TACCCCAAAT GCTCTTCAGG

Claims

The scope of the claims
1 set
RXBN (R ') - A-CO-NHOH
In the formula, R may be substituted hydrocarbon cyclic group, optionally substituted heterocyclic group, Yo Le substituted, vinyl group substituted with a cyclic hydrocarbon group, optionally substituted It represents a Moyoi heterocyclic vinyl or modified amino group substituted with a group.
X is an alkylene group which may be substituted,
Formula: -. (CH 2) m - Y (CH 2) n - ( wherein, Y is either an oxygen atom or a sulfur atom, or be substituted by a lower alkyl group represents an imino group and m and n are each independently represent an integer from 0 1 to 5, and the sum of m and n is an integer of 1 to 2. 0. However, when n is 0, B is a carbonyl group or a sulfonyl group. (CH 2) m and (CH 2) group and n is represented by or.) to be substituted by a substituent group and independent, or
Formula: A (CH 2) p - Z- ( CH 2) q -
(Wherein, Z is a sulfinyl group, a sulfonyl group, a carbonyl group, One NL] - C (= NL 1 ) one NL 1 -, - NL 2 - CO- NL 2 _, - O- C ON L 2 -, - C ON L 3 - or a SO 2 NL 3 - represents a wherein, L 1 is independently a hydrogen atom, lower alkyl group, a lower Arukanoiru group, Aroiru group, a lower alkylsulfonyl group or § Li -. Rusuruhoniru group the stands, L 2 represents a hydrogen atom or a lower alkyl group independently, L 3 is be hydrogen atom or a substituent represents a lower alkyl group. p represents an integer of 0 to 1 5, q is 1 represents an integer between 1 5 and the sum of p and q are integers 1 ~ 2 0. (CH 2 ) p and (CH 2) q is but it may also be substituted with a substituent independently . a group represented by).
B represents a carbonyl group, a methylene group or a sulfonyl Le group.
R 1, when B is a carbonyl group or a sulfonyl group, a hydrogen atom or a substitution which may be a lower alkyl group, when B is a methylene group, a hydrogen atom, a lower alkyl which may be substituted group, optionally substituted lower Arukanoiru group, or Yo Le be substituted, a lower alkylsulfonyl group.
A represents an optionally substituted lower alkyl group 1 also or two substituted methylene group. ]
Matrix meth port protease Ichize inhibitor containing a hydroxamic acid derivative or a pharmaceutically acceptable salt thereof represented in.
2. formula:
R - X 1 - B - N (R 1) -A 1 - CO - NHOH
Wherein, R, R 1 and B are as defined meanings in claim 1.
A 1 and X 1 are the following through Li.
(1) A 1 represents a methylene emissions group substituted with one or two lower alkyl group which may be substituted.
X 1 is an optionally substituted alkylene group with carbon number 3-20,
Formula: - (CH 2) ml -Y- (CH 2) nl -
(Wherein, Y has the same meaning and significance in claim 1. Ml and nl are each independently an integer from 0 1 to 5, and, in integer number of total 3 to 20 m 1 and n 1 there. (CH 2) ml and (CH 2) nl may be substituted with a substituent independently. However, if nl is 0, B is represented by a carbonyl group or a sulfonyl group.) that group or,,
Formula: A (CH 2) pl -Z- (CH 2) ql -
(Wherein, Z has the same definition as meaningful in claim 1.1 is table an integer of 0 to 1 to 5, q 1 represents an integer of 3-1 5 and the sum of p 1 and q 1 are 3 is an integer of 20. represents a (CH 2) pl and (CH 2) group ql is represented by independently may be substituted with a substituent.).
Or,
(2) A 1 has the formula: R 2 - (CH 2) i - Z 1 - (CH 2) j -CH =
(Wherein, R 2 is optionally substituted hydrocarbon cyclic group, substituted by a heterocyclic group which may, be substituted by optionally substituted hydrocarbon cyclic group vinyl group, it may be substituted . represents a vinyl group or modified amino group substituted with not good heterocyclic group Z 1 is, -CONL 2 -, one SO 2 NL 2 - or - 0- CONL 2 - a represents (L 2 are請is synonymous with significance in Motomeko 1.). i represents an integer of 1 to 7, j is 1, 2, 3, represents a 5 or 6. (CH 2) i and (CH 2) "is independently If a substituted methylene group represented by replacement which it may be.} with a substituent Te is
X 1 is a substituted carbon atoms which may be 1 or 2 alkylene groups,
Formula: - (CH 2) m2 -Y- (CH 2) n 2 -
(Wherein, Y has the same meaning and significance in claim 1. M 2 and n 2 each independently represents an integer of 0 to 2, and the sum of m 2 and n 2 is 1 or 2. However, if n 2 is 0, the table B is a carbonyl group or a sulfonyl group. (CH 2) m @ 2 and (CH 2) n 2 is but it may also be substituted with a substituent independently.) is the group or,
Formula: - (CH 2) p 2 -Z- (CH 2) q 2 -
(Wherein, Z has the same definition as meaningful in claim 1. P 2 will table an integer of 0 to 1 5, q 2 is 1 or 2. (CH 2) p 2 and (CH 2) q 2 may be substituted with location substituent independently.) group may represent a represented by. ]
In hydroxamic acid derivative or a pharmaceutically acceptable salt thereof.
3. salt B is acceptable hydroxamic acid derivative or a pharmaceutically according to claim 2, wherein a carbonyl group or a methylene group.
4. X 1 is 5 carbon atoms: an alkylene group of I 2,
Formula: - (CH 2) m3 " Y- (CH 2) n 3 -
(Wherein, Y has the same meaning and significance in claim 1. M 3 and n 3 each independently represents an integer from 0 to 1 2, and the sum of m 3 and n 3 is 4-1 2 integer Ru der. However, when n 3 is 0, B is substituted with a carbonyl Ru group or a sulfonyl group der. (CH 2) m3 and (CH 2) n 3 are independently substituent good.) a group represented by or,
Formula: - (CH 2) P 3 -Z- (CH 2) q 3 -
(Wherein, Z has the same definition as meaningful in claim 1. P 3 represents an integer of 0 to 1 2, q 3 is an integer from 3 1 2, and the sum of p 3 and q 3 are 3 is a 1 2 integer. (CH 2) p 3 and (CH 2) q 3 is but it may also be substituted with a substituent independently.) a group represented by claims 2 or 3, wherein hydroxamic acid derivative or a pharmaceutically acceptable salt thereof.
5.1 is hydrate port Kisamu acid derivative or a pharmaceutically acceptable salt thereof according to claim 2 or 3 wherein the alkylene group of 9-1 2 carbon atoms.
6. hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according to claim. 2 to 5 R is an aromatic heterocyclic Shikimoto be also good Ariru group substituted or unsubstituted.
7. Any hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according to claim. 2 to 5 R is an optionally Futaruimi de group which may be optionally phenyl group or substituted or unsubstituted.
8. scale is chosen carboxyl group, lower alkoxycarbonyl group, an amino group, an amino lower alkyl group, Guanijino lower alkyl group, a nitro group, Shiano group, amidino group, a lower alkyl group, from the group consisting of hydroxyl and lower alkoxy groups Hidorokisa beam acid derivative or a pharmaceutically acceptable salt thereof according to any one of claims 2-5 which is a phenyl group which may be substituted by a group.
9. hydroxamic acid derivative or a pharmaceutically acceptable Ru salt according to any one of claims 2-8 substituted A 1 forces a methylene group substituted with one also alkyl groups.
10. A 1 Chikarami ', phenyl group, 4-hydroxyphenyl group, a carboxyl group, low grade alkoxycarbonyl group, a force Rubamoiru group, - CO- NHOH, amino group, grayed Anijino group, Ulei de group, hydroxyl group, methylthio group, methylsulfonyl group, a methyl sulfinyl group, Imidazoriru group and from the group consisting of Indoriru group 'as set forth in any claim 2-8 Neu deviation is a methylene group substituted with alkyl group which may be substituted with group selected hydroxamic acid derivative or a pharmaceutically acceptable salt thereof.
1 1. A 1 is (3-carboxy-propyl) methylene group, (2-carboxy Ruechiru) methylene group, (carboxyl methyl) methylene group, (3 Ulei de-flop opening pill) methylene group, (4 _ Ureidopuchiru) methylene group, (3 Guanijinopu ​​opening pill) methylene group, (3 Aminopuropiru) methylene or (3 Aminobu chill) a is claim 2-8 was hydroxamic acid derivatives or of any of a methylene group a pharmaceutically acceptable salt.
12. - NH- A 1 - CO- is D- amino claim 2-1 1 Neu hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according to any deviation is the residue of.
1 3. formula:
R 2 - (CH 2) i - Z 1 - (CH 2) j
R - X 2 - B - N (R 1) -CH - CO - NHOH
Wherein, R, R 1 and B are as defined meanings in claim 1. R 2, Z i and j are as defined meanings in claim 2.
X 2 is optionally substituted alkylene group having 1 to 6 carbon atoms,
¾: one (Cn 2 j m 4 - 0- (C 2 n 4 -
(Wherein, m 4 and n 4 each independently represent an integer of 0-6, and the sum of m4 and n 4 represents an integer of 1-6. However, when n 4 is 0 , B is a local Boniru group or a sulfonyl group. (CH 2) m4 and (CH 2) n 4 is a group represented by the independently may be substituted with a substituent.), or,
Formula: A (CH 2) p4 -Z- (CH 2) q4 -
(Wherein, Z has the same definition as meaningful in claim 1. P 4 represents an integer of Less than six, q 4 is an integer of 1-6, and the sum of p 4 and q 4 is 1 represents an integer of 6. represents a (CH 2) p 4 and (CH 2) q 4 may be substituted with a substituent independently.) a group represented by. ]
In claim 2 hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according represented.
14. Salts B is acceptable hydroxamic acid derivative or a pharmaceutically according to claim 1 3, wherein a carbonyl group or a methylene group.
1 5. hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1 3 or 1 4, wherein R 2 is a heterocyclic Shikimoto be also be substituted hydrocarbon cyclic group or a substituted substituted.
1 6. or hydroxamic acid derivative according to claim 1 3 or 14 wherein R 2 is an optionally substituted aromatic hydrocarbon cyclic group or optionally substituted aromatic heterocyclic group optionally is acceptable pharmaceutically salt that.
17. R 2 is the hydroxamic acid derivative or a pharmaceutically acceptable salt of a is claim 1 3 or 14, wherein a phenyl group which may have a substituent at the 4-position.
1 8. Z 1 hydroxamic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1 3-1 7 is a guard CONH-.
1 9. i is an integer from 1 to 5, j is 1 or 2, hydroxamic acid derivative according to claim 1. 3 to 1 8 X 2 is an alkylene group having 1 to 5 carbon atoms or a pharmaceutically acceptable salt thereof.
20. R is a phenyl group which may be substituted, it may be substituted Futaruimi de group, the optionally substituted hexa hydro phthalic imide group, 2 may be substituted H, 3 H- 1, 1, 3 - trioxo one benzo [d] isothiazoloxy one rule 2 I group or substitution which may be 5H, 6 H, 7 H- 5, 7- Jiokiso one pyro port [3, 4-b] pin lysine one 6, - hydroxamic San誘 conductor or a pharmaceutically acceptable salt thereof according to claim 1 3-1 9 an I le group.
21. X 2 is one S_〇 2 NH- (CH 2) q 5 -, or table in one CONH- (CH 2) q 5 i (wherein, Q 5 represents an integer of 1-4.) claim 1 3-20 hydroxamic acid derivative or a pharmaceutically acceptable salt thereof pharmaceutically according to any one of a group is.
22. R 2 is a hydrogen atom, an amino group, a hydroxyl group, Guanijino group, amidino group, a lower alkyl group, a lower Arukiruokishi group, a lower alkylamino group, Amino lower alkyl group, hydroxy-lower alkyl group, Guanijino lower alkyl group or 4-position There substituents in an optionally substituted phenyl group (substituted phenyl group, an alkyl group, an amino group, Shiano group, an alkoxy group, an alkylthio group, a formyl group, a halogen atom, Guanijino group, Guanijino lower alkyl group or amino-lower alkyl Motodea Ru.), and also, i is 2, Z 1 gar is CONH-, j is請Motomeko 1 3-2 1 of hydroxamic acid derivative or a pharmaceutically according to any one of 1 salt to be above acceptable.
2 3. Hydroxamic acid derivative according to claim 2 to 2 2 or medicament containing the pharmacology acceptable salt thereof.
2 4. Claim 2-2 2 or hydroxamic acid derivative according to any matrix meth port Protease Inhibitor containing the pharmacology acceptable salt thereof.
2 5. Matrix meth port protease inhibitor according to claim 1 or 2 4, wherein the inhibitor of matrix meth port Protea Ichize 3.
2 6. Matrix meth port protease inhibitor according to claim 1 or 2 4, wherein the inhibitor of matrix meth port Protea Ichize 1 3.
PCT/JP1997/003542 1996-10-07 1997-10-02 Hydroxamic acids WO1998015525A1 (en)

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