WO1997047599A1

WO1997047599A1 - Succinamide derivatives useful as tnf- and/or mmp inhibitors

Info

Publication number: WO1997047599A1
Application number: PCT/JP1997/002004
Authority: WO
Inventors: Masahiro Neya; Yasuharu Urano; Ichiro Shima; Keiji Hemmi
Original assignee: Hemmi Mitsue; Fujisawa Pharmaceutical Co Ltd
Current assignee: Hemmi Mitsue; Fujisawa Pharmaceutical Co Ltd
Priority date: 1996-06-14
Filing date: 1997-06-11
Publication date: 1997-12-18
Anticipated expiration: 1998-12-14
Also published as: AUPO048296A0; JP2000512290A

Abstract

A compound of formula (I), in which R1 is hydrogen or hydroxy-protective group, R2 is hydrogen or acyl, R3 is hydrogen or lower alkyl, or the formula (II) is (III), R4 is heterocyclic (lower) alkyl, and R5 is lower alkoxy or lower alkylamino, or a pharmaceutically acceptable salt thereof, which is useful as a medicament.

Description

DESCRIPTION SUCCINAMTDEDERIVATIVESUSEFULASTNF-AND/ORMMPINHIBITORS TECHNICAL FIELD

The present invention relates to new compound andpharmaceutically acceptable salts thereof.

More particularly, it relates to new compound andpharmaceutically acceptable salts thereof which are usefulas inhibitors of matrix metalloprotemases (hetemafter tobe referred to as MMP) or the production of tumor necrosisfactor α (hereinafter to be referred to as TNF α), to apharmaceutical composition comprising the same, to use ofthe same as a medicament, and to a method for using thesame therapeutically in the treatment and/or the

prevention of MMP or TNF α mediated diseases.

One object of the present invention is to provide newand useful compounds and pharmaceutically acceptable saltsthereof which have pharmacological activities such as MMPor TNF α inhibitory activity and the like.

Another object of the present invention is to providea pnarmaceutical composition comprising, as an activeingredient, said compound or a pharmaceutically acceptablesalt thereof.

A further object of the present invention is toprovide use of said compounds and pharmaceutically

acceptable salts thereof as a medicament for prophylacticand trerapeutic treatment of MMP or TNF α mediated

diseases.

A still further object of the present invention is toprovide a method for using the same for the treatmentanα/or the prevention of MMP or TNF α mediated diseases inmammals, especially humans.

The compounds of tne present invention have

inhibitory activity on MMP or the production of TNF α, and are useful in the treatment anα/or prevention of a diseasesucn as stroke, arthritis, cancer, tissue ulceration,decubitus ulcer, restenosis, periodontal disease,

epidermolysis bullosa, scleritis, psoriasis and otherdiseases characterized by matrix metalloproteinase

activity, as well as AIDS, sepsis, septic shock and otherdiseases caused by the production of TNF α.

There are a number of enzymes which effect thebreakdown of structural proteins and which are

structurally related metalloproteases. Matrix-degradingmetalloprotease, such as gelatmase (MMP-2, MMP-9),stromelysin (MMP-3) and collagenase (MMP-1), are involvedin tissue matrix degradation and have been implicated inmany pathological conαitions involving abnormal connectivetissue and basement membrane matrix matabolism, such asarthritis (e.g., osteoarthritis and rheumatoid arthritis),tissue ulceration (e.g., corneal, epidermal and gastriculceration), abnormal wound healing, periodonal disease,bone disease (e.g., Paget's disease and osteoporosis),tumor matastasis or invasion as well as HIV-infection.

Tumor necrosis factor is recognized to be involved inmany infections and autoimune diseases. Furthermore, ithas been shown that TNF is the prime mediator of theinflammatory response seen in sepsis and septic shock. DISCLOSURE OF INVENTION

The object compound of the present invention can berepresented by the following general formula :

in which R¹ is hydrogen or hydroxy-protective group, R² is hydrogen or acyl,

R³ is hydrogen cr lower alkyl, or

R⁴ is heterocyclic(lower)alkyl, and

R⁵ is lower alkoxy or lower alkylamino, or pharmaceutically acceptable salts thereof. Further, the compound (I) having the most potent activities can be represented by the following

configuration.

in which R¹, R², R³, R⁴ and R⁵ are each as defined above. According to the present invention, the new compound (I) and salts thereof can be prepared by the processes as shown in the following schemes.

r

in wαich R¹, R², R³, R⁴ and R⁵ are each as defined above, R^ is hyαroxy-protective group,

is acyl,

is protected carboxy(lower)alkanoyl,

is carboxy(lower)alkanoyl,

is protected amino(lower)alkoxycarbonyl,

protected amino(lower)alkanoyl,

lower alkanoyl substituted by protecteα amino and hydroxy, or N-protected

lmidazolidinyl optionally substituted by oxo,

is amino(lower)alkoxycarbonyl,

amino(lower)alkanoyl,

lower alkanoyl substituted by amino and hydroxy, or lmidazolidinyl optionally substituted by oxo,

is protected hydroxy(lower)alkoxycarbonyl, or protected hydroxy(lower)alkanoyl,

is hhydroxy(lower)alkoxycarbonyl, or

hydroxy(lower)alkanoyl,

is lower alkoxycarbonyl(lower)alkylcarbamoyl or lower alkoxycarbonyllower alkanoyl, lower alkylcarbamoyl(lower)alkylcarbamc or lower alkylcarbamoyl(lower)alkanoyl, is lower alkyl,

is lower alkoxy, and

is lower alkylamino.

The starting compound (II) used in the Process 1 maybe new and car. be prepared by the following Preparationsor by a conventional manner. Suitable pharmaceutically acceptable salts of theobject compound (I) may be a conventional non-toxic saltand include an aciα addition salt such as an organic acid salt (e.g. acetate, tri fluoroacetate, maleate, tartrate,fumarate, methanesulfonate, benzenesulfonate, formate,toluenesulfonate, etc.), an inorganic acid salt (e.g.

hydrcchloride, hydrobromide, hydrioαide, sulfate, nitrate,pnosphate, etc.), or a salt with a base such as an aminoacid (e.g. arginine, aspartic acid, glutamic acid, etc.),an alkali metal salt (e.g. sodium salt, potassium salt,etc.), an alkaline earth metal salt (e.g. calcium salt,magnesium salt, etc.), an ammonium salt, an organic basesalt (e.g. trimethylamine salt, trietnylamme salt,pyridine salt, picoline salt, dicyclonexylamine salt,N,N -dibenzylethylenediamine salt, etc.), or the like.

The object compound (I) and pharmaceutically

acceptable salts thereof may include a solvate [e.g.,enclosure compound (e.g., hydrate, etc.)].

In the above an-d subsequent descriptions of thepresent specification, suitable examples and illustrationsof the various definitions which the present inventionincludes withm the scope thereof are explained in detailas follows.

Tie term "lower" is intended to mean 1 to 6 (or 2 to6 for lower alkenyl group), preferably 1 to 4 carbon atoms(or 2 to 4 carbon atoms for the same), and the term

"higher" is intended to mean more than 6, preferably 7 to12 carbon atoms, unless otherwise indicated.

Suitable "hydroxy-protective group" may include acommon one, for example, acyl as mentioned below,

ar(lower)alkyl such as mono- or di- or

triphenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl,phenethyl, naphthylmethyl, etc.), etc.;

trisubstituted silyl such as tri(lower)alkylsilyl (e.g.trimethylsilyl, triethylsilyl, isopropyldimethylsilyl,t-butyldimethylsilyl, diisopropylmethylsilyl, etc.),triarylsilyl (e.g. triphenylsilyl, etc.),

triar(lower)alkylsilyl (e.g. tribenzylsilyl, etc.), etc.; and the like.

Preferable "hydroxy-protective group" thus definedmay be C₆-C₁₀ aroyl, C₆-C₁₀ ar(lower)alkyl and loweralkanoyl, and the most preferable one may be benzyl.

Suitable "acyl" may include an aliphatic acyl, anaromatic acyl, a heterocyclic acyl and an aliphatic acylsubstituted with aromatic or heterocyclic group(s) derivedfrom acids such as carboxylic, carbonic, carbamic,

sulfonic acids, wherein said heterocyclic group(s) may bethe same as those mentioned below.

The alipnatic acyl may include saturated or

unsaturated, acyclic or cyclic ones, such as carbamoyl,oxamoyl, lower alkanoyl optionally substituted by halogen (e.g. chloro, fluoro, lodo, bromo, etc.) (e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl,

isovaieryl, pivaloyl, hexanoyl, tri fluoroacetyl, etc.),lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl,

propanesulfonyl, etc.), lower alkoxycarbonyl (e.g.

methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,t-butoxycarbonyl, etc.), lower alkenoyl (e.g. acryloyl,methacryloyl, crotonoyl, etc.), (C₃-C₇)cycloalkanecarbonyl(e.g. cyclopropanecarbonyl, cyclobutanecarbonyl,

cyclonexanecarbonyl, etc.), (C₃-C₇)cycloalkyl(lower)-alkanoyl (e.g. cyclohexylacetyl, etc.), amidmo, protectedcarboxycarbonyl such as lower alkoxalyl (e.g. methoxalyl,ethoxalyl, t-butoxalyl, etc.), mono- or di(lower)alkyl¬amine(lower)alkanoyl (e.g. dimethylaminoacetyl, etc.);

lower or higher alkylcarbamoyl (e.g. methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,butylcarbamoyl, t-butylcarbamoyl,

2-methylbutylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl,heptylcarbamoyl, octylcarbamoyl, nonylcarbamoyl, etc.),di(lower)alkylcarbamoyl (e.g. dimethylcarbamoyl,

diethylcarbamoyl, dipropylcarbamoyl, dnsopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, dihexylcarbamoyl,etc.), C₃-C₇ cycloalkylcarbamoyl (e.g.

cyclopropylcarbamoyl, cyclobutylcarbamoyl,

eyelopentylcarbamoyl, cyclonexylcarbamoyl,

cycloheptylcarbamoyl, etc.), N-lower alkyl-N-(C₃-C₇)-cycloalkylcarbamoyl (e.g. N-methyl-N-cyclopropylcarbamoyl,N-methyl-N-cyclonexylcarbamoyl, N-ethyl-N-cyclohexylcarbamoyl, N-propyl-N-cyclohexylcarbamoyl,etc.), di(C₃-C₇)cyclohexylcarbamoyl (e.g.

dicyclopropylcarbamoyl, dicyclopentylcarbamoyl,

dicyclohexylcarbamoyl, etc.),

N-[di(lower)alkylcarbamoyl(C₃-C₇)cycloalkyl]carbamoyl

[e.g. N-(1-dιmethylcarbamoylcyclohexyl)carbamoyl, etc.],N-[di(lower)alkylcarbamoyl(lower)alkyl(C₃-C₇)cycloalkyl]-carbamoyl [e.g. N-[1-(dimethylcarbamoylmethyl)cyclohexyl]-carbamoyl, etc.], N-[carbamoyl(lower)alkyl]carbamoyl [e.g.N-[1-carbamoyl]-2-methylbutyl]carbamoyl, etc.],

N-[(lower)alkylcarbamoyl(lower)alkyl]carbamoyl [e.g.

N-(methylcarbamoylmethyl)carbamoyl,

N-(l-ιsopropylcarbamoyl-2-methylbutyl)carbamoyl, etc.], N-[N,N-lower alkylenecarbamoyl(lower)alkyl]carbamoyl [e.g.N-[2-methyl-1-(piperidinocarbonyl)butyl]carbamoyl, etc.],N-[N,N-di(lower)alkylcarbamoyl(lower)alkyl]carbamoyl [e.g.N-(dimethylcarbamoylmethyl)carbamoyl,

N-[1-(dimethylcarbamoyl)ethyl]carbamoyl,

N-[1-(dimethylcarbamoyl)-2-methylpropyl]carbamoyl,

N-[2,2-dimethyl-1-(dimethylcarbamoyl)propyl]carbamoyl,N-[2-methyl-1-(dimethylcarbamoyl)butyl]carbamoyl,

N-[2-methyl-l-(diethylcarbamoyl)butyl]carbamoyl,

N-[3-methyl-l-(dimethylcarbamoyl)butyl]carbamoyl,

N-(1-dimethylcarbamoylpentyl)carbamoyl, etc.],

N-(lower)alkyl-N-[N,N-di(lower)alkylcarbamoyl] (lower)-alkylcarbamoyl [e.g. N-methyl-N-[1-dimethylcarbamoyl-2-methylbutyl]carbamoyl, N-methyl-N-[1-dimethylcarbamoyl-3-methylbutyl]carbamoyl, etc.], and the like. The aromatic acyl may include C₆-C₁₀ aroyl (e.g.

benzoyl, toluoyl, xyloyl, etc.), C₆-C₁₀ arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), C₆-C₁₀arylcarbamoyl (e.g. phenylcarbamoyl, etc.), C₆-C₁₀ aryloxalyl (e.g.

pheny loxalyl, etc.), and the like.

The heterocyclic acyl may include heterocyclic-carbonyl such as furoyl, thenoyl, nicotmoyl,

lsomcotinoyl, oxolanecarbonyl optionally substituted byoxo (e.g. 2-oxo-5-oxolanecarbonyl, etc.),

triazolylcarbonyl, thiadiazolylcarbonyl, indolylcarbonyl,isoindolylcarbonyl, tetrazolylcarbonyl,

morpholinocaroonyl, pyrrolylcarbonyl, pyrazmyicarbonyl,thiomorpholinocarbonyl, pyridinecarbonyl optionallysubstituted by lower alkyl [e.g. 2-(or 3- or 4-)-pyridinecarbonyl, 6-methyl-2-pyndmecarbonyl, 2-methyl-5-pyridinecarbonyl, etc.], quinolmecarbonyl optionallysubstituted by hydroxy (e.g. 2-quinolmecarbonyl, 3-quinolinecarbonyl, 4-hydroxy-2-quinolmecarbonyl, etc.),lower alkyleneaminocarbonyl optionally substituted by oxo(e.g. aziridin-1-ylcarbonyl, azetιdm-1-ylcarbonyl,pyrrolidin-1-ylearbonyl, piperidin-1-ylcarbonyl,

hexahydro-1H-azepin-1-ylcarbonyl, octahydroazocin-1-ylcaroonyl, tetrahydroquinolinecarbonyl,

tetrahydroisoquinolinecarbonyl, dihydropyridinecarbonyl,tetrahydropyridinecarbonyl, 2-oxo-5-pyrrolidinecarbonyl,2-oxo-4-ιmιdazolidmecarbonyl, etc.), heterocyclic-carbamoyl such as pyridylcarbamoyl (e.g.

4-pyridylcarbamoyl, etc.), piperidylcarbamoyl, etc. andthe like.

The aliphatic acyl substituted with aromatic group(s)may include (C₆-C₁₀)ar(lower)alkanoyl such as

phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl,phenylhexanoyl, etc.), (C₆-C₁₀)ar(lower)alkoxycarbonylsuch as phenyl(lower)alkoxycarbonyl (e.g.

benzyloxycarbonyl, phenethyloxycarbonyl, etc.), (C₆-C₁₀)aryloxy(lower)alkanoyl such as

phenoxy(lower)alkanoyl (e.g. phenoxyformyl, phenoxyacetyl,phenoxypropionyl, etc.), ar(lower)alkoxalyl such asphenyl(lower)alkoxalyl (e.g. benzyloxalyl, etc.),

ar(lower)alkenoyl such as phenyl(lower)alkenoyl (e.g.

cinnamoyl, etc.), ar(lower)alkylsulfonyl (e.g.

benzylsulfonyl, etc.), and the like.

The alipnatic acyl substituted with heterocyclicgroup(s) may include heterocyclic(lower)alkanoyl such asthienyl(lower)alkanoyl, lmidazolyl(lower)alkanoyl (e.g. 4-lmidazolylacetyl, etc.), furyl(lower)alkanoyl,

tetrazolyl(lower)alkanoyl, thiazolyl(lower)alkanoyl,thiadiazolyl(lower)alkanoyl, pyridyl(lower)alkanoyl [e.g.pyridin-3-ylacetyl, 3-(pyridin-3-yl)propionyl, etc.],lower alkyleneamino(lower)alkanoyl (e.g. 3-(piperidin-1-yl)propionyl, etc.), etc.;

heterocyclic(lower)alkylcarbamoyl, such as

pyridyl(lower)alkylcarbamoyl, etc.; and the like.

These acyl groups may be further substituted with oneor more, preferably one to three suitable substituentssuch as carboxy, lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), halogen,(e.g. chlorine, bromine, iodine, fluorine), carbamoyl,mono- or di(lower)alkylcarbamoyl (e.g. methylcarbamoyi,etc.), amino, protected amino such as lower alkanoylamino(e.g. formamido, acetamido, propionamido, etc.), and loweralkoxycarbonylamino (e.g. t-butoxycarbonylamino, etc.),mono- or di(lower)alkylamino (e.g. dimethylamino, etc.),lower alkoxycarbonylamino (e.g. t-butoxycarbonylamino,etc.), lower alkylsulfonyl (e.g. methylsulfonyl, etc.),arylsulfonyl (e.g. phenylsulfonyl, tosyl, etc.),

ar(lower)alkyl (e.g. benzyl, etc.), hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,t-butoxy, etc.), carboxy, protected carboxy as mentionedbelow such as lower alkoxycarbonyl (e.g. methoxycarbonyl, etc.), carboxy(lower)alkyl (e.g. carboxymethyl,

carooxyethyl, etc.), protecteα carboxy(lower)alkyl (e.g.t-butoxycarbonylmethyl, etc.), lower alkanoyloxy (e.g.acetoxy, etc.), lower alkoxycarbonyl (e.g.

methoxycarbonyl, etc.), amino- or lmino-protective groupsuch as acyl (e.g. benzyloxycarbonyl, etc.), and the like. Preferable acyl thus defined may be :

- lower alkanoyl (e.g. acetyl, propionyl, etc.);

- di(lower)alkylcarbamoyl (e.g. dimethylcarDamoyl, etc.); - C₆-C₁₀ aroyl (e.g. benzoyl, etc.);

- C₆-C₁₀ arylcarbamoyl (e.g. phenylcarbamoyl, etc.);

- heterocyclecarbonyl such as

pyridinecarbonyl optionally substituted by lower alkyl [e.g. 2-(or 3- or 4-)pyridinecarbonyl, 3-methyl-2- pyridinecarbonyl, 4-methyl-3-pyndmecarbonyl, etc.]; qumolinecarbonyl optionally substituted by hydroxy (e.g. 2-quinolmecarbonyl, 3-quinolinecarbonyl,

4-hydroxy-2-qumolmecarbonyl, etc.); etc.;

- lower alkyleneaminocarbonyl (e.g. pyrrolidin-1- ylcarbonyl, etc.);

- heterocyclic(lower)alkanoyl such as

pyridyl(lower)alkanoyl [e.g. pyridin-3-ylacetyl,

3-(pyridm-3-yl)propionyl, etc.); etc.;

- lower alkanoyl substituted by mono- or

di(lower)alkylamino (e.g. dimethylaminoacetyl, etc.); ana the like;

wherein said heterocyclic group may be saturated orunsaturated 3- to 8-membered (preferably 5- or β-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s),or unsaturated 7- to 12-membered condensed (preferablybicyclic) heterocyclic group containing 1 to 4 nitrogenatom(s). Another preferable acyl thus defined may be : (1) oxamoyl;

(2) lower alkanoyl (e.g. acetyl, propionyl, isobutyryl,

pivaloyl, etc.) optionally substituted by halogen (e.g. trifluoroacetyl, etc.);

(3) lower alkanesuifonyl (e.g. mesyl, ethanesulfonyl, etc.); (4) lower alkoxycarbonyl (e.g. methoxycarbonyl,

ethoxycarbonyl, isopropoxycarboyl, isobutoxycarbonyl, t-butoxycarbonyl, etc.);

(5) (C₃-C₇)cycloalkanecarbonyl (e.g. cyclopropanecarbonyl, etc.);

(6) di(lower)alkylamino(lower)alkanoyl (e.g.

dimethylaminoacetyl, etc.);

(7) lower alkylcarbamoyl (e.g. methylcarbamoyl,

ethylcarbamoyl, isopropylcarbamoyl, t-butylcarbamoyl, etc.);

(8) di(lower)alkylcarbamoyl (e.g. dimethylcarbamoyl, etc.); (9) N-[(lower)alkylcarbamoyl(lower)alkyl]carbamoyl (e.g.

N-(methylcarbamoylmethyl)carbamoyl, etc.);

(10) C₆-C₁₀ aroyl (e.g. benzoyl, etc.);

(11) C₆-C₁₀ arenesulfonyl (e.g. benzenesulfonyl, etc.);

(12) C₆-C₁₀ arylcarbamoyl (e.g. phenylcarbamoyl, etc.);

(13) heterocyclic-carbonyl optionally substituted by the

group consisting of acyl such as C₆-C₁₀

ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), lower alkyl (e.g. methyl, etc.), hydroxy and oxo; said heterocyclic group being

unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. 1H- azepinyl, etc.), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H- 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, perhydroazepmyl (e.g.perhydro-1H-azepmyl, etc.), pyrrolidinyl,

imidazolidinyl, piperidinyl (e.g. piperidino, etc.),piperazinyl, etc.;

unsaturated 7- to 12-membered (more preferably 9-or 10- membered) condensed (preferably bicyclic)heterocyclic group containing 1 to 4 nitrogen atom(s),for example, indolyl, isomdolyl, mdolizmyl,

benzimidazolyl, quinolyl, isoquinolyl, indazolyl,benzotriazolyl, etc.;

unsaturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 2oxygen atom, for example, furyl, etc.;

saturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 2oxygen atom, for example, oxolanyl, etc.; and the like,for example,

- pyrrolylcarbonyl (e.g. 2-pyrrolylcarbonyl, etc.);

- pyridinecarbonyl ([e.g. 2-(or 3- or 4-)pyridine-carbonyl, etc.) optionally substituted by lower alkyl(e.g. 6-methyl-2-pyridinecarbonyl, 2-methyl-5-pyridinecarbonyl, etc.);

- pyrazinylcarbonyl (e.g. pyrazin-2-ylcarbonyl, etc.); - pyrrolidinylcarbonyl (e.g. pyrrolidm-1-ylcarbonyl,etc.) optionally substituted by oxo (e.g. 2-oxopyrrolidm-5-ylcarbonyl, etc.);

- lmidazolizmylcarbonyl optionally substituted by thegroup consisting of oxo and C₆-C₁₀ ar(lower)-alkoxycarbonyl (e.g. 2-oxo-4-imidazolizmecarbonyl, 1-benzyloxycarbonyl-2-oxo-4-imidazolidmecarbonyl, etc.); - quinolinecarbonyl (e.g. 2-quinolinecarbonyl, 3-quinolmecarbonyl, etc.) optionally substituted byhydroxy (e.g. 4-hydroxy-2-quinolmecarbonyl, etc.); - indolylcarbonyl; isoindolylcarbonyl;

- furoyl [e.g. 2-(or 3-)furylcarbonyl, etc.];

- oxolanecarbonyl optionally substituted by oxo (e.g. 2-oxo-5-oxolanecarbonyl, etc.); and the like;

(14) neterocyclic-carbamoyl; said heterocyclic group being unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. 1H- azepmyl, etc.), pyrrolyl, pyrrolmyl, lmidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazmyl, pyridazmyl, triazolyl (e.g. 4H- 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-tnazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepinyl (e.g. perhydro-1H-azepinyl, etc.), pyrrolidinyl,

lmidazolidinyl, piperidinyl (e.g. piperidino, etc.), piperazinyl, etc.;

unsaturated 7- to 12-membered (more preferably 9- to 10-membered) condensed (preferably bicyclic)

heterocyclic group containing 1 to 4 nitrogen atom(s), for example, mdolyl, isoindolyl, mdolizmyl,

benzimidazolyl, quinolyl, isoquinolyl, mdazolyl, benzotriazolyl, etc.;

unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom, for example, furyl, etc.;

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom, for example, oxolanyl, etc.; and the like, for example,

- pyridylcarbamoyl (e.g. 4-pyridylcarbamoyl, etc.); and the like; (15) (C₆-C₁₀)arvloxy(lower)alkanoyl such as

pnenoxy(lower)alkanoyl (e.g. phenoxyformyl, etc.); etc.; (16) heterocyclic(lower)alkanoyl; said heterocyclic group

being

unsaturated 3- to 8-membered (more preferably 5- or β-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. 1H- azepinyl, etc.), pyrrolyl, pyrrolmyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H- 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepinyl (e.g. perhydro-1H-azepmyl, etc.), pyrrolidinyl,

imidazolidinyl, piperidinyl (e.g. piperidino, etc.), piperazinyl, etc.;

heterocyclic group containing 1 to 4 nitrogen atom(s), for example, mdolyl, isomdolyl, indolizinyl,

benzimidazolyl, quinolyl, isoqumolyl, indazolyl,

Penzotriazolyl, etc.;

- imidazolyl(lower)alkanoyl (e.g. 4-imidazolylacetyl, etc.);

- pyridyl(lower)alkanoyl [e.g. pyridin-3-ylacetyl, 3- (pyri din-3-yl)propionyl, etc.);

- piperi dinyl(lower)alkanoyl [e.g. 3-(piperidin-1- yl)propionyl, etc.] ;

(17) lower alkylcarbamoyl(lower)alkanoyl (e.g.

methylcarbamoylacetyl, etc.);

(18) carboxy(lower)alkanoyl (e.g. carboxyacetyl,

3-carboxypropιonyl, etc.);

(19) protected carboxy(lower)alkanoyl such as lower

alkoxycarbonyl(lower)alkanoyl (e.g.

ethoxycarbonylacetyl, etc.); etc.;

(20) hydroxy(lower)alkanoyl (e.g. hydroxyacetyl, 2,3- dihydroxypropionyl, 2,3,4,5,6-pentahydroxyhexanoyl, etc.);

(21) protected hydroxy(lower)alkanoyl such as lower

alkanoyloxy(lower)alkanoyl (e.g. acetoxyacetyl, etc.); etc.;

(22) lower alkoxy(lower)alkanoyl (e.g. methoxyacetyl, etc.); (23) lower alkoxy(lower)alkoxycarbonyl (e.g. 2- methoxyethoxycarbonyl, etc.);

(24) amino(lower)alkoxycarbonyl (e.g. 2-aminoethoxycarbonyl, etc.);

(25) protected amino(lower)alkoxycarbonyl such as C₆-C₁₀

ar(lower)alkoxycarbonylamino(lower)alkoxycarbonyl (e.g. 2-(benzyloxycarbonylamino)ethoxycarbonyl, etc.);

(26) lower alkoxycarbonyl(lower)alkylcarbamoyl (e.g.

methoxycarbonylmethylcarbamoyl, etc.);

(27) lower alkylsulfonyl(lower)alkanoyl (e.g.

methylsulfonylacetyl, etc.);

(28) hydroxy(lower)alkoxycarbonyl (e.g.

2-hydroxyethoxycarbonyl. etc.);

(29) protected hydroxy(lower)alkoxycarbonyl such as lower alkanoyloxy(lower)alkoxycarbonyl (e.g. 2- acetoxyethoxycarbonyl, etc.); etc.;

(30) lower alkanoyl substituted by the group consisting of amino and hydroxy (e.g. 2-amino-3-hydroxypropionyl, etc. ) ;

(31) lower alkanoyl substituted by the group consisting of protected amino and hydroxy such as lower alkanoyl substituted by the group consisting of lower

alkoxycarbonylamino and hydroxy (e.g. 2-t- Dutoxycarbonylamino-3-hydroxypropιonyl, etc.); etc.; (32) amino(lower)alkanoyl (e.g. aminoacetyl, etc.);

(33) protected amino(lower)alkanoyl such as lower

alkanoylamino(lower)alkanoyl (e.g. acetamidoacetyl, etc.), lower alkoxycarbonylamino(lower)alkanoyl (e.g. t-butoxycarbonylaminoacetyl, etc.); etc.;

and the like. Suitable "lower alkyl" or lower alkyl moiety mayinclude, unless otherwise indicated, a straight or

branched one such as methyl, ethyl, propyl, isopropyl,butyl, lsooutyl, tert-outyl, pentyl, hexyl, and the like,in which the most preferred example may be methyl for R³.

Suitable "lower alkoxy" or lower alkoxy moiety mayinclude, unless otherwise indicated, a straight or

branched one such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, andthe like, in which the most preferable example may bemethoxy for R⁵. Preferable "heterocyclic(lower)alkyl" means lower alkylsubstituted by heterocyclic group as mentioned below, inwhich more preferable heterocyclic group may be saturatedor unsaturated 3- to 8-membered (preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4

nitrogen atom(s), or

unsaturated 7- to 12-membered (more preferably 9- to 10-memoered) condensed (preferably bicyclic) heterocyclicgroup containing 1 to 4 nitrogen atom(s), wherein

preferable example of heterocyclic(lower)alkyl may be pyridyl(lower)alkyl, and the most preferable one may be 2-pyridylmethyl and

4-pyridylmethyl. Suitable "heterocyclic group" as mentioned above mayinclude saturated or unsaturated, monocyclic or polycyclicheterocyclic group containing at least one hetero-atomsuch as oxygen, sulfur and nitrogen atom. Preferable heterocyclic group may be

unsaturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, azepinyl (e.g. lH-azepinyl,etc.) pyrrolyl, pyrrolmyl, imidazolyl, pyrazolyl, pyridyland its N-oxide, dihydropyridyl, pyrimidinyl, pyrazmyl,pyridazmyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4

nitrogen atom(s), for example, perhydroazepmyl (e.g.

perhydro-1H-azepinyl, etc.), pyrrolidinyl, lmidazolidinyl,piperidinyl (e.g. piperidmo, etc.), piperazmyl, etc.; unsaturated 7- to 12-membered (more preferably 9- to10-membered) condensed (preferably bicyclic) heterocyclicgroup containing 1 to 4 nitrogen atom(s), for example,mdolyl, isoindolyl, indolizinyl, benzimidazolyl,

quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; saturated 7- to 12-membered (more preferably 9- to 10-membered) condensed (preferably bicyclic) heterocyclicgroup containing 1 to 4 nitrogen atom(s), for example, 7-azabιcyclo[2.2.1]heptyl,

3-azabιcyclo[3.2.2]nonanyl, etc.;

unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,

oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadιazolyl,1,3,4-oxadιazolyl, 1,2,5-oxadιazolyl, etc.), etc.;

saturated 3- to 8-membered (more preferably 5- to 7-memoered) heteromonocyclic group containing 1 to 2 oxygenatom(s) ana 1 to 3 nitrogen atom(s), for example,

morpholmyl (e.g. morpholino, etc.), sydnonyl, etc.;

unsaturated 7- to 12-membered (more preferably 9- to10-merrbered) conαensed (preferably bicyclic) heterocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogenatom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example,

thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazmyl, etc.;

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example,

thiazolidinyl, etc.;

unsaturated 7- to 12-membered (more preferably 9- to10-membered) condensed (preferably bicyclic) heterocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogenatom(s), for example, benzothiazolyl, benzothiadiazolyl,etc.;

unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 oxygenatom(s), for example, furyl, etc.;

saturated 3- to 8-membered (morepreferably 5- or 6-membered) heterocyclic group containing 1 to 2 oxygenatom(s), for example, oxolanyl, etc.;

unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing an oxygen atomand 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;

unsaturated 7- to 12-membered (more preferably 9- to10-membered) condensed (preferably bicyclic) heterocyclicgroup containing 1 to 2 sulfur atom(s), for example,benzothienyl, benzodithnnyl, etc.;

unsaturateα 7- to 12-membered (more preferably 9- to10-membered) condensed (preferably bicyclic) heterocyclicgroup containing an oxygen atom and 1 to 2 sulfur atom(s),for example, benzoxathnnyl, etc., and the like.

Suitable "lower alkylamino" may include conventionalone such as methylamino, ethylamino, propylamino,

lsopropylamino, butylamino, pentylamino, hexylamino, andthe like, in wnich more preferable example may be C₁-C₄alkylamino and the most preferable one may be methylamino. Preferable Examples of R¹, R², R³, R⁴ and R⁵ are asfollows :

R¹ is hydrogen,

R² is hydrogen or acyl,

R³ is hydrogen or lower alkyl,

R⁴ is heterocyclic(lower)alkyl,

wherein said heterocyclic group being saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) [e.g. 2-(or 4-)- pyridylmethyl, etc.], and

R⁵ is lower alkoxy or lower alkylamino. Another preferable examples ofR¹, R², R³, R⁴ and R⁵ areas follows:

R¹ is hydrogen,

R² is hydrogen; acyl such as oxamoyl; lower alkanoyl;

lower alkanesulfonyl; lower alkoxycarbonyl;

(C₃-C₇)cycloalkanecarbonyl;

di(lower)alkylamino(lower)alkanoyl;

lower alkalcarbamoyl; di(lower)alkylcarbamoyl; N-[(lower)alkylcarbamoyl(lower)alkyl]carbamoyl; C₆-C₁₀aroyl; C₆-C₁₀ arenesulfonyl; C₆-C₁₀ arylcarbamoyl;

heterocyclic-carbonyl optionally substituted by thegroup consisting of acyl such as C₆-C₁₀

ar(lower)alkoxycarbonyl, lower alkyl, hydroxy and oxo,said heterocyclic group being

unsaturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 4nitrogen atom(s),

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4nitrogen atom(s),

unsaturated 7- to 12-membered (more preferably 9-to 10-membered) condensed (preferably bicyclic)

heterocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 2oxygen atom(s), or

saturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 2oxygen atom(s);

heterocyclic-carbamoyl, said heterocyclic group being unsaturated 3- to 8-membered (more preferably 5- orβ-membered) heteromonocyclic group containing 1 to 4nitrogen atom(s),

saturated 3- to 8-membered (more preferably 5- or6-membered) heteromonocyclic group containing 1 to 4nitrogen atom(s),

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2oxygen atom(s);

(C₆-C₁₀)aryloxy(lower)alkanoyl;

heterocyclic(lower)alkanoyl, said heterocyclic groupbeing

unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4nitrogen atom(s)

unsaturated 7- to 12-membered (more preferably 9-to 10-membered) condensed (preferably bicyclic)heterocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2oxygen atom(s), or

lower alkylcarbamoyl(lower)alkanoyl;

carboxy(lower)alkanoyl; protected

carboxy(lower)alkanoyl; hydroxy(lower)alkanoyl;

protected hydroxy(lower)alkanoyl;

lower alkoxy(lower)alkanoyl;

lower alkoxy(lower)alkoxycarbonyl;

amino(lower)alkoxycarbonyl;

protected amino(lower)alkoxycarbonyl;

lower alkoxycarbonyl(lower)alkylcarbamoyl;

lower alkylsulfonyl(lower)alkanoyl;

hydroxy(lower)alkoxycarbonyl;

protected hydroxy(lower)alkoxycarbonyl; lower alkanoylsubstituted by the group consisting of amino andhydroxy; lower alkanoyl substituted by the groupconsisting of protected amino and hydroxy; amino(lower)alkanoyl; or protected

amino(lower)alkanoyl;

R³ is hydrogen or lower alkyl, or the formula:

R⁴ is neterocyclic(lower)alkyl,

said heterocyclic group being

unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s),

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s),

heterocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s), or

saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s),

R⁵ is lower alkoxy or lower alkylamino. The processes for preparing the object compound (I)are explained in detail in the following. Process 1

The object compound (I) or a salt thereof can be

prepared by reacting the compound (II) or its reactivederivative at the carboxy group, or a salt thereof withthe compound (III) or its reactive derivative at the amino group, or a salt thereof.

Suitable reactive derivative at the amino group ofthe compound (III) may include Schiff's base type imino orits tautomerie enamme type isomer formed by the reactionof the compound (III) with a carbonyl compound such asaldehyde, ketone or the like; a silyl derivative formed bythe reaction of the compound (III) with a silyl compoundsuch as bis(trimethylsilyl)acetamide,

mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea orthe like; a derivative formed by reaction of the compound(III) with phosphorus trichloride or pnosgene, and thelike.

Suitable salts of the compound (III) and its reactivederivative can be referred to the acid addition salts asexemplified for the compound (I).

Suitable reactive derivative at the carboxy group ofthe compound (II) may include an acid halide, an acidanhydride, an activated amide, an activated ester, and thelike. Suitable examples of the reactive derivatives maybe an acid chloride; an acid azide; a mixed acid anhydridewith acid such as substituted phosphoric acid [e.g.

dialkylphosphoric acid, phenylphosphoric acid,

diphenylphosphoric acid, dibenzylphosphoric acid,

halogenated phosphoric acid, etc.], dialkylphosphorousacid, sulfurous acid, thiosulfuric acid, sulfuric acid,sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyricacid, isobutyric acid, pivalic acid, pentanoic acid,isopentanoic acid, 2-ethylbutyric acid, tri chloroaceticaciα, etc.] or aromatic carboxylic acid [e.g. benzoicacid, etc.]; a symmetrical acid anhydride; an activatedamide with imidazole, 4-substιtuted imidazole,

dimethylpyrazole, triazole or tetrazole; or an activatedester [e.g. cyanomethyl ester, methoxymethyl ester,

+

dimethylimmomethyi [(CH₃)₂N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dmιtrophenylester, tri chlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl

thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester,piperidyl ester, 8-qumolyl thioester, etc.], or an esterwith a N-hydroxy compound [e.g. N,N-dimethylhydroxylamme,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccimmide,

N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.],and the like. These reactive derivatives can optionallybe selected from them according to the kind of the

compound (II) to be used.

Suitable salts of the compound (II) and its reactivederivative may be the same as those for the compound (I).

The reaction is usually carried out in a conventionalsolvent such as water, alcohol [e.g. methanol, ethanol,etc.], acetone, dioxane, acetonitrile, chloroform,

methylene chloride, ethylene chloride, tetrahydrofuran,ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influencethe reaction. These conventional solvent may also be usedm a mixture with water.

In this reaction, when the compound (II) is used in afree acid form or its salt form, the reaction is

preferaoly carried out in the presence of a conventionalcondensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;

N-cyclohexyl-N'-(4-dιethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-dnsopropylcarbodiimide;1-ethyl-3-(3-dιmethylaminopropyl)carbodiimide (WSCD);

N,N'-carbonylbis(2-methylimιdazole);

pentamethyleneketene-N-cyclohexyllmine;

diphenylketene-N-cyclohexylimine, ethoxyacetylene;

1-alkoxy-1-chloroethylene, trialkyl phosphite;

ethyl polyphosphate; isopropyl polyphosphhte; phosphorus oxychloride (phosphoryl chloride);

phosphorus trichloride; diphenylphosphorylazide;

thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.];tripnenylphosphine; 2-ethyl-7-hydroxybenzιsoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide

intramolecular salt; N-hydroxybenzotriazole (HOBT);

1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;so-called Vilsmeier reagent prepared by the reaction ofN,N-dimethylformamide with thionyl chloride, phosgene,trichioromethyl chloroformate, phosphorus oxychloride,etc.; or the like.

The reaction may also be carried out in the presenceof an inorganic or organic base such as an alkali metalbicarbonate, tri (lower)alkylamine (e.g. triethylamme,etc.), pyridine, N-(lower)alkylmorpholme,

N,N-di(lower)alkylbenzylamine, N,N-diiospropyl-N-ethylamine, or the like.

The reaction temperature is not critical, and thereaction is usually carried out under cooling to warming. Process 2

The object compound (I-b) or a salt thereof can beprepared by subjecting the compound (I-a) or a saltthereof to a removal reaction of the phthalimido moiety.

Suitable salts of the compound (I-a) and (I-b) can bereferred to the ones as exemplified for the compound (I).

This reaction can be carried out by a conventionalmethod which can convert the phthalimido moiety to aminomoiety such as reacting with lower alkylamine (e.g.

methylamme, etc.), reacting with hydrazine or its hydrate (e.g. hydrazine monohydrate, etc.), reacting with

arylhydrazme or its salt (e.g. phenylhydrazme

hydrochloride, etc.), reducing with a suitable reducingagent (e.g. sodium borohydride, etc.), reacting with a combination of sodium sulfide or its hydrate (e.g. sodiumsulfide monohydride, etc.) and 1,3-dicyclohexylcarbodnmide (DCC), and the like.

This reaction is usually carried out in a

conventional solvent which does not adversely influencetne reaction such as water, alcohol (e.g. methanol,ethanol, propanol, etc.), dioxane, tetrahydrofuran, aceticacid, buffer solution (e.g. phosphate buffer, etc.), andthe like, or a mixture thereof.

The reaction temperature is not critical and thereaction is usually carried out under from cooling toheating. Process 3

The object compound (i-c) or a salt thereof can beprepared by alkylatmg the amino group of a compound (i-b)or a salt thereof.

Suitable salts of the compounds (i-b) and (i-c) canbe referred to the ones as exemplified for the compound(I).

Suitable alkylating agent used in this reaction mayinclude a conventional one which is capable of alkylatmgamino group to alkylamino group such as dialkyl sulfate(e.g. dimethyl sulfate, diethyl sulfate, etc.), alkylsulfonate (e.g. methyl sulfonate, etc.), alkyl halide (e.g. methyl iodide, ethyl iodide, propyl bromide, etc.),diazoalkanes (e.g. diazomethane, diazoethane, etc.),a combination of formaldehyde and a suitable reducingagent (e.g. sodium cyanoborohydnde, etc.), and the like. This reaction is preferably carried out in thepresence of an inorganic or organic base such as thosegiven m the explanation of the Process 1. Furtner, this reaction is usually carried out in a conventional solvent which does not adversely influencethe reaction such as water, acetone, dichloromethane,methanol, ethanol, propanol, pyridine,

N,N-dimethylformamide, or a mixture thereof.

Tne reaction temperature is not critical and thereaction is usually carried out under from cooling towarming. Process 4

The object compound (I-e) or a salt thereof can beprepared by acylatmg the compound (I-d) or a salt

thereof.

Suitable acylatmg agent used in this reaction may bea conventional acylatmg agent which is capable ofintroducing the acyl group as mentioned before such ascarboxylic acid, carbonic acid, sulfonic acid and theirreactive derivative, for example, an acid halide, an acidanhydride, an activated amide, an activated ester, and thelike. Preferable examples of such reactive derivative mayinclude acid chloride, acid bromide, a mixed acid

anhydride with an acid such as substituted phosphoric acid(e.g. dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphori c acid, dibenzylphosphoric acid,

halogenated phosphoric acid, etc.), dialkylphosphorousacid, sulfurous acid, thiosulfuric acid, sulfuric acid,alkyl carbonate (e.g. methyl carbonate, ethyl carbonate,propyl carbonate, etc.), aliphatic carboxylic acid (e.g.pivalic acid, pentanoic acid, isopentanoic acid,

2-ethylbutyric acid, trichloroacetic acid, etc.), aromaticcarboxylic acid (e.g. benzoic acid, etc.), a symmetricalacid anhydride, an activated acid amide with a

heterocyclic compound containing imino function such asimidazole, 4-substιtuted imidazole, dimethylpyrazole,triazole and tetrazole, an activated ester (e.g.

p-nitrophenyl ester, 2,4-dinιtrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,

mesylpnenyl ester, phenylazophenyl ester, phenyl

thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyridyl ester, piperidinyl ester,8-qumolyl thioester, or an ester with a N-hydroxy

compound sucn as N,N-dimethylhydroxylamine,

1-hydroxy-2-(1H)-pyridone, N-hydroxysuccmimide,

N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorooenzotriazole, etc.), isocyanate compound such asphenyl isocyanate, etc., and the like. This reaction can be carried out m the presence ofan organic or inorganic base such as alkali metal (e.g.lithium, sodium, potassium, etc.), alkaline earth metal(e.g. calcium, etc.), alkali metal hydride (e.g. sodiumhydriαe, etc.), alkaline earth metal hydride (e.g. calciumhydride, etc.), alkali metal hydroxide (e.g. sodiumhydroxide, potassium hydroxide, etc.), alkali metalcarbonate (e.g. sodium carbonate, potassium carbonate,etc.), alkali metal bicarbonate (e.g. sodium bicarbonate,potassium bicarbonate, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodiumacetate, etc.), trialkylamine (e.g. triethylamine, etc.),pyridine compound (e.g. pyridine, lutidine, picolme, 4-dιmethylaminopyridine, etc.), qumolme, and the like. In case that the acylatmg agent is used in a freeform or its salt in this reaction, the reaction is

preferably carried out in the presence of a condensingagent such as a carbodiimide compound [e.g.

N,N'-dicyclohexylcarbodiimide,

N-cyclohexyl-N'-(4-dιethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodnmide, N,N'-dnsopropylcarbodiimide,N-ethyl-N'-(3-dιmethylaminopropyl)carbodiimide, etc.], a ketenimine compound (e.g. N,N'-carbonylbis(2-methylimidazole), pentamethyieneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimme, etc.);

an olefinic or acetylenic ether compounds (e.g.

ethoxyacetylene, β-chlorovmylethyl ether), a sulfonicacid ester of N-hydroxybenzotriazole derivative [e.g.

1-(4-chlorooenzenesulfonyloxy)-6-chloro-1H-benzotriazole,etc.], a combination of trialkylphosphite or

triphenylphosphme and carbon tetrachloride, disulfide ordiazenedicarboxylate (e.g. diehyl diazenedicarboxylate,etc.), a phosphorus compound (e.g. ethyl polyphosphate,isopropyl polyphosphate, phosphoryl chloride, phosphorustrichloride, etc.), thionyl chloride, oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, a reagent (referred to a so-called "Vilsmeierreagent") formed by the reaction of an amide compound suchas N,N-di(lower)alkylformamide (e.g. dimethylformamide,etc.), N-methylformamide or the like, with a halogencompound such as thionyl chloride, phosphoryl chloride,phosgene or the like.

The reaction is usually carried out m a conventionalsolvent which does not adversely influence the reactionsuch as water, acetone, dichloromethane, alcohol (e.g.methanol, ethanol, etc.), tetrahydrofuran, pyridine,N,N-dimethylformamide, etc., or a mixture thereof. The reaction temperature is not critical and thereaction is usually carried out under from cooling toheating. Process 5

The object compound (i-g) or a salt thereof can beprepared by subjecting the compound (i-f) or a saltthereof to a removal reaction of the hydroxy-protectivegroup. Suitable salts of the compounds (i-f) and (i-g) canbe referred to the ones as exemplified for the compound (I).

Tie present reaction is usually carried out by aconventional method such as hydrolysis, reduction, and thelike. (l) Hydrolysis :

Hydrolysis is preferably carried out in the presenceof a base or ar acid. Suitable base may include an alkalimetal hydroxide (e.g. sodium hydroxide, potassium

hydroxide, etc.), an alkaline earth metal hydroxide (e.g.magnesium hydroxide, calcium hydroxide, etc.), alkalimetal hydride (e.g. sodium hydride, potassium hydride,etc.), alkaline earth metal hydride (e.g. calcium hydride,etc.), alkali metal alkoxide (e.g. sodium methoxide,sodium etnoxide, potassium t-butoxide, etc.), an alkalimetal carbonate (e.g. sodium carbonate, potassium

carbonate, etc.), an alkaline earth metal carbonate (e.g.magnesium carbonate, calcium carbonate, etc.), an alkalimetal bicarbonate (e.g. sodium bicarbonate, potassiumbicarbonate, etc.), and the like. Suitable acid may include an organic acid (e.g.

formic acid, acetic acid, propionic acid, trifluoroaceticacid, benzenesulfonic acid, p-toluenesulfonic acid, etc.)and an inorganic acid (e.g. hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, etc.). The acidichydrolysis using trifluoroacetic acid is usually

accelerated by addition of cation trapping agent (e.g.phenol, anisole, etc.).

In case that the hydroxy-protective group is

tri(lower)alkylsilyl, the hydrolysis can be carried out inthe presence of tri(lower)alkylammonium fluoride (e.g.tributylammonium fluoride, etc.). This reaction is usually carried out in aconventional solvent which does not adversely influencethe reaction sucn as water, diehloromethane, alcohol (e.g.methanol, etnanol, etc.), tetrahydrofuran, dioxane,acetone, etc., or a mixture thereof. A liquid base oracid can be also used as the solvent. The reaction temperature is not critical and thereaction is usually carried out under from cooling toheating. (ii) Reduction :

Tne reduction method applicable for this removalreaction may include, for example, reduction by using acombination of a metal (e.g. zinc, zinc amalgam, etc.) ora salt of chrome compound (e.g. chromous chloride,

chromous acetate, etc.) and an organic or inorganic acid(e.g. acetic acid, propionic acid, hydrochloric acid,sulfuric acid, etc.); and conventional catalytic reductionin the presence of a conventional metallic catalyst suchas palladium catalysts (e.g. spongy palladium, palladiumblack, palladium oxide, palladium on carbon, palladiumhydroxide on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.),nickel catalysts (e.g. reduced nickel, nickel oxide, Raneynickel, etc.), platinum catalysts (e.g. platinum plate,spongy platinum, platinum black, colloidal platinum,platinum oxide, platinum wire, etc.), and the like.

ln case that the catalytic reduction is applied, thereaction is preferably carried out in the presence of anacid (e.g. formic acid, etc.).

This reaction is usually carried out in a

conventional solvent which does not adversely influencethe reaction such as water, alcohol (e.g. methanol,ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, etc.), andthe like, or a mixture thereof.

The reaction temperature is not critical and thereaction is usually carried out under from cooling towarming.

In case that the hydroxy-protective group is

allyloxycarbonyl group, it can be deprotected by

hydrogenolysis using a palladium compound.

Suitable palladium compound used in this reaction maybe palladium on carbon, palladium hydroxide on carbon,palladium chloride, a palladium-ligand complex such astetrakis(triphenylphosphme)palladium(0),

bis(dibenzylideneacetone)palladium(0),

di[1,2-bis(diphenyl phosphmo)ethane]palladium(0),tetrakis(triphenylphosphite)palladium(0),

tetrakis(triethyl phosphite)palladium(0), and the like.

This reaction can preferable be carried out in thepresence of a scavenger of allyl group generated in situ,such as amine (e.g. morpholme, N-methylaniline, etc.), anactivated methylene compound (e.g. dimedone,

benzoylacetate, 2-methyl-3-oxovaleric acid, etc.),a cyanohydrin compound (e.g. α-tetrahydropyranyloxybenzyl-cyanide, etc.), lower alkanoic acid or a salt thereof(e.g. formic acid, acetic acid, ammonium formate, sodiumacetate, etc.), N-hydroxysuccinimide, and the like.

This reaction can be carried out in the presence of abase such as lower alkylamine (e.g. butylamine,

triethylamine, etc.), pyridine, and the like.

When palladium-ligand complex is used in this

reaction, the reaction can preferably be carried out inthe presence of the corresponding ligand (e.g.

triphenylphosphme, triphenyl phosphite, triethyl

phosphite, etc.).

This reaction is usually carried out in a

conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol,dioxane, tetrahydrofuran, acetonitrile, chloroform,diehloromethane, dichloroethane, ethyl acetate, etc., or amixture thereof.

The reaction can be selected according to the kind ofhydroxy-protective group to be eliminated. Process 6

The compound (I-i) or a salt thereof can be preparedby reacting the compound (I-h) or a salt thereof with thecompound (IV) or its reactive derivative at the aminogroup, or a salt thereof.

Suitable salts of the compounds (I-g) and (I-h) maybe the same as those for the compound (I).

Suitable salts of the compound (IV) may be the sameacid addition salts as exemplified for the compound (I).

Suitable reactive derivative of the compound (IV) canbe referred to the ones as exemplified for the compound(III).

The reaction is usually carried out in a conventionalsolvent which does not adversely influence the reactionsuch as water, acetone, dioxane, dimethylformamide,diehloromethane, chloroform, pyridine, etc., or a mixturethereof.

The reaction temperature is not critical and thereaction is usually carried out under from cooling towarming. Process 7

The compound (I-k) or a salt thereof can be preparedby subjecting the compound (I-j) or a salt thereof to aremoval reaction of the carboxy-protective group on

Suitable salts of the compounds (I-k) and (I-j) maybe the same as those for the compound (I). The reaction is usually carried out in substantiallythe same manner as those for the process 5, and thereforetne reagents to be used and tne reaction condition (e.g.solvent, reaction temperature, etc.) can be referred tothose of the Process 5. Process 8

The compound (I-m) or a salt thereof can be preparedby subjecting the compound (I-ℓ) or a salt thereof to aremoval reaction of the amino-protective group on

Suitable salts of the compounds (1-ℓ) and (I-m) maybe the same as those for the compound (I). The reaction is usually carried out in substantiallythe same manner as those for the Process 5, and thereforethe reagents to be used and the reaction condition (e.g.solvent, reaction temperature, etc.) can be referred tothose of the Process 5. Process 9

The compound (I-o) or a salt thereof can be preparedby subjecting the compound (I-n) or a salt thereof to aremoval reaction of the hydroxy-protective group on

²f Suitable salts of the compounds (I-n) and (I-o) maybe the same as those for the compound (I). The reaction is usually carried out in substantiallythe same manner as those for the Process 5, and thereforethe reagents to be used and the reaction condition (e.g.solvent, reaction temperature, etc.) can be referred tothose of the Process 5. Process 10

The compound (I-q) or a salt thereof can be preparedby reacting the compound (I-p) or a salt thereof withlower alkylamine.

Suitable salts of the compounds (I-p) and (I-q) maybe the same as those for the compound (I). The reaction is usually carried out in a conventionalsolvent which does not adversely influence the reactionsuch as water, acetone, diehloromethane, alcohol (e.g.

methanol, ethanol, etc.), tetrahydrofuran, pyridine,

N,N-dimethylformamide, etc., or a mixture thereof. The reaction temperature is not critical and thereaction is usually carried out under from cooling towarming. The compounds obtained by the above processes can beisolated and purified by a conventional method such aspulverization, recrystallization, column chromatography,reprecipitation, or the like.

The object compound (I) can be transformed into itssalt in a conventional manner.

It is to be noted that the compound (I) and the othercompounds may include one or more stereoisomers due toasymmetric carbon atoms, and all of such isomers andmixture thereof are included withm the scope of thisinvention. Collagenases initiate the degradation of collagen invertebrates and in addition to their normal function inthe metabolism of connective tissue and wound healing, ithas been implicated in a number of pathological conditionssuch as joint destruction in rheumatoid arthritis,

periodontal disease, corneal ulceration, tumor metastasis, osteoarthritis, decubitus restenosis after thepercutaneous transluminal coronary angiopsty,

osteoporosis, proriasis, chronic active heatitis,

autoimmune Keratitis, and the like, and therefore thecompound of the present invention is useful for treatingand/or preventing such pathological conditions. For therapeutic purpose, the peptide compound (I) anda pharmaceutically acceptable salt thereof of the presentinvention can be used in a form of pharmaceutical

preparation containing one of said compounds, as an activeingredient, in admixture with a pharmaceutically

acceptable carrier such as an organic or inorganic solidor liquid excipient suitable for oral, parenteral orexternal administration. The pharmaceutical preparationsmay be capsules, tablets, dragees, granules, solution,suspension, emulsion, sublmgual tablet, suppositories,ointment, and the like. If desired, there may be includedin these preparations, auxiliary substances, stabilizingagents, wetting or emulsifying agents, buffers and othercommonly used additives. While the dosage of the compound (I) will varydepending upon the age and condition of the patient, inthe case of intravenous administration, a daily dose of 0.01 - 100 mg of the active ingredient per kg weight of ahuman being, m the case of intramuscular administration,a daily dose of 0.05 - 100 mg of the same per kg weight ofa human being, in case of oral administration, a dailydose of 0.1 - 100 mg of the same per kg weight of a humanbeing is generally given for the treatment of collagenase-mediated diseases. In order to illustrate the usefulness of the objectcompound (I), the pharmacological test data of a representative compound of the compound (I) are shown inthe following. Inhibitory activity of collagenase 1. Test method

Human collagenase was prepared from the culturemedium of human skin fibroblast stimulated by

mterleukm-lβ (1 ng/ml). Latent collagenase was

activated by incubation with trypsin (200 μg/ml) at 37°Cfor 60 minutes and the reaction was stopped by addingsoybean trypsin inhibitor (800 μg/ml). Collagenaseactivity was determined using FTTC-labeled calf skin typeI collagen. FITC-collagen (2.5 mg/ml) was incubated at37°C for 120 minutes with the activated collagenase andtest compound in 50 mM Tris buffer (containing 5 mM CaCl₂,200 mM NaCl and 0.02% NaN₃, pH 7.5). After stopping theenzyme reaction by adding equal volume of 70% ethanol-200mM Tris buffer (pH 9.5), the reaction mixture was

centri fuged, and collagenase activity was estimated bymeasuring the fluorescence intensity of supernatant at 495nm (excitation) and 520 nm (emission). 2. Test Compound Compound A (The compound of Example 12-4; 3. Test Result

The following examples are given for purpose ofillustrating the present invention in detail. In these examples, there are employed the followingabbreviations in addition to the abbreviations adopted bythe lUPAC-IUB.

The following Preparations and Examples are given forthe purpose of illustrating the present invention in moredetail.

Preparation 1

Thionyl chloride (73 ml) was added dropwise into

absolute ethanol (300 ml) at 0°C. After L-4-pyridylalanineD-tartrate (31.6 g) was added portionwise, the suspension wasslowly heated to reflux and stirred overnight. The solventwas evaporated to one third volume in vacuo, and was

triturated with ethyl acetate to give L-4-pyridylalanineethyl ester dihydrochloride (24.7 g).

= +24.0° (c 0.99, H₂O)

mp : 185-186°C

NMR (D₂O, δ) : 3.60 (1H, dd, J=14, 7Hz), 3.68 (1H, dd, J=14, 8Hz), 3.82 (3H, s), 4.71 (1H, dd, J=8, 7Hz), 8.08 (2H, d, J=7Hz), 8.80 (2H, d, J=7Hz) HPLC : 8.4 minutes(min.) (Crownpak CR(+),

4 mmΦ x 15 cm, pH 1.0 HClO₄aq., 210 nm, flow rate 0.5 ml/min., at R.T.)

MASS : M+H=181 Preparation 2

To a solution of (3R)-3-carboxy-5-methyl-2- (phthalimidomethyl)hexanoic acid tert-butyl ester (5.00 g) inDMF (50 ml) were added HOBT (2.08 g), WSCD (2.39 g), L-4-pyridylalanine methyl ester dihydrochloride (3.90 g), andN,N-dnsopropyl-N-ethylamine (4.03 g) at 0°C. The mixturewas stirred at room temperature for 15 hours. The reactionmixture was poured into brine, and was extracted with ethylacetate. The extract was washed with saturated ammoniumchloride, saturated sodium bicarbonate, and brine

successibly. The organic layer was dried over magnesiumsulfate (MgSO₄) and was concentrated in vacuo. The residuewas purified by silica gel column chromatography (eluent :ethyl acetate) to give N-[(2R)-4-tert-butoxy-2-isobutyl-3- (pnthalimidomethyl)succinyl]-L-4-pyridylalanine methyl ester (5.63 g).

mp : 66-69°C NMR (CDCI₃, δ) : 0.74 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 1.11 (1H, ddd, J=13, 9, 4Hz), 1.27 (9H, s), 1.50 (1H, m), 1.71 (1H, ddd, J=13, 9, 4Hz), 2.65 (1H, m), 2.92 (1H, m), 3.11 (1H, dd, J=14, 8Hz), 3.28 (1H, dd, J=14, 6Hz), 3.58-3.64 (2H, m), 3.75 (3H, s), 5.00 (1H, ddd, J=8, 7.5, 6Hz), 6.88 (1H, d, J=7.5Hz), 7.18 (2H, d, J=7Hz), 7.69-7.77 (2H, m), 7.81-7.90 (2H, m), 8.49 (2H, d, J=7Hz) HPLC : 9.3, 9.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 35:65, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=552 Preparation 3

To a solution of N-[(2R)-4-tert-butoxycarbonyl-2-isobutyl-3-(phthalimidomethyl)succinyl]-L-4-pyridylalaninemethyl ester (5.52 g) in diehloromethane (30 ml) was addedtrifluoroacetic acid (30 ml) at 0°C. The reaction mixturewas stirred at room temperature for 1.5 hours. After thesolvent was concentrated in vacuo, the residue was trituratedwith ethyl acetate to give N-[(2R,3R)-4-hydroxy-2-isobutyl-3-(phthalimidomethyl)succinyl)-L-4-pyridylalanine methyl estertrifluoroacetate (3.50 g).

= -14.7° (c 0.30, 1N-HClaq.)

mp : 190-194°C

NMR (DMSO-d₆, δ) : 0.78 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, ddd, J=13, 11, 2Hz), 1.36 (1H, m), 1.51 (1H, ddd, J=13, 11, 2Hz), 2.43-2.57 (1H, m), 2.62-2.76 (2H, m), 3.10 (1H, dd, J=14, 12Hz), 3.40 (1H, dd, J=14, 5Hz), 3.50 (1H, m), 3.65 (3H, s), 4.89 (1H, ddd, J=12, 8, 5Hz), 7.75 (2H, d, J=βHz), 7.82-7.92 (4H, m), 8.62 (2H, d, J=6Hz), 8.72 (1H, d, J=8Hz)

HPLC : 3.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=496 Preparation 4

Thionyl chloride (73 ml) was added dropwise into

D = +22.6° (c 0.54, 1N-HClaq.)

mp : 160-166°C

NMR (DMSO-d₆, δ) : 1.14 (3H, t, J=7Hz), 3.47 (1H, dd, J=15, 7.5Hz), 3.55 (1H, dd, J=15, 7Hz), 4.15 (2H, m), 4.55 (1H, br), 8.10 (2H, d, J=7Hz), 8.91 (2H, d, J=7Hz), 8.98 (1H, br)

HPLC : 12.3 min. (Crownpak CR(+), 4 mmΦ x 15 cm, pH 1.0

HC10₄aq., 210 nm, flow rate 0.6 ml/min., at R.T.) MASS : M+H=195 Preparation 5

L-4-Pyridylalanine ethyl ester dihydrochloride (24.3 g)was dissolved in H₂O and the pH was adjusted to 8-9 by theaddition of sodium hydrogen carbonate. The solution wassaturated with sodium chloride and was extracted with

chloroform. The extract was dried over MgSO₄ and

concentrated to dryness to give L-4-pyridylalanine ethylester as a pale yellow oil (15.6 g).

NMR (CDCl₃, δ) : 1.23 (3H, t, J=7Hz), 1.49 (2H, br), 2.86 (1H, dd, J=14, 7.5Hz), 3.05 (1H, dd, J=14, 6Hz), 3.73 (1H, dd, J=7.5, 6Hz), 4.17 (2H, q,

J=7Hz), 7.15 (2H, d, J=7Hz), 8.53 (2H, d, J=7Hz) HPLC : 11.2 min. (Crownpak CR(+), 4 mmΦ x 15 cm, pH 1.0

HClO₄aq., 210 nm, flow rate 0.6 ml/min., at R.T.) MASS : M+H=195 Preparation 6

L-4-Pyridylalanine ethyl ester (14.79 g) was dissolvedinto a solution of 20% methylamme in methanol (60 ml), andthe mixture was stirred for 4 hours at room temperature. Thesolution was evaporated to give L-4-pyridylalanine

methylamide (12.59 g).

_D = +20.7° (c 0.55, MeOH)

mp : 48-52°C

NMR (DMSO-d₆, δ) : 1.71 (2H, br), 2.57 (3H, d, J=5Hz), 2.62 (1H, dd, J=14, 8Hz), 2.90 (1H, dd, J=14, 5Hz), 3.38 (1H, dd, J=8, 5Hz), 7.21 (2H, d, J=6Hz), 7.82 (1H, q, J=5Hz), 8.44 (2H, d, J=6Hz)

HPLC : 11.2 min. (Crownpak CR(+), 4 mmΦ x 15 cm, pH 1.0

HC10₄aq., 210 nm, flow rate 0.6 ml/min., at R.T.) MASS : M+H=180 Preparation 7

To a solution of (3R)-3-carboxy-5-methyl-2- (phthalimidomethyl)hexanoic acid tert-butyl ester (10.13 g)m DMF (100 ml) were added HOBT (3.87 g), WSCD·HCl (5.49 g),and L-4-pyridylalanine methylamme (4.89 g) at 0°C. Themixture was stirred at room temperature for 3 nours. Thereaction mixture was poured into brine, and was extractedwith ethyl acetate. The extract was washed with saturatedammonium chloride, saturated sodium bicarbonate, and brinesuccessibly. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was purified by silicagel column chromatography (eluent : methanol/ethyl acetate =1/10) to give N-[(2R)-4-tert-butoxy-2-isobutyl-3-(phthalimidomethyl)succinyl]-L-4-pyridylalanine methylamide(13.8 g).

mp : 92-95°C

NMR (CDCl₃, δ) : 0.67-0.88 (7H, m), 1.13 (1H, m), 1.28 (9Hx3/4, s), 1.31 (9Hxl/4, s), 1.65 (1H, m), 2.50 (1Hx1/4, m), 2.62 (1HX3/4, m), 2.77 (3Hx3/4, d, J=5Hz), 2.80 (3Hx1/4, d, J=5Hz), 2.90 (1H, m), 3.11 (1H, m), 3.27 (1H, m), 3.52-3.60 (2H, m), 4.72 (1Hx1/4, m), 4.78 (1HX3/4, m), 6.31 (1HX3/4, m), 6.48 (1Hx1/4, m), 6.94 (1HX3/4, d, J=8Hz), 7.14 (1Hx1/4, d, J=8Hz), 7.20 (2h, d, J=7Hz), 7.68-7.78 (2H, m), 7.80 (2H, m), 8.47 (2Hx3/4, d, J=7Hz), 8.50 (2Hxl/4, d, J=7Hz)

HPLC : 6.0, 6.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 35:65, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=551 Preparation 8

N-[(2R)-4-Hydroxy-2-isobutyl-3-(phthalimidomethyl)-succinyl]-L-4-pyridylalanine methylamide trifluoroacetate wasobtained in substantially the same manner as that of

Preparation 3.

mp : 180-185°C

NMR (DMSO-d₆, δ) : 0.72-0.87 (6H, m), 0.92 (1H, m), 1.33 (1H, m), 1.49 (1H, m), 2.47-2.70 (3H, m), 2.59 (3Hx1/4, d, J=5Hz), 2.62 (3Hx3/4, d, J=5Hz), 2.97 (1H, dd, J=14, 11.5Hz), 3.17 (1H, dd, J=14, 5Hz), 3.48 (1H, m), 4.59 (1Hx1/4, m), 4.75 (1HX3/4, m), 7.68 (2Hx3/4, d, J=7Hz), 7.72 (2Hxl/4H, d, J=7Hz), 7.80-7.91 (4H, m), 7.96 (1H, m), 8.40 (1Hx1/4, d, J=8Hz), 8.54 (1HX3/4, d, J=8Hz), 8.57 (2Hx3/4, d, J=8Hz), 8.72 (2Hxl/4, d, J=7Hz)

HPLC : 5.1, 8.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., ar R.T.)

MASS : M+H=495 Preparation 9 L-2-Pyridylalanine methyl ester dihydrochloride wasobtained m substantially the same manner as that of

Preparation 4.

D² = +28.3° (c 1.03, H₂0)

mp : 209-213°C

NMR (DMSO-d₆, δ) : 3.58 (2H, d, J=7Hz), 3.67 (3H, s), 4.62 (1H, br), 7.70 (1H, m), 7.80 (1H, br d,

J=7.5Hz), 8.23 (1H, m), 8.71 (1H, d, J=5Hz), 8.91 (2H, br)

HPLC : 10.4 min. (Crownpak CR(+), 4 mmΦ x 15 cm, pH 1.0

HClO₄aq., 210 nm, flow rate 0.5 ml/min., at R.T.) MASS : M+H=181 Preparation 10

L-2-Pyridylalanine methyl ester dihydrochloride (10.0 g)was dissolved in saturated sodium hydrogen carbonate (10 ml). The solution was saturated with sodium chloride and extractedwith chloroform (300 ml x 3). After the extract was

concentrated to dryness, the residue was dissolved in 40%methylamme in methanol (30 ml). The mixture was stirred for 1 hour at room temperature. The solution was evaporated togive L-2-pyridylalanine methylamide (7.0 g).

Rf : 0.19 (methanol/chloroform = 1/5) Preparation 11

N-[(2R,3R)-4-tert-Butoxy-2-isobutyl-3- (phthalimidomethyl)succinyl]-L-2-pyridylalanine methyl esterwas obtained in substantially the same manner as that of

Preparation 7.

Rf : major isomer 0.42, minor isomer 0.46

(methanol/chloroform = 1/10) Preparation 12

N-[(2R)-4-tert-Butoxy-2-isobutyl-3-(phthalimidomethyl)-succinyl]-L-2-pyridylalanine methylamide (14.0 g) was dissolved in trifluoroacetic acid (30 ml) at 0°C. Thereaction mixture was stirred at room temperature for 0.5hour. After the solvent was concentrated in vacuo, theresidue was poured into saturated sodium hydrogen carbonate.The solution was extracted with chloroform. The organiclayer was concentrated in vacuo and the residue was

triturated with ethyl acetate to give N-[(2R)-4-hydroxy-2-isobutyl-3-(phthalimidomethyl)succinyl)-L-2-pyridylalaninemethylamide (3.50 g).

HPLC : 3.7, 4.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.) Preparation 13

To a stirred suspension of glycine methyl ester

hydrochloride (1.70 g) in diehloromethane (15 ml) was addedtri ethylamine (3.01 g) and phenyl chloroformate (2.12 g) at0°C. The mixture was stirred at 0°C for 30 minutes. Thereaction mixture was poured into water and was extracted withdiehloromethane. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated mvacuo. The residue was purified by a silica gel columncnromatography (ethyl acetate:hexane = 1:1) to give

N-phenoxycarbonylglycme methyl ester (1.37 g) as a whitecrystal.

mp : 46-47°C

NMR (CDCl₃, δ) : 3.79 (3H, s), 4.07 (2H, d, J=7Hz), 5.52 (1H, br), 7.13 (2x1H, d, J=7.5Hz), 7.20 (1H, dd, J=7.5, 7.5Hz), 7.36 (2x1H, dd, J=7.5, 7.5Hz) MASS : M+H=210 Preparation 14

N-[(2R)-4-tert-Butoxy-2-isobutyl-3- phthalimidomethylsuccinyl]-L-3-pyridylalanine methyl ester was obtained in substantially the same manner as that of Preparation 7.

mp : 65-68°C

NMR (CDCl₃, δ) : 0.75-0.90 (6H, m), 1.10 (1H, ddd,

J=11, 11, 3Hz), 1.27 (3x3H, s), 1.50 (1H, m), 1.70 (1H, m), 2.67 (1H, m), 2.90 (1H, m), 3.13 (1H, dd, J=14, 8Hz), 3.27 (1H, dd, J=14, 6Hz), 3.52 (1H, dd, J=14, 7Hz), 3.69 (1H, dd, J=14, 5Hz), 3.74 (3H, s), 4.98 (1H, m), 6.96 (1H, dd, J=14, 5Hz), 7.22 (1H, dd, J=7.5, 5Hz), 7.62 (1H, m), 7.68-7.76 (2H, m), 7.8G (2H, m), 8.40-8.52 (2H, m)

HPLC : 12.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

acetonitrile:water:trifluoroacetic acid

(MeCN:H₂O:TFA) = 35:65:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=552 Preparation 15

N-[(2R,3R)-4-Hydroxy-2-isobutyl-3-phthalimidomethylsuccinyl]-L-3-pyridylalanine methyl estertrifluoroacetate was obtained in substantially the samemanner as that of Preparation 8.

D⁵ = -18.5° (c 0.17, 1N-HClaq.)

mp : 174-177°C (dec.)

NMR (DMSO-d₆, δ) : 0.77 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, m), 1.35 (1H, m), 1.50 (1H, m), 2.45-2.58 (1H, m), 2.68 (1H, m), 2.79 (1H, dd, J=13, 5Hz), 3.05 (1H, dd, J=13, 11Hz), 3.32 (1H, dd, J=13, 4Hz), 3.54 (1H, dd, J=13, 12Hz), 3.64 (3H, s), 4.79 (1H, ddd, J=11, 8, 4Hz), 7.69 (1H, dd, J=7.5, 6Hz), 7.81-7.91 (4H, m), 8.23 (1H, d, J=7.5Hz), 8.51 (1H, d, J=6Hz), 8.69 (1H, d, J=8Hz), 8.73 (1H, s)

HPLC : 4.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm, MeCN :

0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.) MASS : M+H=496 Example 1-1)

To a solution of N-[(2R,3R)-4-hydroxy-2-isobutyl-3-(phthalimidomethyl)sucemyl]-L-4-pyridylalanine methyl estertrifluoroacetate (3.26 g) and HOBT (0.87 g) m DMF (30 ml)was added WSCD (1.00 g) at 0°C. After the mixture wasstirred for 10 minutes, O-benzylhydroxylamme hydrochloride(1.02 g) and N,N-diisopropyl-N-ethylamme (0.84 g) wereadded. The mixture was stirred at room temperature for 15hours. The mixture was poured into brine (100 ml). Theprecipitate was collected by filtration and was washed withwater and ethyl acetate to give N-[(2R,3R)-4-(N-benzyloxyamino)-2-isobutyl-3-(phthalimidomethyl)suceinyl]-L-4-pyridylalanine methyl ester (2.10 g).

= -52.8° (c 0.30, DMSO)

mp : 245-248°C (dec.)

NMR (DMSO-d₆, δ) : 0.70-0.84 (1H, m), 0.76 (3H, d,

J=7Hz), 0.80 (3H, d, J=7Hz), 1.30-1.47 (2H, m), 2.29-2.57 (3H, m), 2.89 (1H, dd, J=14, 12Hz), 3.20 (1H, dd, J=14, 4Hz), 3.45 (1H, m), 3.64 (3H, s), 4.25 (1H, d, J=12Hz), 4.54 (1H, d, J=12Hz), 4.77 (1H, ddd, J=12, 8, 4Hz), 7.05 (2H, d, J=7.5Hz), 7.15-7.27 (3H, m), 7.30 (2H, d, J=7Hz), 7.85 (4H, s), 8.28 (2H, d, J=7Hz), 8.64 (1H, d, J=8Hz), 11.06 (1H, s)

HPLC : 9.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=601 Example 1-2)

To a solution of N-[(2R)-4-hydroxy-2-isobutyl-3- (phthalimidomethyl)succinyl]-L-4-pyridylalanine methylamidetrifluoroacetate (5.18 g) and HOBT (1.27 g) m DMF (50 ml) was added WSCD (1.46 g) at 0°C. After the mixture wasstirred for 10 minutes, O-benzylhydroxylamine hydrochloride (1.63 g) and N,N-dιιsopropyl-N-ethylamine (1.34 g) wereadded. The mixture was stirred at room temperature for 4hours. The mixture was poured into brine (100 ml). Theprecipitate was collected by filtration and was washed withwater and ethyl acetate to give N-[(2R,3R)-4-(N-benzyloxyamino)-2-isobutyl-3-(phthalimidomethyl)succinyl]-L-4-pyridylalanine methylamide (3.40 g).

D = +2.8° (c 0.10, DMSO)

mp : 263-269°C (dec.)

NMR (DMSO-d₆, δ) : 0.70-0.85 (1H, m), 0.73 (3H, d,

J=7Hz), 0.81 (3H, d, J=7Hz), 1.22-1.45 (2H, m), 2.21 (1H, ddd, J=13, 3, 2Hz), 2.32 (1H, ddd, J=11, 11, 3Hz), 2.50 (1H, dd, J=13, 11Hz), 2.61 (3H, d, J=5Hz), 2.80 (1H, dd, J=14, 11Hz), 3.00 (1H, dd, J=14, 5Hz), 3.40 (1H, dd, J=13, 11Hz), 4.26 (1H, d, J=12Hz), 4.55 (1H, d, J=12Hz), 4.67 (1H, ddd, J=11, 8, 5Hz), 7.03-7.09 (2H, m), 7.15-7.25 (3H, m), 7.30 (2H, d, J=6Hz), 7.85 (4H, s), 7.90 (1H, d, J=5Hz), 8.23 (2x1H, d, J=6Hz), 8.45 (1H, d, J=8Hz) HPLC : 6.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=600 Example 1-3)

To a solution of N-[(2R)-4-hydroxy-2-isobutyl-3-(phthalimidomethyl)sucemyl]-L-2-pyridylalanine methylamide(7.0 g) and HOBT (2.9 g) m DMF (140 ml) was added WSCD (3.3g) at room temperature. After the mixture was stirred for 10minutes, O-benzylhydroxylamme hydrochloride (3.4 g) and N,N-diisopropyl-N-ethylamine (5 ml) were added. The mixture wasstirred at room temperature for 5 hours. The mixture waspoured into ethyl acetate (100 ml). The insoluble solid was collected by filtration to give N-[(2R)-4-(N-benzyloxyamino)-2-isobutyl-3-(phtnalimidomethyl)succinyl]-L-2-pyridylalamnemethylamine ι3.50 g).

HPCL : 9.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.) Example 2-1)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-(phtnalimidomethyl)succinyl]-L-4-pyridylalanine methyl ester(2.51 g) was dissolved into a solution of 40% methylamme inmethanol (50 ml), and the mixture was stirred for 15 hours atroom temperature. The solution was evaporated and theresidue was dissolved into lN-hydrochloric acid. The

solution was evaporated again and the residue was trituratedwith water. The precipitate was filtered off and the

filtrate was evaporated. The residue was triturated withmethanol - ethyl acetate to give N-[(2R,3R)-3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide dihydrochloride (2.22 g).

= -33.0° (c 0.32, 1N-HClaq.)

mp : 192-199°C

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.84 (1H, m), 1.25 (1H, m), 1.40 (1H, m), 2.30-2.46 (2H, m),2.52-2.80 (2H, m), 2.60 (3H, d, J=4.5Hz), 3.14 (1H, dd, J=14, 11Hz), 3.28 (1H, dd, J=14, 5Hz), 4.67 (1H, ddd, J=11, 8, 5Hz), 4.83 (1H, d, J=11Hz), 4.87 (1H, d, J=11Hz), 7.31-7.48 (5H, m), 8.00 (2H, d, J=7Hz), 8.11 (2H, br), 8.21 (1H, q, J=4.5Hz), 8.63 (1H, d, J=8Hz), 8.91 (2H, d, J=7Hz)

MASS : M+H=470 Example 2-2)

To a suspension of N-[(2R,3R)-4-(N-benzyloxyamino)-2- isobutyl-3-(phthalimidomethyl)sucemyl]-4-pyridyIalaninemethylamide (484 mg) in ethanol was added hydrazine

monohydrate (0.5 ml). The mixture was refluxed for 2 hours.The solution was evaporated and to the residue was addedchloroform. After the insoluble material was filtered off,the filtrate was concentrated in vacuo to give N-[(2R,3R)-3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide (293 mg).

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.74-0.89 (1H, m), 0.79 (3H, d, J=7Hz), 1.18-1.38 (2H, m), 1.87- 2.00 (2H, m), 2.25 (1H, m), 2.41 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.80 (1H, dd, J=13, 10Hz), 2.94 (1H, dd, J=13, 4Hz), 4.55 (1H, ddd, J=10, 8, 4Hz), 4.78 (2H, s), 7.18-7.43 (7H, m), 7.87 (1H, d, J=4.5Hz), 8.30 (1H, d, J=8Hz), 8.45 (2H, d, J=7Hz) MASS : M+H=470 Example 2-3)

To a suspension of N-(2R,3R)-4-(N-benzyloxyamino)-2-isobutyl-3-(phthalimidomethyl)succinyl]-L-2-pyridylalaninemethylamide (3.5 g) in ethanol was added hydrazine

monohydrate (3.5 ml). The mixture was refluxed for 30minutes. The solution was evaporated and to the residue wasadded chloroform. After the insoluble material was filteredoff, the filtrate was evaporated and triturated with ethylacetate to give N-[(2R,3R)-3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-2-pyridylalaninemethylamide (1.7 g).

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.86 (1H, m), 0.77 (3H, d, J=7Hz), 1.15-1.40 (2H, m), 1.84- 1.98 (2H, m), 2.19 (1H, dd, J=13, 10Hz), 2.38 (1H, m), 2.55 (3H, d, J=4Hz), 2.95 (1H, dd, J=14, 11Hz), 3.07 (1H, dd, J=14, 5Hz), 4.71 (1H, ddd, J=11, 8, 5Hz), 4.77 (2H, s), 7.20 (1H, dd, J=7.5, 5Hz), 7.26 (1H, d, J=7.5Hz), 7.31-7.42 (5H, m), 7.64-7.76 (2H, m), 8.25 (1H, d, J=7.5Hz), 8.46 (1H, br d, J=5Hz) MASS : M+H=470 Example 3

To a solution of N-[(2R,3R)-3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-2-pyridylalaninemethylamide (50 mg) in methanol (10 ml) was added 37%

formaldehyde solution (87 mg). After being stirred for 30minutes soαium cyanoborohydride (67 mg) was added and the pHwas adjusted to 3 by the addition of 1N hydrochloric acid(HCl). The mixture was stirred at room temperature for 30minutes. Methanol was evaporated and the residue was pouredinto chloroform and the solution was extracted with 1N-HCl.The aqueous layer was neutralized with sodium hydrogencarbonate and re-extracted with chloroform. The organiclayer was dried over MgSO₄ and concentrated in vacuo. Theresidue was triturated with ethyl acetate to give N-[(2R,3R)-4-(N-benzyloxyamino)-2-isobutyl-3-(methylaminomethyl)-succinyl]-L-2-pyridylalanine methylamide (412 mg).

[ ]²D^{3 =} -39.2° (c 0.13, 1N-HClaq.)

mp : 179-182°C

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=6Hz), 0.77 (3h, d, J=6Hz), 0.80 (1H, m), 1.19-1.40 (2H, m), 1.86

(0.5xlH, s, rotamer), 2.13 (0.5xlH, s, rotamer), 1.92-2.52 (4H, m), 2.57 (3H, d, J=5Hz), 2.93-3.13 (2H, m), 4.67-4.85 (3H, m), 7.17-8.40 (12H, m) TLC : Rf 0.20 (CHCI₃:MeOH=5:1) Example 4-1)

To a solution of N-[(2R,3R)-N-3-aminomethyl-4-(N-benzyloxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine

methylamide (247 mg) and picolmic acid (62 mg) in DMF (5 ml)were added HOBT (75 mg) and WSCD (90 mg) at 0°C. The mixturewas stirred at 0°C for 1.5 hours. DMF was evaporated and theresidue was poured into water. The precipitate was collected by filtration and washed with water and ethyl acetate to giveN-[(2R,3R)-4-(N-benzyloxyamino)-2-isobutyl-3-[(2-pyridylcarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemethylamide (136 mg).

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.79 (3H, d, J=7riz), 0.84 (1H, m), 1.29 (1H, m), 1.37 (1H, m), 2.36 (1H, ddd, J=10, 9, 4Hz), 2.45-2.63 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.78-2.91 (2H, m), 2.97 (1H, dd, J=14, 6Hz), 3.18 (1H, m), 4.57 (1H, m), 4.57 (1H, d, J=11Hz), 4.71 (1H, d, J=11Hz), 7.20-7.33 (7H, m), 7.60 (1H, m), 7.87 (1H, q, J=4.5Hz), 7.95- 8.05 (2H, m), 8.25 (1H, dd, J=6, 6Hz), 8.37 (2H, d, J=7Hz), 8.45 (1H, d, J=8Hz), 8.62 (1H, br d,

J=5Hz), 11.10 (1H, s)

HPLC : 10.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=575 The following compounds were obtained in substantiallythe same manner as that of Example 4-1). Example 4-2)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(6-methylpyridin-2-yl)carbonylaminomethyl]succinyl]-L-4-pyridylalanine methylamide

= -23.5° (c 0.21, 1N-HClaq.)

mp : 248-254°C

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.84 (1H, m), 1.30 (1H, m), 1.39 (1H, m), 2.35 (1H, ddd, J=10, 9, 4Hz), 2.45-2.63 (1H, m), 2.48 (3H, s), 2.58 (3H, d, J=5Hz), 2.80-2.91 (1H, m), 2.85 (1H, dd, J=14, 11Hz), 2.97 (1H, dd, J=14, 5Hz), 3.13 (1H, m), 4.55 (1H, d, J=11Hz), 4.58 (1H, ddα, J=11, 8, 5Hz), 4.75 (1H, d, J=11Hz), 7.20-7.33 (7h, n), 7.45 (lh, br d, J=7.5Hz), 7.78-7.92 (3H, m), 8.14 (1H, dd, J=6, 6Hz), 8.38 (2H, d, J=6Hz), 8.43 (1H, d, J=8Hz), 11.13 (1H, s)

HPLC : 6.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=589 Example 4-3)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(2-pyridylcarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemethylamide

= -21.6° (c 0.27, 1N-HClaq.)

mp : 252-256°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.84 (1H, m), 1.30 (1H, m), 1.37 (1H, m), 2.36 (1H, ddd, J=9, 9, 4Hz), 2.47-2.61 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.78-2.91 (2H, m), 2.91 (1H, dd, J=14, 5Hz), 3.20 (1H, m), 4.57 (1H, m), 4.57 (1H, d, J=11Hz), 4.72 (1H, d, J=11Hz), 7.20-7.31 (7H, m), 7.60 (1H, m), 7.87 (1H, q, J=4.5Hz), 7.96- 8.05 (2H, m), 8.26 (1H, dd, J=6, 6Hz), 8.37 (2H, d, J=7Hz), 8.45 (1H, d, J=8Hz), 8.63 (1H, br d,

J=4Hz), 11.09 (1H, s)

HPLC : 10.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=575 Example 4-4)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(3-pyridylcarbonyl)aminomethyl]succinyl]-L-4-pyri dylalaninemethylamide

= -23.8° (c 0.20, 1N-HClaq.)

mp : 246-250°C (dec.) NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) , 0.77-0.90 (1H, m) , 0.80 (3H, d, J=7Hz) , 1.28 (1H, m), 1.40 (1H, m) , 2.33 (1H, ddd, J=9, 9, 4Hz) , 2.45-2.56 (1H, m) , 2.59 (3H, d, J=4.5Hz) , 2.74-3.03 (2H, m), 2.85 (1H, dd, J=14, 11Hz) , 2.98 (1H, dd, J=14, 5Hz) , 4.58 (1H, d, J=12Hz), 4.61 (1H, m), 4.74 (1H, d,

J=12Hz), 7.21-7.32 (7H, m), 7.49 (1H, dd, J=7.5, 5Hz), 7.88 (1H, q, J=4.5Hz), 8.12 (1H, br d,

J=7.5Hz), 8.33-8.45 (2H, m), 8.38 (2H, d, J=6Hz), 8.68 (1H, d, J=5Hz), 8.95 (1H, s), 11.04 (1H, s) HPLC : 9.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=575 Example 4-5)

N-[(2R,3R)-4-(N-(Benzyloxyamino)-2-isobutyl-3-[(3-pyridylcarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemethylamide

2 = -23.3° (c 0.24, 1N-HClaq.)

mp : 256-258°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.77-0.89 (1H, m), 0.80 (3H, d, J=7Hz), 1.28 (1H, m), 1.40 (1H, m), 2.33 (1H, ddd, J=9, 9, 4Hz), 2.44-2.55 (1H, m), 2.59 (3H, d, J=4.5Hz), 2.74-2.87 (1H, m), 2.85 (1H, dd, J=13, 10Hz), 2.90-3.03 (1H, m), 2.98 (1H, dd, J=13, 5Hz), 4.58 (1H, d, J=11Hz), 4.61 (1H, m), 4.73 (1H, d, J=11Hz), 7.21-7.31 (7H, m), 7.49 (1H, dd, J=7.5, 5Hz), 7.89 (1H, q, J=4.5Hz), 8.12 (1H, ddd, J=7.5, 1.5, 1.5Hz), 8.34-8.45 (2H, m), 8.37 (2H, d, J=6Hz), 8.69 (1H, dd, J=5, 1.5Hz), 8.95 (1H, d, J=1.5Hz), 11.04 (1H, s)

HPLC : 4.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.) MASS : M+H=575 Example 4-6)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(4-pyridylcarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemethylamide

= -26.3° (c 0.24, 1N-HClaq.)

mp : 255-259°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.75-0.90 (1H, m), 0.80 (3H, d, J=7Hz). 1.28 (1H, m), 1.40 (1H, m), 2.33 (1H, m), 2.58 (3H, d, J=4.5Hz), 2.68-3.03 (5H, m), 4.58 (1H, d, J=11Hz), 4.61 (1H, m), 4.72 (1H, d, J=11Hz), 7.20-7.32 (7H, m), 7.68 (2H, d, J=6Hz), 7.88 (1H, q, J=4.5Hz), 8.37 (2H, d, J=6Hz), 8.41 (1H, d, J=8Hz), 8.48 (1H, dd, J=5, 5Hz), 8.70 (2H, d, J=6Hz), 11.04 (1H, s)

HPLC : 8.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=575 Example 4-7)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(6-methylpyridin-3-yl)carbonylaminomethyl]succinyl]-L-2-pyridylalanine methylamide

= -26.0° (c 0.05, 1N-HClaq.)

mp : 240-242°C (dec.)

HPLC : 3.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=485 Example 4-8)

N-[ (2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[ (2-qumolinecarbonyl)aminomethyl]succinyl]-L-2-pyridylalanine methylamide

HPLC : 17.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.) Example 4-9)

N-[ (2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[3-qumolmecarbonyl)aminomethyl]succinyl]-L-2-pyridylalaninemethylamide

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=6Hz) , 0.81 (3H, d, J=6Hz) , 0.84 (1H, m), 1.28 (1H, m) , 1.43 (1H, m) , 2.32-2.57 (2H, m), 2.59 (3H, d, J=5Hz), 2.80-2.90 (1H, m), 2.94-3.02 (1H, m), 3.03 (1H, dd, J=12, 9Hz) , 3.14 (1H, dd, J=12, 6Hz) , 4.58 (1H, d,

J=11.3Hz) , 4.76 (1H, d, J=11.3Hz) , 4.78 (1H, m), 7.07 (1H, ddd, J=7.5, 6, 1.5Hz) , 7.12-7.25 (5H, m), 7.30 (1H, dd, J=7.5, 1.5Hz), 7.63 (1H, ddd, J=7.5, 6, 1.5Hz) , 7.70 (1H, dd, J=7.5, 1.5Hz) , 7.74-7.80 (1H, m), 7.86 (1H, ddd, J=7.5, 6, 1.5Hz) , 8.07 (2H, ddd, J=7.5, 6, 1.5Hz) , 8.39-8.44 (2H, m), 8.37-8.46 (2H, m), 8.56-8.61 (1H, m), 8.77 (1H, d, J=1.5Hz), 9.25 (1H, d, J=1.5Hz)

HPLC : 6.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=625 Example 4-10)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(6-methylpyridin-2-yl)carbonylaminomethyl]succinyl]-L-2-pyridylalanine methylamide

HPLC : 7.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=589 Example 4-11)

N-[(2R,3R)-4-(N-Benzyloxyamino)-3-[(4-hydroxyqumolin-2-yl)carbonylaminomethyl]-2-isobutylsuccinyl]-L-2-pyridylaianine methylamide

HPLC : 5.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min. at R.T.)

MASS : M+H=641 Example 4-12)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(1-pyrrolidinylcarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemethylamide

= -17.2° (c 0.26,

1N-HClaq.)

mp : 213-216°C (dec.)

NMR (DMSO-d₆, δ) : 0.68 (3H, d, J=7Hz) , 0.75 (3H, d, J=7Hz) , 0.82 (1H, m) , 1.19 (1H, m) , 1.34 (1H, m), 1.66-1.82 (4H, m) , 2.26 (1H, m), 2.44 (1H, m), 2.55 (3H, d, J=4.5Hz) , 2.70-3.03 (4H, m), 3.05-3.24 (4H, m), 4.53 (1H, m), 4.70 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 5.67 (1H, br), 7.23 (2H, d, J=6Hz), 7.35 (5H, s), 7.85 (1H, q, J=4.5Hz), 8.31 (1H, d, J=8Hz), 8.40 (2H, d, J=6Hz), 10.95 (1H, s) HPLC : 4.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=567 Example 4-13)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(3-pyridylcarbonyl)aminomethyl]succinyl]-L-2-pyridylalaninemethylamide

HPLC : 3.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min. at R.T.) Example 4-14)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(2-pyridylcarbonyl)aminomethyl]sucemyl]-L-2-pyridylalaninemethylamide

HPLC : 6.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.) Example 5-1)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[N-methyl-N-(2-qumolylcarbonyl)amino]methylsuccinyl]-L-2-pyridylalanine methylamide

HPLC : 3.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 40:60, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=639 Example 5-2

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[N-methyl-N-[(6-methylpyndin-2-yl)carbonylamino]methylsuccinyl]-L-2-pyridylalanine methylamide

HPLC : 5.3 min. (Nucleosil 5C18, 4 mmΦx 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min. at R.T.)

MASS : M+H=603 Example 5-3)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[N-methyl-N-(3-pyridylcarbonyl)aminomethyl]sucemyl]-L-2-pyridylalaninemethylamide

NMR (CDCl₃, δ) : 0.79 (3H, d, J=6Hz), 0.86 (3H, d,

J=6Hz), 0.86-1.50 (3H, m), 0.95 (1H, m), 2.72 (3H, d, J=5Hz), 2.96 (3H, s), 3.04-3.14 (4H, m), 3.17- 3.39 (2H, m), 4.71-4.97 (3H, m), 7.12-8.69 (13H, m) HPLC : 12.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm, MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.) Example 5-4)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[N-methyl-N-(2-pyridylcarbonyl)aminomethyl]sucemyl]-L-2-pyridylalaninemethylamide

HPLC : 6.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=589 Example 6-1)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[3-(pyridin-3-yl)propionylaminomethyl]succinyl]-L-4-pyridylalanine methylamide

_D = -47.9° (c 0.25, 1N-HClaq.)

mp : 249-253°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.73-0.89 (1H, m), 0.77 (3H, d, J=7Hz), 1.24 (1H, m), 1.37 (1H, m), 2.19 (1H, m), 2.24-2.35 (2H, m), 2.42 (1H, m), 2.56 (3H, d, J=5Hz), 2.64 (1H, m), 2.71-2.89 (4H, m), 2.96 (1H, dd, J=14, 5Hz), 4.58 (1H, m), 4.70 (1H, d, J=11Hz), 4.78 (1H, d, J=11Hz), 7.19-7.42 (6H, m), 7.23 (2H, d, J=6Hz), 7.52-7.64 (2H, m), 7.85 (1H, q, J=5Hz), 8.25-8.47 (3H, m), 8.37 (2H, d, J=6Hz), 11.02 (1H, s)

HPLC : 6.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=603 Example 6-2)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3-[(3-pyridyl)acetamidomethyl]succinyl]-L-4-pyridylalamne methylamide

_D = -52.5° (c 0.22, 1N-HClaq. )

mp : 258-261°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.87

(1H, m), 0.76 (3H, d, J=7Hz) , 1.23 (1H, m),

1.37 (1H, m), 2.20 (1H, m), 2.42 (1H, m), 2.54 (3H, d, J=4.5Hz), 2.62-2.75 (2H, m), 2.81 (1H, dd, J=14, 11Hz) , 2.95 (1H, dd, J=14, 5Hz) , 3.35 (2H, d, J=6Hz) , 4.56 (1H, m), 4.64 (1H, d, J=11Hz), 4.75 (1H, d, J=11Hz), 7.23 (2H, d, J=6Hz), 7.30 (1H, dd, J-7.5, 5Hz), 7.35 (5H, s), 7.62 (1H, m), 7.80-7.95 (2H, m), 8.27-8.46 (5h, m), 11.06 (1H, s)

HPLC : 5.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H=589 Example 7

To a solution of N-[(2R,3R)-3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide (413 mg) and N,N-dnsopropyl-N-ethylamine (142mg) in DMF (8 ml) was added N,N-dimethylcarbamoyl chloride(105 mg) at 0°C. The mixture was stirred at room temperatureovernight. The solution was evaporated. The precipitate wascollected by filtration and was washed with water and ethylacetate. That solid was further purified by silica gelcolumn chromatography (eluent : methanol/ethyl acetate=1/10)to give N-[(2R,3R)-4-(N-benzyloxyamino)-3-(N',N'-dimethylureido)methyl-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide (276 mg).

D = 23.2° (c 0.26, 1N-HClaq.)

mp : 209-211°C (dec.)

NMR (DMSO-d₆, δ) : 0.77 (3H, d, J=7Hz), 0.84 (3H, d, J=7Hz), 0.91 (1H, m), 1.18 (1H, m), 1.34 (1H, m), 2.27 (1H, m), 2.43 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.67-3.03 (3H, m), 2.71 (6H, s), 2.98 (1H, dd, J=14, 5Hz), 4.52 (1H, m), 4.70 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 5.90 (1H, dd, J=5, 4Hz), 7.23 (2H, d, J=6Hz), 7.36 (5H, s), 7.85 (1H, q, J=4.5Hz), 8.32 (1H, d, J=8Hz), 8.40 (2H, d, J=6Hz), 10.95 (1H, s)

HPLC : 5.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=541 Example 8-11

To a solution of N-[ (2R,3R)-3-aminometnyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide (380 mg) in DMF (3 ml) and pyridine (3 ml) wereadded acetic anhydride (103 mg) at room temperature. Themixture was stirred at room temperature for 2 hours. DMF wasevaporated and the residue was poured into water. Theprecipitate was collected by filtration and washed with waterand ethyl acetate to give N-[(2R,3R)-3-acetamιdomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide (367 mg).

= -37.7° (c 0.28, 1N-HClaq.)

mp : 253-256°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), C.74-0.87 (1H, m), 0.78 (3H, d, J=7Hz), 1.25 (1H, m), 1.36 (1H, m), 1.70 (3H, s), 2.17 (1H, m), 2.41 (1H, m),

2.53-2.69 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.76 (1H, m), 2.84 (1H, dd, J=14, 11Hz), 2.96 (1H, dd, J=14, 5Hz), 4.56 (1H, ddd, J=11, 8, 5Hz), 4.72 (1H, d, J=11Hz), 4.79 (1H, d, J=11Hz), 7.24 (2H, d, J=6Hz), 7.28-7.43 (5H, m), 7.53 (1H, dd, J=6, 6Hz), 7.86 (1H, q, J=4.5Hz), 8.31 (1H, d, J=8Hz), 8.38 (2H, d, J=6Hz), 11.00 (1H, s) HPLC : 5.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=512 Example 8-2)

N-[(2R,3R)-4-(N-Benzyloxyamino)-2-isobutyl-3- (prcpionylaminomethyl)succinyl]-L-4-pyidylalanine methylamidewas ootained in substantially the same manner as that ofExample 8-1).

= -49.7° (c 0.21, 1N-HClaq.)

mp : 245-247°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.86 (1H, m), 0.77 (3H, d, J=7Hz), 0.93 (3H, t, J=7.5Hz), 1.23 (1H, m), 1.35 (1H, m), 1.97 (2H, q, J=7.5Hz), 2.17 (1H, m), 2.42 (1H, m), 2.55 (3H, d, J=5Hz), 2.60-2.90 (3H, m), 2.96 (1H, dd, J=13, 5Hz), 4.57 (1H, m), 4.70 (1H, d, J=11Hz), 4.78 (1H, d,

J=11Hz), 7.24 (2H, d, J=6Hz), 7.28-7.52 (6H, m), 7.86 (1H, q, J=5Hz), 8.31 (1H, d, J=8Hz), 8.38 (2H, d, J=6Hz), 11.00 (1H, s)

HPLC : 6.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=526 Example 9

N-[(2R,3R)-4-(N-Benzyloxyamino)-3-(N,N-dimethylamino)-acetamidomethyl-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide was obtained in substantially the same manner asthat of Example 4-1).

= -56.3° (c 0.23, 1N-HClaq.)

mp : 243-248°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.74-0.87 (1H, m), 0.78 (3H, d, J=7Hz), 1.25 (1H, m), 1.35 (1H, m), 2.16 (2x3H, s), 2.20 (1H, m), 2.44 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.65 (1H, m), 2.75 (2H, s), 2.77-2.91 (2H, m), 2.95 (1H, dd, J=14, 5Hz), 4.55 (1H, m), 4.72 (1H, d, J=11Hz), 4.77 (1H, d,

J=11Hz), 7.20-7.29 (3H, m), 7.36 (5H, s), 7.85 (1H, q, J=4.5Hz), 8.33-8.43 (3H, m), 11.07 (1H, s) HPLC : 5.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=555 Example 10

N-[(2R,3R)-3-Benzamιdomethyl-4-(N-benzyloxyaminoj-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide was obtainedin substantially the same manner as that of Example 4-1).

= -15.8° (c 0.22, HCOOH)

mp : 243-247°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.75-0.91 (1H, m), 0.80 (3H, d, J=7Hz), 1.26 (1H, m), 1.39 (1H, m), 2.3β (1H, m), 2.45-2.63 (1H, m), 2.57 (3H, d, J=5Hz), 2.76-2.90 (2H, m), 2.91-3.05 (2H, m), 4.57 (1H, d, J=11Hz), 4.60 (1H, m), 4.72 (1H, d,

J=11Hz), 7.19-7.33 (7H, m), 7.38-7.54 (3H, m), 7.74-7.84 (2H, m), 7.88 (1H, q, J=5Hz), 8.14 (1H, br), 8.31-8.47 (3H, m), 10.99 (1H, s)

HPLC : 6.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. - 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=575 Example 11

To a solution of N-[(2R,3R)-3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide (356 mg) in DMSO (6 ml) was added phenyl

isocyanate (93 mg). The mixture was stirred at 50°C for 2 hours. The solvent was evaporated and the residue was pouredinto water. Tne precipitate was collected by filtration andwashed with water and ethyl acetate to give N-[(2R,3R)-4- (N-benzyloxyamino)-2-isobutyl-3-[(N'-phenylureido)methyl]-sucemyl]-L-4-pyridylalanine methylamide (409 mg).

D = -36.5° (c 0.19, HCOOH)

r.p : 239-243°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.82 (1H, m), 1.24 (1H, m), 1.37 (1H, m), 2.25 (1H, m), 2.41 (1H, m), 2.57 (3H, d, J=5Hz), 2.70-2.92 (3H, m), 2.98 (1H, dd, J=14, 5Hz), 4.57 (1H, m), 4.74 (1H, d, J=11Hz), 4.80 (1H, d,

J=11Hz), 5.91 (1H, br), 6.88 (1H, dd, J=7, 7Hz), 7.14-7.43 (11H, m), 7.85 (1H, q, J=5Hz), 8.31 (1H, d, J=8Hz), 8.35-8.47 (3H, m), 11.15 (1H, s)

HPLC : 7.9 mm, (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H=589 Example 12-1

To a solution of N-[(2R,3R)-4-(N-benzyloxyamino)-2-isobutyl-3-[(2-pyridylcarbonyl)aminomethyl]sucemyl]-L-4-pyridylalanine methylamide (115 mg) in a mixture of

cyclohexene (1 ml) and ethanol (20 ml) was added 10%

palladium on carbon. The mixture was stirred under refluxfor 2.5 hours. After the catalyst was filtered off, thefiltrate was evaporated. The resulting residue was

triturated with ethyl acetate to give N-[(2R,3R)-4-(N-hydroxyamino)-2-isobutyl-3-[(2-pyridylcarbonyl)aminomethyl]-sucemyl]-L-4-pyridylalanine methylamide (91 mg).

mp : 239-242°C

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.91 (1H, m), 1.30 (1H, m), 1.41 (1H, m), 2.38 (1H, ddd, J=9, 9, 4Hz), 2.47-2.61 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.80-2.91 (1H, m), 2.35 (1H, dd, J=14, 11Hz), 2.96 (1H, dd, J=14, 5Hz), 3.24 (1H, m), 4.57 (1H, ddd, J=11, 8, 5Hz), 7.25 (2H, d, J=7Hz), 7.60 (1H, dd, J=6, 6Hz), 7.87 (1H, q,

J=4.5Hz), 7.95-8.06 (2H, m), 8.17 (1H, dd, J=5.5, 5.5Hz), 8.37 (2H, d, J=7Hz), 8.43 (1H, d, J=8Hz), 8.63 (1H, d, J=6Hz), 8.85 (1H, s), 10.50 (1H, s) HPLC : 8.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=485 The following compounds were obtained in substantiallythe same manner as that of Example 12-1). Example 12-2

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(6-methylpyridin-3-yl)carbonylaminomethyl]sucemyl]-L-4-pyridylalanine methylamide

2D = -37.4° (c 0.29, 1N-HClaq.)

mp : 237-242°C

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.91 (1H, ddd, 13, 3, 3Hz), 1.30 (1H, m), 1.41 (1H, m), 2.38 (1H, ddd, J=9, 9, 4Hz), 2.53 (3H, s), 2.58 (3H, d, J=4.5Hz), 2.80-2.91 (1H, m), 2.85 (1H, dd, J=14, 11Hz), 2.96 (1H, dd, J=14, 5Hz), 3.24 (1H, m), 4.57 (1H, ddd, J=11, 8, 5Hz), 7.25 (2H, d, J=7Hz), 7.45 (1H, br-d, J=7.5Hz), 7.78-7.91 (3H, m), 8.10 (1H, dd, J=5.5, 5.5Hz), 8.37 (2H, d, J=7Hz), 8.41 (1H, d, J=8Hz), 8.86 (1H, s), 10.51 (1H, s)

HPLC : 4.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 15:85, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=499 Example 12-3)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(2-pyridyicarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemethylamide

2D = -30.1° (c 0.31, 1N-HClaq.)

mp : 240-242°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.91 (1H, m), 1.29 (1H, m), 1.41 (1H, m), 2.38 (1H, ddd, J=9, 9, 4Hz), 2.48-2.61 (1H, m), 2.58 (3H, d, J=4.5Hz), 2.80-2.91 (1H, m), 2.85 (1H, dd, J=14, 11Hz), 2.96 (1H, dd, J=14, 5Hz), 3.24 (1H, m), 4.56 (1H, ddd, J=11, 8, 5Hz), 7.25 (2H, d, J=7Hz), 7.60 (1H, m), 7.86 (1H, q, J=4.5Hz), 7.96- 8.05 (2H, m), 8.16 (1H, dd, J=6, 6Hz), 8.37 (2H, d, J=6Hz), 8.42 (1H, d, J=8Hz), 8.62 (1H, br d,

J=5Hz), 8.85 (1H, s), 10.49 (1H, s)

HPLC : 9.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=485 Example 12-4)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(3-pyridylcarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemethylamide

= -27.7° (c 0.20, 1N-HClaq.)

mp : 229-235°C

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, m), 1.27 (1H, m), 1.43 (1H, m), 2.35 (1H, ddd, J=9, 9, 4Hz), 2.43-2.55 (1H, m), 2.59 (3H, d, J=4.5Hz), 2.75 (1H, m), 2.84 (1H, dd, J=14, 12Hz), 2.92-3.08 (1H, m), 2.98 (1H, dd, J=14, 5Hz), 4.60 (1H, ddd, J=12, 8, 5Hz), 7.26 (2H, d, J=7Hz), 7.49 (1H, dd, J=7.5, 5Hz), 7.88 (1H, q, J=4.5Hz), 8.10 (1H, ddd, J=7.5, 1.5, 1.5Hz), 8.23 (1H, dd, J=6, 6Hz), 8.47 (2H, d, J=6Hz), 8.50 (1H, d, J=8Hz), 8.68 (1H, dd, J=5, 5Hz), 8.73 (1H, s) , 8.92 (1H, d, J=1.5hz), 10.35 (1H, s)

HPLC : 4.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=485 Example 12-5)

To a solution of N-[(2R,3R)-4-(N-benzyloxyamino)-2-isobutyl-3-[(4-pyridylcarbonyl)aminometnyl]sucemyl]-L-4-pyridylalanine methylamide (375 mg) in a mixture of

cyclohexene (2 ml), formic acid (3.5 ml) and ethanol (20 ml)was added 5% palladium on barium sulfate. The mixture wasstirreα under reflux for 12 hours. After the catalyst wasfiltered off, the filtrate was evaporated. The resultingresidue was triturated with ethyl acetate to give N-[(2R,3R)-4-(N-hydroxyamino)-2-isobutyl-3-(4-pyridylcarbonyl)-aminomethylsuecinyl]-L-4-pyridylalanine methylamide (16 mg).

= -27.6° (c 0.30, 1N-HClaq.)

mp : 243-248°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, m), 1.28 (1H, m), 1.42 (1H, m), 2.35 (1H, ddd, J=9, 9, 3Hz), 2.45-2.55 (1H, m), 2.58 (3H, o, J=4.5Hz), 2.76 (1H, m), 2.84 (1H, dd, J=14, 11Hz), 2.92-3.08 (1H, m), 2.97 (1H, dd, J=14, 5Hz), 4.60 (1H, ddd, J=11, 8, 5Hz), 7.26 (2H, d, J=7Hz), 7.49 (1H, dd, J=7.5, 5Hz), 7.88 (1H, q, J=4.5Hz), 8.10 (1H, ddd, J=7.5, 1.5, 1.5Hz), 8.22 (1H, dd, J=5.5, 5.5Hz), 8.37 (2H, d, J=7Hz), 8.40 (1H, d, J=8Hz), 8.69 (1H, dd, J=5, 1.5Hz), 8.75 (1H, s), 8.92 (1H, d, J=1.5Hz), 10.36 (1H, s) HPLC : 4.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.) MASS : M+H=485 The following compounds were obtained in substantiallythe same manner as that of Example 12-5). Example 12-6)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(4-pyridylcarbonyl)aminomethyl]succinyl]-L-4-pyridylalaninemetnylamide

= -30.2° (c 0.34, 1N-HClaq.)

mp : 244-248°C (dec.)

NMR (DMSO-d₆, δ) : 0.75 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.89 (1H, m), 1.28 (1H, m), 1.43 (1H, m), 2.35 (1H, m), 2.43-2.54 (1H, m), 2.59 (3H, α, J=5Hz), 2.72 (1H, m), 2.84 (1H, dd, J=14, 12Hz), 2.91-3.08 (2H, m), 4.60 (1H, m), 7.25 (2H, d, J=6Hz), 7.67 (2H, d, J=6Hz), 7.88 (1H, q, J=5Hz), 8.25-8.44 (4H, m), 8.65-8.78 (3H, m), 10.35 (1H, s)

HPLC : 4.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=485 Example 12-7)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[3

(pyridin-3-yl)propionylaminomethyl]succinyl]-L-4-pyridylalanine methylamide

= -23.3° (c 0.30, 1N-HClaq.)

mp : 241-246°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) 0.77 (3H, d, J=7Hz), 0.86 (1H, m), 1.23 (1H, m) 1.38 (1H, m), 2.21 (1H, m), 2.31 (2H, t, J=7Hz), 2.40 (1H, m) , 2.55 (3H, d, J=5Hz), 2.61-2.89 (5H m), 2.95 (1H, dd, J=13, 4Hz), 4.55 (1H, m), 7.23 (2H, d, J==6Hz) 7.30 (1H, dd, J=7.5, 5Hz), 7.46 (1H, dα, J=6, 6Hz), 7.60 (1H, m), 7.85 (1H, q, J=5Hz), 8.30 (1H, d, J=8Hz), 8.34-3.44 (4H, m), 8.78 (1H, s), 10.35 (1H, s)

HPLC : 3.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=513 Example 12-8)

N-[ (2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[ (3-pyri αylacetamiαo)methyl]succinyl]-L-4-pyridylaIanine

methylamide

D = -35.2° (c 0.24, 1N-HClaq. )

mp : 230-236°C (dec. )

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) , 0.78 (3H, d, J=7Hz) , 0.86 (1H, m) , 1.23 (1H, m), 1.38 (1H, m), 2.21 (1H, m), 2.41 (1H, m) , 2.55 (3H, d, J=4Hz) , 2.61-2.88 (3H, m) , 2.95 (1H, dd, J=13, 4Hz) , 3.37 (2H, s) , 4.55 (1H, m), 7.22 (2H, d, J=6Hz) , 7.31 (1H, m), 7.64 (1H, m), 7.77 (1H, m), 7.84 (1H, q, J=4Hz), 8.29 (1H, d, J=8Hz), 8.34 (2H, d, J=6Hz), 8.37-8.45 (2H, m), 8.67 (1H, s), 10.38 (1H, s) HPLC : 3.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05. TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=499 Example 12-9)

N-[(2R,3R)-3-(N,N-Dimethylamino)acetamidomethyl-4-(N-hydroxyamino)-2-isobutylsuccinyl]-L-4-pyridylalanine

methylamide

α _D = -29.5° (c 0.26, 1N-HClaq.)

mp : 230-235°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.87 (1H, m), 1.26 (1H, m), 1-38 (1H, m), 2.11 (1H, m), 2.13 (2x3H, s), 2.33 (1H, m), 2.58 (3h, d, J=4Hz), 2.63 (1H, m), 2.76-3.01 (5H, m), 4.55 (1H, m), 7.25 (2H, d, J=6Hz), 7.25 (1H, m), 7.86 (1H, q, J=4Hz), 8.35 (1H, d, J=8Hz), 8.39 (2H, d, J=6Hz), 8.80 (1H, s), 10.44 (1H, s)

HPLC : 3.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=465 Example 12-10)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[3-(6-methylpιridin-3-yl)carbonylaminomethyl]sucemyl]-L-2-pyridylalanine metnylanide

= -37.9° (c 0.14, 1N-HClaq.)

mp : 204-207°C

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=6Hz), 0.78 (3H, d, J=6Hz), 0.88 (1H, ddd, J=12, 9, 1.5Hz), 1.24 (1H, m), 1.43 (1H, ddd, J=12, 9, 1.5Hz), 2.32-2.49 (2H, m), 2.50 (3H, s), 2.57 (3H, d, J=5Hz), 2.70-2.80 (1H, m), 2.93-3.02 (1H, m), 3.00 (1H, dd, J=12, 9Hz), 3.11 (1H, dd, J=12, 6Hz), 4.76 (1H dd, J=9, 6Hz), 7.06 (1H, ddd, J=7.5, 6, 1.5Hz), 7.26 (1H, d, J=7.5Hz), 7.32 (1H, d, J=7.5Hz), 7.60 (1H, ddd, J=7.5, 6, 1.5Hz), 7.73-7.80 (1H, m), 8.00 (1H, dd, J=7.5, 1.5Hz), 8.18 (1H, br s), 8.37-8.44 (2H, m), 8.82 (1H, d, J=1.5Hz)

HPLC : 8.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=499 Example 12-11)

N-[ (2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[ (2-qumolmecarbonyl)aminomethyl]sucemyl]-L-2-pyridylalanine methylamide

= -60.0° (c 0-10, 1N-HClaq.)

rp : 232-236°C

NMP (DMSO-d₆, δ) : 0.74 (3H, d, J=6Hz), 0.80 (3ri, d, J=6Hz), 0.86 (1H, m), 1.28 (1H, m), 1.46 (1H, m), 2.42 (2H, m), 2.61 (3H, d, J=5Hz), 2.85-3.3C (4H, m), 4.80 (1H, m), 7.50-8.74 (13H, m)

HPLC : 3.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H=535 Example 12-12)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(2-qumolmecarbonyl)aminomethyl]succinyl]-L-2-pyridylalaninemethylamide

D = -35.6° (c 0.09, 1N-HClaq.)

mp : 244-246°C

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=6Hz), 0.80 (3H, d, J=6Hz), 0.91 (1H, m), 1.27 (1H, m), 1.45 (1H, m), 2.36-2.56 (2H, m), 2.59 (3H, d, J=5Hz), 2.76-3.06 (2H, m), 3.04 (1H, dd, J=12, 9Hz), 3.14 (1H, do, J=12, 6Hz), 4.79 (1H, m), 7.07 (1H, ddd, J=7.5, 6, 1.5Hz), 7.29 (1H, dd, J=7.5, 1.5Hz), 7.62 (1H, ddd, J=7.5, 6, 1.5Hz), 7.70 (1H, dd, J=7.5, 1.5Hz), 7.74-7.80 (1H, m), 7.86 (1H, ddd, J=7.5, 6, 1.5Hz), 8.05-8.10 (2H, m), 8.36-8.46 (2H, m), 8.72-8.80 (2H, m), 9.23 (1H, s)

HPLC : 3.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=535 Example 12-13)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[N-methyl-N- (2-qjmclylcaroonyl)amino]metnylsucemyl]-L-2-pyridylalaninemethylamide

= -37.5° (o 0.12, 1N-HClaq.)

mp : 203-205C

NMR (CD₃OD, δ) : 0.69-0.94 (6H, m), 1.03-1.48 (3H, m), 2.25-2.61 (2H, m), 2.65 (0.5x3H, s, rotamer), 2.75 (C.5x3H, s, rotamer), 2.83 (0.5x3H, s, rotamer), 2.95 (0.5x3H, s, rotamer), 2.97-3.65 (4H, m), 4.67- 4.96 (1H, m), 7.27-8.66 (10H, m)

HPLC : 7.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=485 Example 12-14)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(6-metnylpyridm-2-yl)carbonylaminomethyl]succinyl]-L-2-pyridylalanine methylamide

= -42.9° (c 0.14, 1N-HClaq.)

mp : 248-252°C

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=6Hz), 0.78 (3H, d, J=6Hz), 0.90 (1H, ddd, J=12, 9, 1.5Hz), 1.28 (1H, m), 1.43 (1H, ddd, J=12, 9, 1.5Hz), 2.31-2.52 (2H, m), 2.54 (3H, s), 2.57 (3H, d, J=5Hz), 2.85 (1H, m), 3.03 (1H, dd, J=12, 9Hz), 3.13 (1H, dd, J=12, 6Hz), 3.21 (1H, m), 4.73 (1H, dd, J=9, 6Hz), 7.05 (1H, ddd, J=7.5, 6, 1.5Hz), 7.26 (1H, dd, J=7.5, 1.5Hz), 7.45 (1H, dd, J=7.5, 1.5Hz), 7.57-7.89 (4H, m), 8.11 (1H, m), 8.35-8.43 (2H, m), 8.86 (1H, s) HPLC : 22.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=499 Example 12-15) N-[ (2R,3R)-4-(N-Hydroxyamino)-2-isobutyI-3-[N-methyl-N-[ (6-methylpyri din-2-yl)carbonyl]aminomethyl]suceinyl]-L-2-pyridyalanine methylamide

= 40.0° (c 0.14, 1N-HClaq.)

no 196-198°C

NMR. (CD₃OD ', δ) 0.74-0.90 (6H, m), 1.06 (1H, m), 1.35 (1H, m), 1.48 (1H, m), 2.35-2.57 (2H, m), 2.59 (0.5x3H, d, J=5Hz, rotamer), 2.68 (3H, s), 2.73 (0.5x3H, d, J=5Hz, rotamer), 2.89 (3H, s), 3.00- 3.40 (4H, m), 4.67-4.95 (1H, m), 7.18-8.54 (7H, m) HPLC : 14.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=513 Example 12-16)

N-[ (2R,3R)-4-(N-Hydroxyamino)-3-[ (4-hyαroxyqumolin-2-yl)caroonylaminomethyl]-2-isobutylsuccinyl]-L-2-pyriαylalanine methylamide

mp : 209-211°C (dec.)

NMR (DMSO-d₆, δ) : 0.68-1.02 (7H, m), 1.30 (1H, m), 1.45 (1H, m), 2.27-2.84 (5H, m) , 2.95-3.30 (4H, m) , 4.77 (1H, m), 6.23 (1H, m), 7.07 (1H, m) , 7.20-7.35 (2H, m), 7.50-7.67 (2H, m) , 7.70-7.90 (2H, m), 8.07 (1H, m), 8.32-8.50 (3H, m), 8.82 (1H, br) HPLC : 4.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H=551 Example 12-17)

N-[(2R,3R)-3-(N',N'-Dimethylureido)methyl-4-(N-hydroxyamino)-2-isobutylsuccinyl1-L-4-pyridyIalanine

methylamide

]²D ⁼ -26.3° (c 0.26, 1N-HClaq.)

mp : 200-204°C (dec. )

NMR (DMSO-d₆, δ) : 0.7C (3H, d, J=7Hz) , 0.75 (3H, d, J=7Hz) , 0.87 (1H, m) , 1.20 (1H, m), 1.37 (1H, m), 2.30 (1H, m) , 2.44 (1H, m) , 2.57 (3H, d, J=5Hz) , 2.68-3.04 (4H, m), 2.73 (2x3H, s) , 4.51 (1H, m) , 5.67 (1H, dd, J=5, 5Hz), 7.24 (2H, d, J=6Hz), 7.86 (1H, σ, J=4.5Hz), 8.32 (1H, d, J=8Hz), 8.40 (2H, d, J=6Hz), 8.77 (1H, s), 10.29 (1H, s)

HPLC : 5.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-⁺ =451 Example 12-18)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(1-pyrrolidinylcarbonyl)aminomethyl]succinyl]-L-4-pyridylaIaninemethylamide

D = -21.4° (c 0.31, 1N-HClaq.)

mp : 216-219°C

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.76 (3H, d, J=7Hz), 0.88 (1H, m), 1.19 (1H, m), 1.37 (1H, m), 1.71-1.85 (4H, m), 2.28 (1H, m), 2.45 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.76 (1H, m), 2.87 (1H, dd, J=14, 11Hz), 2.92-3.05 (2H, m), 3.08-3.26 (4H, m), 4.52 (1H, m), 5.42 (1H, dd, J=6, 5Hz), 7.24 (2H, d, J=7Hz), 7.87 (1H, q, J=4.5Hz), 8.32 (1H, d, J=8Hz), 8.41 (2H, d, J=7Hz), 8.77 (1H, s), 10.30 (1H, s) HPLC : 3.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 15:85, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=477 Example 12-19)

N-[(2R,3R)-3-Benzamidomethyl-4-(N-hydroxyamino)-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide ²D = -30.1° (c 0.23, 1N-HClaq. )

mp : 238-242°C (dec. )

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz) , 0.80 (3H, d, J=7Hz) , 0.90 (1H, m) , 1.27 (1H, m) , 1.43 (1H, m) , 2.40 (1H, m), 2.45-2.63 (1H, m), 2.58 (3H, d,

J=4Hz), 2.75-3.14 (4H, m), 4.58 (1H, m), 7.21-7.30 (2H, m), 7.38-7.57 (3H, m), 7.77 (2H, d, J=7Hz), 7.88 (1H, q, J=4Hz), 7.95 (1H, br), 8.32-8.45 (3H, m), b.74 (1H, s), 10.35 (1H, s)

HPLC : 5.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 15:85, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=484 Example 12-20)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(3-pyridylcarbonyl)aminomethyl]succinyl]-L-2-pyridylalaninemethylamide

[α]²D⁵ = -35.2° (c 0.17, 1N-HClaq.)

mp : 220-223°C

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=6Hz) , 0.79 (3H, d, J=6Hz) , 0.89 (1H, ddd, J=12, 9, 1.5Hz) , 1.25 (1H, m), 1.43 (1H, ddd, J=12, 9, 1.5Hz) , 2.31-2.50 (2H, m) , 2.57 (3H, d, J=5Hz) , 2.72-2.82 (1H, m) , 2.93- 3.02 (1H, m), 3.00 (1H, dd, J=12, 9Hz) , 3.11 (1H, dd, J=12, 6Hz) , 4.75 (1H, dd, J=9, 6Hz) , 7.07 (1H, ddd, J=7.5, 6, 1.5Hz) , 7.18 (1H, dd, J=7.5, 1.5Hz) , 7.49 (1H, dd, J=7.5, 6Hz) , 7.61 (1H, ddd, J=7.5, 6, 1.5Hz) , 7.76-7.83 (1H, m), 8.12 (1H, dd, J=7.5, 1.5Hz) , 8.33 (1H, br s) , 8.37-8.46 (2H, m) , 8.68 (1H, d, J=6Hz), 8.93 (1H, s)

HPLC : 6.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=485 Example 12-21)

N-[ (2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(2-pyridylcarbonyl)aminomethyl]succinyl]-L-2-pyridylalaninemetnylamide

= -42.3' (c 0.04, 1N-HClaq.)

mp : 265-268°C

NMR (0.5N-DCl, δ) : 0.52-0.60 (6H, m), 0.83 (1H, m), 0.95 (1H, m), 1.26 (1H, m), 2.33-2.40 (2H, m), 2.46 (3H, s), 2.65 (1H, m), 3.13 (1H, m), 3.23-3.43 (2H, m), 7.63-3.73 (8H, m)

HFLC : 3.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : MτH=485

Example 12-22) N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[N-methyl-N-(3-pyridylcarbonyl)aminomethyl]succinyl]-L-2-pyridylalaninemethylamide

= -46.0° (c 0.05, 1N-HClaq.)

mp : 125-128°C

NMR (CD₃OD, δ) : 0.78-0.95 (6H, m), 1.08 (1H, m), 1.38 (1H, m), 1.58 (1H, m), 2.46-2.65 (2H, m), 2.72 (0.3x3H, br s, minor rotamer), 2.76 (0.7x3H, br s, major rotamer), 2.83 (0.7χ3H, br s, major rotamer), 2.93 (0.3x3H, br s, minor rotamer), 3.04-3.33 (4H, m), 3.17-3.39 (2H, m), 4.87 (1H, m), 7.25-8.70 (8H, m)

HPLC : 6.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M÷H=499 Example 12-23)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[N-methyl-N- (2-pyridylcarbonyl)amino]methylsuccinyl]-L-2-pyridylaianinemethylamide

D = -35.8° (c 0.12, 1N-HClaq.)

mp : 208-211°C

NMR (CD₃OD, δ) : 0.76-0.91 (6H, m), 1.05 (1H, m), 1.36 (1H, m), 1.54 (1H, m), 2.36 (1H, m), 2.56 (1H, m), 2.63 (0.5x3H, s, rotamer), 2.73 (0.5x3H, s, rotamer), 2.76 (0.5x3H, s, rotamer), 2.90 (0.5x3H, s, rotamer), 3.00-3.42 (4H, m), 4.67-4.96 (1H, m), 7.24-8.64 (8H, m)

HPLC : 10.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=499 Example 12-24

N-[(2R,3R)-3-Acetamidomethyl-4-(N-hydroxyamino)-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

² _D ⁵ = -30.5°C (c 0.30, IN-HCiaq.)

mp : 246-250°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.85 (1H, m), 1.23 (1H, m), 1.38 (1H, m), 1.71 (3H, s), 2.18 (1H, m), 2.41 (1H, m), 2.56 (3H, d, J=5Hz), 2.65-2.75 (2H, m), 2.83 (1H, dd, J=14, 11Hz), 2.95 (1H, dd, J=14, 6Hz), 4.55 (1H, ddd, J=11, 8, 6Hz), 7.23 (2H, d, J=6Hz), 7.37 (1H, dd, J=6, 6Hz), 7.85 (1H, q, J=5Hz), 8.30 (1H, d,

J=8Hz), 8.38 (2H, d, J=6Hz), 8.73 (1H, s), 10.33 (1H, s)

HPLC : 4.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/minn, at R.T.)

MASS : M+H=422 Example 12-25) N-[ (2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3- (propionylaminomethyl)sucemyl]-L-4-pyridylalanine

rretnylamide

[α]² _D ³ = -32.6° (c 0.30, 1N-HClaq. )

mp : 238-241°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) , 0.77 (3H, d, J=7Hz) , 0.85 (1H, m), 0.96 (3H, t, J=7Hz) , 1.23 (1H, m) , 1.38 (1H, ddd, J=11, 11, 3Hz) , 1.97 (2H, q, J=7Hz) , 2.20 (1H, m), 2.41 (1H, m ) , 2.56 (3H, d, J=5Hz) , 2.62-2.90 (3H, m) , 2.96 (1H, dd, J=14, 5Hz), 4.55 (1H, m), 7.25 (2H, d, J=6Hz), 7.28 (1H, m), 7.86 (1H, q, J=5Hz), 8.30 (1H, d, J=8Hz), 8.37 (2H, d, J=6Hz), 8.72 (1H, s), 10.31 (1H, s)

HPLC : 4.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 1:10, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=436 Example 12-26)

N-[(2R,3R)-4-(N-Hydroxyamino)-2-isobutyl-3-[(N'-phenyIureido)methyl]succinyl]-L-4-pyridylalamine methylamide

D = -36.7° (c 0.28, 1N-HClaq.)

mp : 250-254°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.90 (1H, m), 1.25 (1H, m), 1.42 (1H, m), 2.25 (1H, m), 2.40 (1H, m), 2.57 (3H, d, J=5Hz), 2.77-2.92 (3H, m), 2.98 (1H, dd, J=14, 6Hz), 4.57 (1H, m), 5.81 (1H, dd, J=β, 4Hz), 6.87 (1H, dd, J=7, 7Hz), 7.15-7.28 (4H, m), 7.36 (2H, d, J=7.5Hz), 7.85 (1H, q, J=5Hz), 8.30 (1H, d, J=8Hz), 8.40 (2H, d, J=6Hz), 8.46 (1H, s), 8.85 (1H, s), 10.54 (1H, s)

HPLC : 3.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.) MASS : M+H=499 Example 13

N-[(2R,3?)-3-Ammomethyl-4-(N-benzyloxyamino)-2-isoputylsuccinyl]-L-4-pyridylalanine methylamide (1.73 g) wasdissolved in water (15 ml) and the pH was adjusted to 8-9 bythe addition of sodium hydrogen carbonate. The precipitatewas collected by filtration to give N-[(2R,3R)-[3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalanine metnylamide (1.02 g).

NMR (DM50-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.88 (1H, m), 0.77 (3H, d, J=7Hz), 1.15-1.40 (2H, m), 1.85- 2.00 (2H, m), 2.23 (1H, m), 2.41 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.79 (1H, dd, J=14, 12Hz), 2.94 (1H, dd, J=14, 4Hz), 4.55 (1H, ddd, J=12, 8, 4Hz), 4.76 (2H, s) , 7:25 (2H, d, J=6Hz) , 7.28-7.44 (5H, m), 7.85 (1H, q, J=4.5Hz) , 8.29 (1H, d, J=8Hz) , 8.44 (2H, d, J=6Hz)

MASS : M+H=470 Example 14

N-[(2R,3R)-4-Benzyloxyamino-2-isobutyl-3-phthalimidomethylsuccinyl]-L-3-pyridylalamne methyl esterwas obtained in substantially the same manner as that ofExample 1-1).

= -6.3° (c 0.20, AcOH)

mp : 214-219°C (dec.)

NMR (DMSO-d₆, δ) : 0.70-0.85 (1H, m), 0.75 (3H, d,

J=6.5Hz), 0.80 (3H, d, J=6.5Hz), 1.30-1.46 (2H, m), 2.40 (1H, ddd, J=11, 10, 3Hz), 2.46-2.61 (1H, m), 2.90 (1H, dd, J=14, 11Hz), 3.17 (1H, dd, J=14, 5Hz), 3.50 (1H, dd, J=13, 11Hz), 3.62 (3H, s), 4.25 (1H, c, J=11Hz), 4.54 (1H, d, J=11Hz), 4.67 (1H, ddc, J=11, 8, 5Hz), 7.05 (2x1H, d, J=7.5Hz), 7.12- 7.28 (4H, m), 7.70 (1H, br d, J=7.5Hz), 7.85 (4H, m), 8.13 (1H, d, J=5Hz), 8.46 (1H, br), 8.65 (1H, d, J=7.5Hz), 11.06 (1H, s)

HPLC : 5.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.C5. TFAaq. = 35:65, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=601 Example 15

N-[(2R,3R)-3-Aminomethyl-4-benzyloxyamino-2-isobutylsuccinyl]-L-3-pyrioylalanine methylamide was obtainedin substantially the same manner as that of Example 2-1).

= -35.5° (c 0.31, 1N-HClaq.)

mp : 198-201°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.88 (1H, m), 0.78 (3H, d, J=7Hz), 1.17-1.39 (2H, m), 1.78- 1.97 (2H, m), 2.21 (1H, dd, J=13, 3Hz), 2.40 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.79 (1H, dd, J=14, 11Hz), 2.94 (1H, dd, J=14, 4Hz), 4.36 (2H, or), 4.51 (1H, ddd, J=11, 8, 4Hz), 4.75 (1H, d, J=11Hz), 4.79 (1H, d, J=11Hz), 7.25-7.43 (5H, m), 7.29 (1H, dd, J=7.5, 5Hz), 7.65 (1H, br d, J=7.5Hz), 7.88 (1H, q, J=4.5Hz), 8.30 (1H, d, J=8Hz), 8.40 (1H, d, J=5Hz), 8.46 (1H, d, J=1.5Hz)

HPLC : 5.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 20:80:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=470 The Object Compounds listed in the following Table 1were prepared, m substantially the same manner as that ofExample 4-1), by reacting the Starting Compounds with theReagent as shown below.

The physico-chemical properties of the Object Compounds of Table 1 were described hereinafter. Example 16-1

=

-14.6° (c 0.21, IH-HClaq.

mp : 229-232°C (dec.)

NMR [DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.73-0.87 (1H, m), 0.79 (3H, d, J=7Hz), 1.18-1.42 (2H, m), 1.35 (3x3H, s), 2.13 (1H, m), 2.45 (1H, m), 2.47-2.60 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.65 (1H, m), 2.81 (1H, dd, J=14, 11Hz), 2.94 (1H, dd, J=14, 5Hz), 4.55 (1H, ddd, J=11, 8, 5Hz), 4.71 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 6.32 (1H, dd, J=5, 5Hz), 7.25 (2x1H, d, J=7Hz), 7.30-7.43 (5H, m), 7.85 (1H, q, J=4.5Hz), 8.36 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 10.95 (1H, s) HPLC : 7.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 30:70:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=570 Example 16-2)

[ ]

= -53.9° (c 0.20, 4N-HClaq,

mp : 263-267°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.87 (1H, m), 0.78 (3H, d, J=7Hz), 0.94 (3H, d, J=7Kz), 0.95 (3H, d, J=7Hz), 1.23 (1H, m), 1.37 (1H, m), 2.11- 2.33 (2H, m), 2.42 (1H, m), 2.53-2.78 (2H, m), 2.57 (3H, d, J=5Hz), 2.83 (1H, dd, J=13, 11Hz), 2.97 (1H, dd, J=13, 5Hz), 4.57 (1H, ddd, J=11, 8, 5Hz), 4.70 (1H, d, J=11Hz), 4.78 (1H, d, J=11Hz), 7.25 (2x1H, d, J=6Hz), 7.30-7.45 (6H, m), 7.87 (1H, d, J=5Hz), 8.33 (1H, d, J=8Hz), 8.38 (2x1H, d, J=6Hz), 11.0 (1H, s)

HPLC : 8.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=540 Example 16-3)

²D = -55.2° (c 0.20, 1N-HClaq.)

mp : 212-215°C

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.77 (3H, d, J=7Kz), 0.81 (1H, m), 1.02 (9H, s), 1.20 (1H, m), 1.36 (1H, m), 2.25 (1H, m), 2.43 (1H, m), 2.57 (3H, d, J=5Hz), 2.65 (1H, m), 2.75-2.90 (2H, m), 2.97 (1H, dd, J=14, 5Hz), 4.55 (1H, m), 4.69 (1H, d, J=11Hz), 4.79 (1H, d, J=11Hz), 7.09 (1H, m), 7.24 (2x1H, d, J=6Hz), 7.28-7.41 (5H, m), 7.87 (1H, d, J=5Hz), 8.33 (1H, d, J=8Hz), 8.37 (2x1H, d, J=6Hz), 8.40 (1H, d, J=8Hz), 11.00 (1H, s) HPLC : 5.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. - 35:65, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=540 Example 16-4)

D = -10.9° (c 0.22, lN-HClaq.)

mp 223-241°C (dec.)

NMR MSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.73-0.87 (1H, m), 0.78 (3H, d, J=7Hz), 1.13 (3H, t, J=7Hz), 1.19- 1.42 (2H, m), 2.14 (1H, ddd, J=9, 9, 4Hz), 2.43 (1H, m), 2.45-2.60 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.70 (1H, m), 2.81 (1H, dd, J=14, 11Hz), 2.94 (1H, dd, J=14, 5Hz), 3.92 (2H, q, J=7Hz), 4.55 (1H, ddd, J=11, 8, 5Hz), 4.70 (1H, d, J=11Hz), 4.76 (1H, d, J=11Hz), 6,67 (1H, dd, J=5, 5Hz), 7.25 (2x1H, d, J=7Hz), 7.30-7.42 (5H, m), 7.85 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.39 (2x1H, d, J=7Hz), 10.96 (1H, s)

HPLC : 7.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=542 Example 16-5)

]²D = -50.7° (c 0.12, 1N-HClaq.)

mp : 216-220°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.81 (1H, m), 1.24 (1H, m), 1.37 (1H, m), 2.21 (1H, m), 2.39-2.60 (2H, m), 2.55 (3H, d,

J=4.5Hz), 2.83 (1H, dd, J=14, 10Hz), 2.97 (1H, dd, J=14, 5Hz), 3.05 (1H, m), 3.20 (1H, dd, J=10, 4Hz), 3.47 (1H, dd, J=10, 10Hz), 4.53-4.67 (2H, m), 4.71 (1H, d, J=11Hz), 4.79 (1H, d, J=11Hz), 5.16 (2H, s), 7.22 (2x1H, d, J=6Hz), 7.25-7.47 (11H, m), 7.90 (1H, q, J=4.5Hz), 8.03 (1H, dd, J=6, 5Hz), 8.34 (1H, d, J=8Hz), 8.37 (2x1H, d, J=6Hz), 11.17 (1H, s)

HPLC : 7.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 30:70:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=715 Example 16-6)

2D = -40.7° (c 0.20, 1N-HClaq.)

mp : 228-231°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.80 (1H, m), 1.17 (3H, t, J=7Hz), 1.24 (1H, m), 1.37 (1H, m), 2.20 (1H, ddd, J=9, 9, 4Hz), 2.42 (1H, m), 2.56 (3H, d, J=5Hz), 2.71 (1H, m), 2.77-2.90 (1H, m), 2.83 (1H, dd, J=14, 11Hz), 2.95 (1H, dd, J=14, 6Hz), 3.10 (1H, d, J=14Hz), 3.16 (1H, d, J=14Hz), 4.05 (2H, q, J=7Hz), 4.57 (1H, ddd, J=11, 8, 5Hz), 4.72 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 7.23 (2x1H, d, J=7Hz), 7.30-7.42 (5H, m), 7.80-7.90 (2H, m), 8.32 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 11.06 (1H, s)

HPLC : 4.6 min. (Nuclecsil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=584 Example 16-7)

[α]²D⁵ = -22.4° (c 0.21, lN-HClaq.

mp : 247-250°C (dec.)

NMR DMSO-d₆ δ) : 0.70 (3H, d, J=7Hz), 0.75 (3H, d, J=7Hz), 0.80 (1H, m), 1.22 (1H, m), 1.36 (1H, m), 2.20 (1H, ddd, J=9, 9, 4Hz), 2.37 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.69-2.91 (2H, m), 2.96 (1H, dd, J=14, 6Hz), 3.62 (1H, dqq, J=7.5, 7, 7Hz), 4.54 (1H, m), 4.74 (1H, d, J=11Hz), 4.80 (1H, d,

J=11Hz), 5.46 (1H, dd, J=6, 6Hz), 5.66 (1H, d, J=7.5Hz), 7.24 (2H, d, J=6Hz), 7.30-7.43 (5H, m), 7.84 (1H, q, J=4.5Hz), 8.27 (1H, d, J=8Hz), 8.41 (2H, d, J=6Hz), 11.10 (1H, s)

HPLC : 9.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS ..: M+H=555 Example 16-8)

= -20.2° (c 0.23, 1N-HClaq.)

mp : 236-238°C (dec.)

NMR (DMSO-d₆, δ) : 0.68 (3H, d, J=7Hz), 0.74 (3H, d, J=7Hz), 0.80 (1H, m), 0.95 (3H, t, J=7.5Hz), 1.19 (1H, m), 1.35 (1H, ddd, J=12, 11, 3Hz), 2.20 (1H, ddd, J=11, 10, 3Hz), 2.37 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.67-2.90 (3H, m), 2.91-3.02 (3H, m), 4.53 (1H, m), 4.73 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 5.53 (1H, dd, J=6, 5Hz), 5.74 (1H, t, J=6Hz), 7.23 (2x1H, d, J=6Hz), 7.29-7.42 (5H, m), 7.83 (1H, q, J=4.5Hz), 8.25 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 11.09 (1H, s)

HPLC : 6.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=541 Example 16-9)

= -49.9° (c 0.25, 1N-HClaq.)

mp : 222-226°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.77 (3H, d, J=7Hz) , 0.80 (1H, m) , 1.16-1.55 (8H, m), 2.06-2.53 (10H, m) , 2.57 (3H, d, J=4.5Hz) , 2.65 (1H, m) , 2.77 (1H, m) , 2.83 (1H, dd, J=14, 10Hz), 2.96 (1H, dd, J=14, 4Hz), 4.57 (1H, ddd, J=11, 8, 4Hz), 4.73 (1H, d, J=11Hz), 4.79 (1H, d, J=11Hz), 7.24 (2x1H, d, J=6Hz), 7.28-7.43 (5H, m), 7.74 (1H, dd, J=5, 5Hz), 7.86 (1H, q, J=4.5Hz), 8.31 (1H, α, J=8Hz), 8.39 (2x1H, d, J=6Hz), 11.03 (1H, s)

HPLC : 4.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=609 Example 16-10)

= -20.7° (c 0.23, 1N-HClaq.)

mp : 215-219°C (dec. )

NMR (DMSO-d₆, δ) : 0.69 (3H, d, J=7Hz) , 0.75 (3H, d, J=7Hz), 0.80 (1H, m) , 1.11-1.26 (1H, m) , 1.20 (9H, s) , 1.36 (1H, m) , 2.17 (1H, m), 2.36 (1H, m), 2.57 (3H, d, J=5Hz) , 2.68 (1H, m), 2.80-2.92 (1H, m), 2.86 (1H, dd, J=14, 10Hz) , 2.98 (1H, dd, J=14, 6Hz) , 4.55 (1H, ddd, J=10, 8, 6Hz) , 4.66 (1H, d, J=12Hz) , 4.71 (1H, d, J=12Hz) , 5.44 (1H, dd, J=6, 6Hz), 5.66 (1H, s), 7.24 (2H, d, J=7Hz), 7.30-7.43 (5H, m), 7.82 (1H, q, J=5Hz), 8.26 (1H, d, J=8Hz), 8.41 (2H, d, J=7Hz), 11.10 (1H, s)

HPLC : 5.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=569 Example 16-11)

= -38.3° (c 0.12, 1N-HClaq.)

mp : 237-243°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.80 (1H, m), 1.25 (1H, m), 1.36 (1H, m), 2.06 (3H, s), 2.20 (1H, m), 2.44 (1H, m), 2.56 (3H, d, J=5Hz), 2.68-2.90 (3H, m), 2.96 (1H, dd, J=14, 6Hz), 4.33 (1H, d, J=14Hz), 4.38 (1H, d, J=14Hz), 4.56 (1H, ddd, J=10, 8, 6Hz), 4.71 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 7.24 (2H, d, J=6Hz), 7.30- 7.41 (5H, m), 7.76 (1H, dd, J=6, 6Hz), 7.86 (1H, q, J=5Hz), 8.34 (1H, d, J=8Hz), 8.39 (2H, d, J=6Hz), 11.05 (1H, s)

HPLC : 6.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=570 Example 16-12)

= -9.8° (c 0.21, 1N-HClaq.)

mp : 228-233°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.79 (3H, d, J=7Kz), 0.80 (1H, m), 1.26 (1H, m), 1.33 (1H, m), 2.15 (1H, m), 2.43 (1H, m), 2.45 (3H, d, J=4.5Hz), 2.62-2.89 (3H, m), 2.95 (1H, dd, J=14, 4Hz), 3.47 (3H, s), 4.56 (1H, ddd, J=10, 8, 4Hz), 4.70 (1H, d, J=12Hz), 4.77 (1H, d, J=12Hz), 6.77 (1H, dd, J=5, 5Hz), 7.26 (2x1H, d, J=6Hz), 7.29-7.44 (5H, m), 7.87 (1H, q, J=4.5Hz), 8.34 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 10.98 (1H, s)

HPLC : 6.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=528 Example 16-13)

= -38.7° (c 0.21, 1N-HClaq. )

mp : 233-236°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.79 (3H, d, J=7Hz) , 0.80 (1H, m) , 1.25 (1H, m), 1.34 (1H, m), 2.21 (1H, ddd, J=9, 9, 3Hz), 2.45 (1H, m), 2.56 (3H, d, J=4.5Hz) , 2.65 (1H, ddd, J=13, 5, 5Hz) , 2.82 (1H, dd, J=14, 10Hz), 2.85 (1H, m), 2.95 (1H, dd, J=14, 5Hz), 3.27 (3H, s), 3.70 (2H, s), 4.55 (1H, ddd, J=10, 8, 5Hz), 4.71 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 7.25 (2x1H, d, J=6Hz), 7.27 (1H, do, J=5, 5Hz), 7.31-7.40 (5H, m), 7.85 (1H, q, J=4.5Hz), 8.38 (2x1H, d, J=6Hz), 8.39 (1H, d,

J=8Hz), 11.05 (1H, s)

HPLC : 5.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=542 Example 16-14)

= -18.4° (c 0.23, 1N-HClaq.)

mp : 239-243°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.82 (1H, m), 1.28 (1H, m), 1.35 (1H, m ), 2.17 (1H, ddd, J=10, 9, 3Hz), 2.37-2.52 (2H, m), 2.56 (3H, d, J=4.5Hz), 2.67 (3H, s), 2.79-2.94 (1H, m), 2.84 (1H, dd, J=14, 10Hz), 2.93 (1H, dd, J=14, 5Hz), 4.51 (1H, ddd, J=10, 8, 5Hz), 4.77 (1H, d, J=11Hz), 4.81 (1H, d, J=11Hz), 6.84 (1H, dd, J=6, 6Hz), 7.27 (2x1H, d, J=7Hz), 7.31-7.44 (5H, m), 7.87 (1H, q, J=4.5Hz), 8.34 (1H, d, J=8Hz), 8.45 (2x1H, d, J=7Hz), 11.11 (1H, s)

HPLC : 5.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=548 Example 16-15)

= -15.2° (c 0.17, 1N-HClaq.)

mp : 212-214°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.82 (1H, m), 1.26 (1H, m), 1.37 (1H, m), 2.24 (1H, m), 2.41 (1H, m) , 2.57 (3H, d, J=4.5Hz) , 2.77 (2H, m) , 2.85 (1H, dd, J=14, 11Hz) , 2.97 (1H, dd, J=14, 6Hz) , 4.58 (1H, ddd, J=11, 8, 6Hz) , 4.73 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 6.17 (1H, t, J=6Hz) , 7.23-7.40 (9H, m) , 7.87 (1H, q, J=4.5Hz) , 8.29 (2x1H, br d, J=5Hz), 8.34 (1H, d, J=8Hz), 8.41 (2x1H, d, J=6Hz), 8.90 (1H, s), 11.18 (1H, s) HPLC : 6.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=590 Example 16-16)

= -6.3° (c 0.13, 1N-HClaq.)

mp : 227-229°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.73 (3H, d, J=7Hz), 0.84 (1H, m), 1.25 (1H, m), 1.38 (1H, m), 2.31 (1H, m), 2.42 (1H, m), 2.44-2.55 (1H, m), 2.47 (3H, d, J=4.5Hz), 2.62 (1H, dd, J=14, 8Hz), 2.74 (1H, dd, J=14, 7Hz), 2.87 (1H, m), 4.42 (1H, ddd, J=8, 8, 7Hz), 4.79 (1H, d, J=11Hz), 4.83 (1H, d, J=11Hz), 7.07 (2x1H, d, J=6Hz), 7.31-7.47 (5H, m), 7.50-7.63 (4H, m), 7.68-7.77 (2H, m), 7.80 (1H, q, J=4.5Hz), 8.26-8.40 (3H, m), 11.17 (1H, s) HPLC : 6.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05. TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=610 Example 16-17)

= -30.6° (c 0.21, 1N-HClaq.)

mp : 232-238°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.86 (1H, m), 0.78 (3H, d, J=7Hz), 1.25 (1H, m), 1.32 (1H, m), 2.19 (1H, m), 2.40-2.58 (2H, m), 2.56 (3H, d, J=4.5Hz), 2.82 (1H, dd, J=14, 12Hz), 2.88-3.02 (2H, m), 3.35-3.63 (4H, m), 3.90-4.00 (2H, m), 4.36 (1H, m), 4.52-4.68 (4H, m), 4.73 (1H, d, J=11Hz), 4.78 (1H, d, J=11Hz), 5.35 (1H, d, J=4Hz), 7.22-7.31 (1H, m), 7.25 (2x1H, d, J=6Hz), 7.32-7.42 (5H, m), 7.85 (1H, q, J=4.5Hz), 8.35-8.43 (1H, m), 8.40 (2x1H, d, J=6Hz), 11.00 (1H, s)

HPLC : 7.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=648 Example 16-18)

= -48.0° (c 0.27, AcOH)

mp : 218-220°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.82 (1H, m), 1.29 (1H, m), 1.37 (1H, m), 2.20 (1H, ddd, J=9, 9, 3Hz), 2.41-2.61 (2H, m), 2.57 (3H, d, J=4Hz), 2.70 (1H, m), 2.81 (1H, dd, J=14, 11Hz), 2.96 (1H, dd, J=14, 6Hz), 4.60 (1H, ddd, J=11, 8, 6Hz), 4.74 (1H, d, J=11Hz), 4.81 (1H, d, J=11Hz), 7.09 (2x1H, d, J=7.5Hz), 7.18 (1H, dd, J=7.5, 7.5Hz), 7.27 (2x1H, d, J=6Hz), 7.31-7.52 (8H, m), 7.88 (1H, q, J=4Hz), 8.42 (2x1H, d,

J=6Hz), 11.11 (1H, s)

HPLC : 7.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=590 Example 16-19)

= +6. c 0.21, AcOH)

mp : 229-234°C (dec.

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz) , 0.81 (3H, d, J=7Hz) , 0.84 (1H, m), 1.29 (1H, m), 1.41 (1H, m), 2.34 (1H, ddd, J=11, 10, 3Hz) , 2.46-2.65 (1H, m) , 2.58 (3H, d, J=4.5Hz) , 2.78-2.93 (2H, m), 2.99 (1H, dd, J=14, 4Hz) , 3.08 (1H, m), 4.56 (1H, d, J=11Hz), 4.61 (1H, m) , 4.75 (1H, d, J=11Hz), 7.02 (1H, dd, J=7.5, 7.5Hz) , 7.10 (1H, s) , 7.12-7.35 (8H, m), 7.43 (1H, d, J=7.5Hz), 7.59 (1H, d, J=7.5Hz), 7.87 (1H, q, J=4.5Hz), 8.12 (1H, dd, J=6, 6Hz), 8.38 (2x1H, d, J=8Hz), 8.44 (1H, d, J=8Hz), 11.00 (1H, s), 11.45 (1H, s)

HPLC : 5.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 35:65, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=613 Example 16-20)

= -36.9° (c 0.24, AcOH)

mp : 250-256°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.84 (1H, m), 1.23 (1H, m), 1.40 (1H, m), 2.32-2.54 (2H, m), 2.60 (3H, d, J=4.5Hz), 2.88 (1H, dd, J=14, 11Hz), 2.93-3.07 (3H, m), 4.50-4.67 (1H, m), 4.57 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 7.02-7.31 (9H, m), 7.40 (1H, dd, J=8, 8Hz), 7.65 (1H, dd, J=5, 5Hz), 7.90 (1H, q, J=4.5Hz), 8.02 (1H, d, J=1Hz), 8.14 (1H, d, J=7.5Hz), 8.30-8.48 (3H, m), 10.99 (1H, s), 11.48 (1H, d, J=1Hz)

HPLC : 4.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 35:65, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=613 Example 16-21)

= -37.0° (c 0.23, AcOH)

mp : 238-242°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.75-0.88 (1,, m), 0.79 (3H, d, J=7Hz), 1.25 (1H, m), 1.33 (1H, m), 2.15 (1H, m), 2.45 (1H, m), 2.48-2.62 (1H, m ), 2.57 (3H, d, J=4.5Hz), 2.70 (1H, m), 2.82 (1H, dd, J=14, 11Hz), 2.95 (1H, dd, J=14, 5Hz), 3.23 (3H, s), 3.47 (2H, t, J=5Hz), 3.94-4.07 (2H, m), 4.57 (1H, ddd, J=11, 8, 5Hz), 4.70 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 6.80 (1H, dd, J=5, 5Hz), 7.25 (2x1H, d, J=6Hz), 7.32-7.42 (5H, m), 7.87 (1H, q, J=4.5Hz), 8.37 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 10.95 (1H, s)

HPLC : 7.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS M+H=572 Example 16-22

= -38.1° (c 0.23, AcOH)

mp : 256-260°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.74-0.91 (1H, m), 0.79 (3H, d, J=7Hz), 0.85 (2x3H, d, J=7Hz), 1.26 (1H, m), 1.33 (1H, m), 1.80 (1H, tqq, J=7, 7, 7Hz), 2.15 (1H, ddd, J=11, 9, 3Hz), 2.44 (1H, m), 2.46-2.60 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.70 (1H, m), 2.81 (1H, dd, J=14, 11Hz), 2.93 (1H, dd, J=14, 6Hz), 3.68 (2H, d, J=7Hz), 4.56 (1H, ddd, J=11, 8, 6Hz), 4.69 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 6.70 (1H, dd, J=6, 6Hz), 7.25 (2x1H, d, J=7Hz), 7.30-7.41 (5H, m), 7.87 (1H, q, J=4.5Hz), 8.28 (1H, d, J=8Hz), 8.35 (1H, d, J=8Hz), 8.38 (2x1H, d, J=7Hz), 10.98 (1H, s)

HPLC : 7.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=570 Example 16-23)

= -73.6° (c 0.25, AcOH)

mp : 253-258°C (dec.)

NMR (DMSO-d₆, δ) : 0.53-0.65 (4H, m), 0.70 (3H, d,

J=7Hz) , 0.77 (3H, d, J=7Hz) , 0.80 (1H, m) , 1.23 (1H, m) , 1.36 (1H, ddd, J=13, 11, 2Hz) , 1.51 (1H, m) , 2.20 (1H, ddd, J=11, 9, 3Hz) , 2.41 (1H, ddd, J=11, 8, 3Hz) , 2.56 (3H, d, J=4.5Hz) , 2.63-2.90 (2H, m) , 2.83 (1H, dd, J=14, 11Hz) , 2.95 (1H, dd, J=14, 5Hz) , 4.55 (1H, ddd, J=11, 8, 5Hz) , 4.72 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 7.25 (2x1H, br d, J=6Hz), 7.30-7.43 (5H, m), 7.79 (1H, dd, J=5.5, 5.5Hz), 7.85 (1H, q, J=4.5Hz), 8.32 (1H, d, J=8Hz), 8.39 (2H, br), 11.03 (1H, s)

HPLC : 6.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 254 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=538 Example 16-24)

= -12.3° (c 0.20, 1N-HClaq.)

mp : 222-231°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.74-0.87 (1H, m), 0.78 (3H, d, J=7Hz), 1.12 (2x3H, d, J=7Hz), 1.26 (1H, m), 1.33 (1H, m), 2.14 (1H, ddd, J=10, 9, 3Hz), 2.45 (1H, m), 2.47-2.61 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.70 (1H, m), 2.81 (1H, dd, J=14, 10Hz), 2.94 (1H, dd, J=14, 4Hz), 4.55 (1H, ddd, J=11, 8, 4Hz), 4.62-4.78 (1H, m), 4.68 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 6.56 (1H, dd, J=5.5, 5.5Hz), 7.25 (2x1H, d, J=6Hz), 7.28-7.42 (5H, m), 7.86 (1H, q, J=4.5Hz), 8.36 (1H, d, J=8Hz), 8.38 (2x1H, d,

J=6Hz), 10.96 (1H, s)

HPLC : 9.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=556 Example 16-25)

+17.0° (c 0.21, 1N-HClaq.)

mp : 237-241°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.83 (1H, m), 1.26 (1H, m), 1.38 (1H, m), 2.31 (1H, ddd, J=10, 9, 3Hz), 2.48 (1H, m), 2.58 (3H, d, J=4.5Hz), 2.72-2.90 (1H, m), 2.87 (1H, dd, J=14, 11Hz), 2.94-3.10 (1H, m), 2.98 (1H, dd, J=14, 5Hz), 4.56 (1H, ddd, J=11, 8, 5Hz), 4.56 (1H, d, J=12Hz), 4.74 (1H, d, J=12Hz), 6.05 (1H, br), 6.75 (1H, br), 6.83 (1H, br), 7.20-7.35 (7H, m), 7.64 (1H, dd, J=5.5, 5.5Hz), 7.87 (1H, q, J=4.5Hz), 8.38 (2x1H, d, J=6Hz), 8.40 (1H, d, J=6Hz), 10.95 (1H, s), 11.31 (1H, br)

HPLC : 8.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=563 Example 16-26_

= -1.5° (c 0.20, 1N-HClaq.)

mp : 224-227°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.79 (3K, d, J=7Hz), 0.83 (1H, m), 1.27 (1H, m), 1.37 (1H, m), 2.36 (1H, ddd, J=9, 9, 4Hz), 2.47-2.60 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.80 (1H, m), 2.83 (1H, dd, J=14, 10Hz), 2.96 (1H, dd, J=14, 5Hz), 3.18 (1H, m), 4.57 (1H, m), 4.59 (1H, dd, J=12Hz), 4.71 (1H, d, J=12Hz), 7.21-7.31 (7H, m), 7.87 (1H, q,

J=4.5Hz), 8.37 (2x1H, d, J=6Hz), 8.46 (1H, d, J=8Hz), 8.72 (1H, br), 8.87 (1H, d, J=2Hz), 9.15 (1H, s), 11.05 (1H, s) HPLC : 6.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=576 Example 16-27)

= -29.4° (c 0.20, 1N-HClaq.)

mp : 225-229°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz) , 0.78 (3H, d, J=7Hz) , 0.82 (1H, m) , 1.12 (3H, t, J=7.5Hz) , 1.28 (1H, m), 1.36 (1H, m), 2.17 (1H, ddd, J=11, 9, 3Hz) , 2.32-2.53 (2H, m) , 2.57 (3H, d, J=4.5Hz) , 2.72-2.93 (2H, m), 2.92 (1H, dd, J=14, 5Hz) , 4.50 (1H, m), 4.78 (1H, d, J=11Hz), 4.82 (1H, d,

J=11Hz), 6.85 (1H, dd, J=6, 5Hz) , 7.27 (2x1H, d, J=6Hz), 7.31-7.44 (5H, m), 7.88 (1H, q, J=4.5Hz), 8.34 (1H, d, J=8Hz), 8.45 (2x1H, d, J=6Hz), 11.10 (1H, s)

HPLC : 6.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05. TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=562 Example 16-28)

= -1.3° (c 0.26, 1N-HClaq.)

mp : 225-231°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.74-0.90 (1H, m), 0.78 (3H, d, J=7Hz), 1.26 (1H, m), 1.38 (1H, m), 2.31 (1H, ddd, J=10, 9, 3Hz), 2.45 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.71-3.05 (3H, m), 2.98 (1H, dd, J=14, 5Hz), 4.52-4.64 (1H, m), 4.58 (1H, d, J=12Hz), 4.74 (1H, d, J=12Hz), 6.83 (1H, s), 7.20- 7.37 (7H, m), 7.70 (1H, s), 7.87 (1H, q, J=4.5Hz), 7.95 (1H, dd, J=5.5, 5.5Hz), 8.13 (1H, s), 8.31- 8.46 (3H, m), 11.00 (1H, s) HPLC : 9.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=564 Example 16-29)

= +26.8° (c 0.23, 1N-HClaq.)

mp : 236-241°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.75-0.90 (1H, m), 0.80 (3H, d, J=7Hz), 1.26 (1H, m), 1.37 (1H, m), 2.32 (1H, ddd, J=10, 9, 3Hz), 2.42-2.55 (1H, m), 2.59 (3H, d, J=4.5Hz), 2.72 (1H, ddd, J=13, 5.5, 5Hz), 2.84 (1H, dd, J=14, 11Hz), 2.91-3.06 (1H, m), 2.96 (1H, dd, J=14, 5Hz), 4.57 (1H, d, J=11Hz), 4.58 (1H, ddd, J=11, 8, 5Hz), 4.73 (1H, d, J=11Hz), 6.60 (1H, dd, J=3, 2Hz), 7.08 (1H, d, J=3Hz), 7.22-7.37 (7H, m), 7.81 (1H, d, J=2Hz), 7.88 (1H, q, J=4.5Hz), 7.96 (1H, dd, J=5.5, 5.5Hz), 8.38 (2x1H, d, J=7Hz), 8.42 (1H, d, J=8Hz), 11.00 (1H, s)

HPLC : 8.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow race 1.0 ml/min., at R.T.)

MASS : M+H=564 Example 16-30)

= -35.8° (c 0.22, 1N-HClaq.)

mp : 250-257°C (dec.)

NMR (DMSO-d₆, δ) : 0.67-0.88 (1H, m), 0.73 (3H, d,

J=7Hz), 0.80 (3H, d, J=7Hz), 1.27 (1H, m), 1.37 (1H, m), 2.22 (1H, ddd, J=10, 10, 4Hz), 2.36-2.52 (2H, m), 2.58 (3H, d, J=4.5Hz), 2.89 (1H, dd, J=14, 11Hz), 3.04 (1H, dd, J=14, 5Hz), 4.65 (1H, ddd, J=11, 8, 5Hz), 4.66 (1H, d, J=11Hz), 4.76 (1H, d, J=11Hz), 7.35 (5x1H, s), 7.46 (2x1H, d, J=6Hz), 7.91 (1H, q, J=4.5Hz), 8.45 (1H, d, J=8Hz), 8.48 (2x1H, br d, J=6Hz), 9.20 (1H, dd, J=5.5, 5.5Hz), 11.16 (1H, s)

HPLC : 10.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=566 Example 16-31)

= -69.3° (c 0.28, 1N-HClaq.)

mp : 258-265°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.74-0.89 (1H, m), 0.78 (3H, d, J=Ηz), 1.25 (1H, m), 1.37 (1H, m), 1.85-2.28 (5H, m), 2.45 (1H, m), 2.54-2.81 (2H, m), 2.57 (3H, d, J=4.5Hz), 2.84 (1H, dd, J=14, 11Hz), 2.97 (1H, dd, J=14, 5Hz), 3.91 (1H, m), 4.59 (1H, m), 4.72 (1H, d, J=11Hz), 4.79 (1H, d,

J=11Hz), 7.26 (2x1H, d, J=6Hz), 7.30-7.43 (5H, m), 7.70-7.80 (2H, m), 7.92 (1H, q, J=4.5Hz), 8.32-8.46 (3H, m), 11.11 (1H, s)

HPLC : 4.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=581 Example 16-32)

= -1.5° (c 0.08, 1N-HClaq.)

mp 222-229°C (dec.)

NMR DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.74-0.86 (1H, m), 0.78 (3H, d, J=7Hz), 1.25 (1H, m), 1.33 (1H, m), 2.13 (3H, ddd, J=9, 8Hz), 2.43 (1H, m), 2.45- 2.60 (1H, m), 2.56 (3H, d, J=5Hz), 2.67 (1H, m), 2.81 (1H, dd, J=14, 10Hz), 2.95 (1H, dd, J=14, 4Hz), 3.21 (2H, m), 3.91 (2H, m), 4.57 (1H, ddd, J=10, 8, 4Hz), 4.70 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 5.01 (2H, s), 6.74 (1H, dd, J=5, 5Hz), 7.24 (2x1H, d, J=6Hz), 7.27-7.41 (11H, m), 7.86 (1H, q, J=5Hz), 8.35 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 10.90 (1H, s)

HPLC : 6.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05. TFAaq. = 35:65, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=691 Example 16-33)

= -44.1° (c 0.28,

1N-HClaq.)

mp : 199-205°C (dec.)

NMR (DMSO-d₆, δ) : 0.69 (3H, d, J=7Hz) , 0.75 (3H, d, J=7Hz) , 0.80 (1H, m) , 1.21 (1H, m ) , 1.35 (1H, m), 1.88 (1H, m), 2.21 (1H, ddd, J=9, 9, .Hz) , 2.35- 2.60 (2H, m), 2.55 (3H, d, J=4.5Hz) , 2.66-2.90 (2H, m), 2.96 (1H, dd, J=14, 5Hz) , 3.30 (2H, s) , 4.55 (1H, m), 4.64 (1H, d, J=11Hz), 4.75 (1H, d,

J=11Hz), 6.87 (1H, br) , 7.22 (2x1H, d, J=6Hz) , 7.35 (5xlH, s) , 7.50 (1H, s) , 7.72 (1H, dd, J=6, 6Hz), 7.86 (1H, q, J=4.5Hz), 8.32-8.45 (3H, m), 11.21 (1H, br)

HPLC : 5.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=578 Example 16-34)

= -44.4° (c 0.10, 1N-HClaq.

mp 263-270°C (dec.)

NMR DMSO-d₆, δ! 0.70 (3H, d, J=7Hz), 0.72-0.86 (1H, m), 0.76 (3H, d, J=7Hz), 1.22 (1H, m), 1.35 (1H, m), 2.12-2.48 (6H, m), 2.53-2.70 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.73-2.88 (2H, m), 2.96 (1H, dd, J=14, 6Hz), 4.57 (1H, m), 4.71 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 7.24 (2x1H, d, J=6Hz), 7.28-7.42 (5H, m), 7.60 (1H, dd, J=6, 6Hz), 7.85 (1H, q, J=4.5Hz), 8.31 (1H, d, J=8Hz), 8.38 (2x1H, d, J=6Hz), 10.98 (1H, s)

HPLC : 5.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : MτH=570 Example 16-35)

= -43.2° (c 0.22, 1N-HClaq.)

mp : 251-267°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.80 (1H, m), 1.23 (1H, m), 1.45 (1H, m), 1.84 (3H, s), 2.18 (1H, m), 2.45 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.71-2.90 (3H, m), 2.96 (1H, dd, J=14, 6Hz), 3.60 (2H, d, J=5Hz), 4.55 (1H, m), 4.72 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 7.23 (2x1H, d, J=6Hz), 7.30-7.43 (5H, m), 7.55 (1H, t, J=5Hz), 7.85 (1H, q, J=4.5Hz), 8.02 (1H, t, J=5Hz), 8.31 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 11.02 (1H, s)

HPLC : 4.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=569 Example 16-36)

= -36.7° (c 0.23, 1N-HClaq.)

mp : 250-253°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.74-0.88 (1H, m), 0.78 (3H, d, J=7Hz), 1.18-1.42 (2H, m), 2.21 (1H, ddd, J=10, 9, 4Hz), 2.47 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.63 (1H, ddd, J=13, 5, 4Hz), 2.82 (1H, dd, J=14, 11Hz), 2.84-3.01 (1H, m), 2.95 (1H, dd, J=14, 5Hz), 3.46 (1H, m ), 3.58 (1H, m), 3.83 (1H, m), 4.55 (1H, m), 4.71-4.90 (1H, m), 4.72 (1H, d, J=11Hz), 4.78 (1H, d, J=11Hz), 5.51 (1H, d, J=5Hz), 7.21-7.30 (1H, m), 7.25 (2x1H, d, J=6Hz), 7.32-7.42 (5H, m), 7.86 (1H, q, J=4.5Hz), 8.35-8.43 (1H, m), 8.39 (2x1H, d, J=6Hz), 11.06 (1H, s)

HPLC : 4.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=558 Example 16-37)

-21.9° (c 0.23, 1N-HClaq.)

mp : 214-221°C (dec.)

NMR (DMSO-d₆, δ) : 0.69 (3H, d, J=7Hz), 0.75 (3H, d, J=7Hz), 0.81 (1H, m), 1.20 (1H, m), 1.36 (1H, m), 2.21 (1H, ddd, J=9, 9, 4Hz), 2.38 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.70-2.91 (3H, m), 2.96 (1H, dd, J=14, 6Hz), 3.61 (3H, s), 3.73-3.80 (2H, m), 4.54 (1H, m), 4.75 (1H, d, J=11Hz), 4.80 (1H, d,

J=11Hz), 5.97 (1H, dd, J=6, 6Hz), 6.21 (1H, dd, J=6, 6Hz), 7.23 (2x1H, d, J=7Hz), 7.31-7.43 (5H, m), 7.83 (1H, q, J=4.5Hz), 8.26 (1H, d, J=8Hz), 8.41 (2x1H, d, J=7Hz), 11.09 (1H, s)

HPLC : 5.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=585 Example 16-38)

) = -15.9° (c 0.20, 1N-HClaq.)

mp : 238-242°C (dec.)

NMR (DMSO-d₆, δ) : 0.68 (3H, d, J=7Hz), 0.74 (3H, d, J=7Hz), 0.80 (1H, m), 1.20 (1H, m), 1.34 (1H, m), 2.20 (1H, ddd, J=9, 9, 4Hz), 2.37 (1H, m), 2.51 (3H, d, J=4.5Hz), 2.56 (3H, d, J=4.5Hz), 2.68-2.33 (2H, m), 2.85 (1H, dd, J=14, 10Hz), 2.97 (1H, dd, J=14, 6Hz), 4.53 (1H, ddd, J=10, 8, 6Hz), 4.74 (1H, d, J=11Hz), 4.79 (1H, d, J-11Hz), 5.61 (1H, dd, J=6, 6Hz), 5.66 (1H, q, J=4.5Hz), 7.24 (2x1H, d, J=6Hz), 7.31-7.42 (5H, m), 7.85 (1H, q, J=4.5Hz), 8.27 (1H, d, J=8Hz), 8.41 (2x1H, d, J=6Hz), 11.06 (1H, s)

HPLC : 5.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=527 Example 16-39)

= -56.2° (c 0.22, 1N-HClaq.

mp : 243-247°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.76 (3H, d, J=7Hz), 0.80 (1H, m), 1.22 (1H, m), 1.34 (1H, m), 2.20 (1H, ddd, J=9, 9, 4Hz), 2.47 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.69 (1H, m), 2.80-2.96 (1H, m), 2.83 (1H, dd, J=14, 11Hz), 2.96 (1H, dd, J=14, 5Hz), 3.45-3.63 (2H, m), 3.84 (1H, m), 4.53 (1H, ddd, J=11, 8, 5Hz), 4.72 (1H, d, J=11Hz), 4.79 (1H, d, J=11Hz), 4.89 (1H, br), 5.48 (1H, d, J=6Hz), 7.23 (2x1H, d, J=6Hz), 7.30-7.40 (6H, m), 7.84 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 11.10 (1H, s)

HPLC : 10.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=558 Example 16-40)

= -45.3° (c 0.20, 1N-HClaq.)

mp : 254-259°C (dec.) NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=6.5Hz) , 0.74-0.90 (1H, m), 0.78 (3H, d, J=6.5Hz), 1.25 (1H, m), 1.38 (1H, m), 2.19 (1H, m), 2.41 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.66-2.97 (3H, m), 2.95 (1H, dd, J=14, 6Hz), 3.11 (3H, s), 3.97 (2H, s), 4.60 (1H, m), 4.74 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 7.25 (2x1H, d, J=6Hz), 7.31-7.42 (5H, m), 7.91 (1H, q, J=4.5Hz), 8.14 (1H, dd, J=6, 6Hz), 8.36 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 11.12 (1H, s)

HPLC : 6.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H-588 Example 16-41)

= -11.2° (c 0.21, 1N-HClaq.)

mp : 236-239°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.89 (1H, m), 0.78 (3H, d, J=7Hz), 1.26 (1H, m), 1.33 (1H, m), 1.98 (3H, s), 2.14 (1H, m), 2.35-2.60 (2H, m), 2.56 (3H, d, J=4.5Hz), 2.69 (1H, m), 2.81 (1H, dd, J=13, 11Hz), 2.94 (1H, dd, J=13, 5Hz), 4.03-4.20 (4H, m), 4.56 (1H, ddd, J=11, 8, 5Hz), 4.69 (1H, d, J=11Hz), 4.76 (1H, d, J=11Hz), 6.88 (1H, dd, J=5, 5Hz), 7.25 (2x1H, d, J=6Hz), 7.30-7.42 (5H, m), 7.87 (1H, q, J=4.5Hz), 8.35 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 10.96 (1H, s)

HPLC : 9.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=600 Example 16-42)

= -55.4° (c 0.23, AcOH)

mp : 231-234°C (dec.) NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz) , 0.73-0.86 (1H, m) , 0.78 (3H, d, J=7Hz) , 1.22 (1H, m) , 1.28-1.42 (1H, m) , 1.33 (3x3H, s) , 2.42-2.60 (2H, m), 2.57 (3H, d, J=4.5Hz) , 2.75 (1H, m), 2.80 (1H, dd, J=14, 10Hz), 2.97 (1H, dd, J=14, 5Hz) , 3.54 (2H, dd, J=6, 6Hz), 3.97 (1H, dt, J=8, 6Hz), 4.62 (1H, m) , 4.66 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 5.00 (1H, t, J=6Hz), 6.54 (1H, d,, J=8Hz) , 7.26 (2x1H, d, J=6Hz) , 7.31-7.40 (5H, m), 7.59 (1H, dd, J=6, 6Hz) , 7.90 (1H, q, J=4.5Hz) , 8.33-8.41 (1H, m) , 8.37 (2x1H, d, J=6Hz), 11.03 (1H, s)

HPLC : 5.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 30:70, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=657 Example 16-43)

= -41.3° (c 0.20, 1N-HClaq.)

mp : 241-245°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.74-0.85 (1H, m), 0.78 (3H, d, J=7Hz), 1.25 (1H, m), 1.36 (1H, m), 2.08-2.23 (2H, m), 2.30-2.54 (5H, m), 2.59 (3H, d, J=5Hz), 2.70 (1H, m), 2.80 (1H, dd, J=14, 11Hz), 2.96 (1H, dd, J=14, 5Hz), 4.60 (1H, m), 4.70 (1H, d, J=11Hz), 4.73-4.82 (1H, m), 4.78 (1H, d,

J=11Hz), 7.26 (2x1H, d, J=6Hz), 7.31-7.40 (5H, m), 7.83-7.93 (2H, m), 8.31-8.42 (1H, m), 8.36 (2x1H, d, J=6Hz), 11.09 (1H, s)

HPLC : 6.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 25:75:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=582 Example 16-44)

= -52 .8°(c 0.20, 1N-HClaq. )

mp : 250-256°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.74-0.88 (1H, m) , 0.79 (3H, d, J=7Hz), 1.27 (1H, m), 1.36 (1H, m), 2.02-2.25 (2H, m), 2.26-2.54 (5H, m), 2.57 (3H, d, J=5Hz), 2.63 (2H, m), 2.81 (1H, dd, J=13, 11Hz), 2.96 (1H, dd, J=13, 5Hz), 4.60 (1H, m), 4.70-4.83 (1H, m), 4.71 (1H, d, J=11Hz), 4.78 (1H, d,

J=11Hz), 7.27 (2x1H, d, J=6Hz), 7.30-7.42 (5H, m), 7.83-7.98 (2H, m), 8.30-8.46 (3H, m), 11.09 (1H, s) HPLC : 6.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA= 25:75:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=582 Example 16-45)

= -40.0° (c 0.19, 1N-HClaq.)

mp : 223-227°C (dec. )

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.78 (3H, d, J=7Hz), 0.81 (1H, m) , 1.25 (1H, m) , 1.30-1.46 (1H, m) , 1.36 (3x3H, s) , 2.19 (1H, m), 2.45 (1H, m), 2.56 (3H, d, J=4.5Hz) , 2.70-2.90 (3H, m) , 2.97 (1H, dd, J=14, 5Hz) , 3.45 (1H, dd, J=15, 5Hz) , 3.51 (1H, dd, J=15, 5Hz) , 4.56 (1H, m), 4.72 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 6.81 (1H, dd, J=5, 5Hz) , 7.24 (2x1H, d, J=6Hz) , 7.28-7.42 (5H, m), 7.50 (1H, dd, J=5, 5Hz), 7.86 (1H, q, J=4.5Hz), 8.32 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 11.03 (1H, s)

HPLC : 4.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 35:65:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=627 Example 16-46)

= -10.5° (c 0.22, 1N-HClaq. )

mp 259-263°C (dec. ) NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.74-0.88 (1H, m), 0.78 (3H, d, J=7Hz) , 1.27 (1H, m), 1.33 (1H, m), 2.23 (1H, ddd, J=9, 9, 4Hz) , 2.45-2.60 (2H, m) , 2.56 (3H, d, J=4.5Hz) , 2.82 (1H, dd, J=14, 11Hz) , 2.93 (1H, dd, J=14, 6Hz) , 3.02 (1H, m), 4.55 (1H, ddd, J=11, 8, 6Hz) , 4.66 (1H, d, J=11Hz), 4.74 (1H, d, J=11Hz), 7.25 (2x1H, d, J=6Hz), 7.30-7.39 (5H, m), 7.80 (1H, br) , 7.86 (1H, q, J=4.5Hz) , 8.01-8.10 (2H, m), 8.28 (2x1H, d, J=6Hz) , 8.35 (1H, d,

J=8Hz), 11.02 (1H, s)

HPLC : 5.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 25:75:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=541 Example 16-47)

= -17.2° (c 0.21, 1N-HClaq.)

mp : 234-238°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.83 (1H, m), 1.21-1.42 (2H, m), 2.17 (1H, ddd, J=9, 9, 3Hz), 2.35-2.47 (2H, m), 2.56 (3H, d, J=4.5Hz), 2.72 (3H, s), 2.77-3.00 (3H, m), 4.48 (1H, m), 4.77 (1H, d, J=11Hz), 4.81 (1H, d,

J=11Hz), 6.83 (1H, dd, J=6, 6Hz), 7.25-7.45 (5H, m), 7.30 (1H, dd, J=7.5, 5Hz), 7.67 (1H, br d, J=7.5Hz), 7.87 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.39 (1H, br d, J=5Hz), 8.48 (1H, s), 11.10 (1H, s)

HPLC : 5.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 25:75:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=548 Example 16-48)

= -36.9° (c 0.22, 1N-HClaq. )

mp : 228-230°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.74-0.85 (1H, m), 0.78 (3H, d, J=7Hz), 1.25 (1H, m), 1.35 (1H, m), 2.05 (3H, s), 2.16 (1H, m), 2.41 (1H, m), 2.46- 2.61 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.71 (1H, m), 2.81 (1H, dd, J=14, 11Hz), 2.95 (1H, dd, J=14, 5Hz), 4.30 (1H, d, J=15Hz), 4.37 (1H, d, J=15Hz), 4.51 (1H, m), 4.70 (1H, d, J=11Hz), 4.79 (1H, d, J=11Hz), 7.19 (1H, dd, J=7.5, 5Hz), 7.28-7.41 (5H, m), 7.63 (1H, br d, J=7.5Hz), 7.73 (1H, dd, J=5, 5Hz), 7.84 (1H, q, J=4.5Hz), 8.28-8.36 (2H, m), 8.43 (1H, s), 11.03 (1H, s)

HPLC : 6.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 25:75:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=570 Example 16-49)

= -11.5° (c 0.22, 1N-HClaq.)

mp : 230-234°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.86 (1H, m), 0.78 (3H, d, J=7Hz), 1.13 (3H, t, J=7Hz), 1.20- 1.40 (2H, m), 2.13 (1H, ddd, J=9, 9, 4Hz), 2.43 (1H, m), 2.45-2.59 (1H, m), 2.55 (3H, d, J=5Hz), 2.65 (1H, m), 2.80 (1H, dd, J=14, 11Hz), 2.93 (1H, dd, J=14, 5Hz), 3.92 (2H, q, J=7Hz), 4.52 (1H, m), 4.70 (1H, d, J=11Hz), 4.76 (1H, d, J=11Hz), 6.69 (1H, dd, J=5, 5Hz), 7.21 (1H, dd, J=7.5, 5Hz), 7.31-7.41 (5H, m), 7.65 (1H, br d, J=7.5Hz), 7.85 (1H, q, J=5Hz), 8.28-8.37 (2H, m), 8.44 (1H, br s), 10.96 (1H, s)

HPLC : 8.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₉O:TFA = 25:75:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=542 Tne following compounds were obtained in substantiallythe same manner as that of Example 12-5). Example 17-1)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-isobutyrylaminomethylsueeinyl]-L-4-pyridylalamne methylamide

= -32.9° (c 0.19, 1N-HClaq.)

mp : 249-252°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.76 (3H, d, J=7hz), 0.85 (1H, m), 0.93 (3H, d, J=7Hz), 0.94 (3H, d, J=7Hz), 1.22 (1H, m), 1.38 (1H, m), 2.14- 2.32 (2H, m), 2.40 (1H, m), 2.55 (3H, d, J=4Hz), 2.60-2.89 (3H, m), 2.96 (1H, dd, J=14, 5Hz), 4.55 (1H, m), 7.19-7.32 (3H, m), 7.85 (1H, q, J=4Hz), 8.30 (1H, d, J=8Hz), 8.36 (2x1H, d, J=6Hz), 8.70 (1H, s), 10.29 (1H, s)

HPLC : 5.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=450 Example 17-2)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-pivaloylaminomethylsuccinyl]-L-4-pyridylalanine methylamide

= -30.0° (c 0.21, 1N-HClaq.)

mp : 226-229°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.77 (3H, d, J=7Hz) , 0.86 (1H, m) , 1.04 (9H, s) , 1.22 (1H, m) , 1.37 (1H, m), 2.28 (1H, ddd, J=11, 10, 3Hz), 2.44 (1H, m), 2.53-2.65 (1H, m) , 2.56 (3H, d, J=5Hz) , 2.82-2.98 (1H, m), 2.84 (1H, dd, J=14, 11Hz) , 2.96 (1H, dd, J=14, 5Hz) , 4.54 (1H, ddd, J=11, 8, 5Hz) , 6.87 (1H, dd, J=5.5, 5.5Hz) , 7.24 (2x1H, d, J=6Hz) , 7.86 (1H, q, J=5Hz), 8.36 (1H, d, J=8Hz) , 8.37 (2x1H, d, J=6Hz), 8.73 (1H, s) , 10.29 (1H, s) HPLC : 6.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05°. TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H=462 Example 17-3)

N-[(2R,3R)-3-Ethoxycarbonylaminomethyl-4-nydroxyamino-2-lsobutylsuccinyl]-L-4-pyridylalanine methylamide

= -23.5° (c 0.24, 1N-HClaq.)

mp : 232-237°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.86 (1H, m), 1.14 (3H, t, J=7Hz), 1.27 (1H, m), 1.38 (1H, m), 2.17 (1H, ddd, J=11, 9, 3Hz), 2.42 (1H, m), 2.44-2.60 (1H, m), 2.56 (3H, d, J=5Hz), 2.76 (1H, m), 2.81 (1H, dd, J=13, 10Hz), 2.95 (1H, dd, J=13, 5Hz), 3.92 (2H, q, J=7Hz), 4.55 (1H, ddd, J=10, 8, 5Hz), 6.50 (1H, dd, J=5, 4Hz), 7.25 (2H, d, J=7Hz), 7.85 (1H, q, J=5Hz), 8.32 (1H, d, J=8Hz), 8.40 (2H, d, J=7Hz), 8.76 (1H, s), 10.32 (1H, s)

HPLC : 5.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=452 Example 17-4

N-[ (2R,3R)-4-Hydroxyamino-2-isobutyl-3-methylcarbamoyl-acetamidomethylsuccinyl]-L-4-pyridylalanine methylamide

= -27.1° (c 0.25, 1N-HClaq.)

mp : 225-231°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.77 (3H, d, J=7Hz) , 0.86 (1H, m), 1.22 (1H, m), 1.38 (1H, m) , 2.21 (1H, m), 2.44 (1H, m), 2.56 (3H, d, J=5Hz) , 2.60 (3H, d, J=4Hz) , 2.70-2.81 (2H, m) , 2.83 (1H, dd, J=14, 11Hz) , 2.96 (1H, dd, J=14, 5Hz) , 2.97 (2H, s), 4.55 (1H, m), 7.23 (2x1H, d, J=7Hz), 7.77 (1H, dd, J=5, 5Hz), 7.84-7.99 (2H, m), 8.34-8.43 (2H, m), 8.38 (2x1H, d, J=7Hz)

HPLC : 4.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=479 Example 17-5)

N-[(2R,3R)-3-Ethoxycarbonylacetamidomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine

methylamide

= -31.8° (c 0.21, 1N-HClaq.)

mp : 226-232°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.87 (1H, m), 1.20 (3H, t, J=7Hz), 1.24 (1H, m), 1.40 (1H, m), 2.22 (1H, m), 2.42 (1H, m), 2.56 (3H, d, J=5Hz), 2.74-2.90 (3H, m), 2.96 (1H, dd, J=14, 5Hz), 3.13 (1H, d, J=15Hz), 3.18 (1H, d, J=15Hz), 4.07 (2H, q, J=7Hz), 4.56 (1H, m), 7.19- 7.31 (2H, br), 7.72 (1H, dd, J=6, 6Hz), 7.85 (1H, q, J=5Hz), 8.25-8.48 (2H, br), 8.30 (1H, d, J=8Hz), 8.77 (1H, s), 10.38 (1H, s)

HPLC : 6.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=494 Example 17-6)

N-[ (2R,3R)-4-Hydroxyamino-2-isobutyl-3-(3-ιsopropyl-ureidomethyl)sucemyl]-L-4-pyridylalanine methylamide

= -25.4° (c 0.21, 1N-HClaq.)

mp : 222-227°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.75 (3H, d, J=7Hz), 0.88 (1H, m), 1.00 (2x3H, d, J=7Hz), 1.20 (1H, m) , 1.39 (1H, m) , 2.37 (1H, m), 2.57 (3H, d, J=5Hz) , 2.75-2.84 (2H, m) , 2.86 (1H, dd, J=14, 10Hz) , 2.97 (1H, dd, J=14, 6Hz) , 3.62 (1H, dqq, J=7, 7, 7Hz) , 4.54 (1H, ddd, J=10, 8, 6Hz) , 5.35 (1H, dd, J=6, 6Hz) , 5.72 (1H, d, J=7Hz) , 7.25

(2x1H, br d, J=6Hz), 7.30-7.43 (5H, m), 7.84 (1H, q, J=5Hz), 8.25 (1H, α, J=8Hz), 8.42 (2x1H, br d, J=6Hz), 8.80 (1H, s), 10.46 (1H, s)

HPLC : 5.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=465 Example 17-7)

N-[(2R,3R)-3-(3-Ethylureιdomethyl)-4-hydroxyamino-2-isobutylsuccinyl]-L-4-ρyridylalamne methylamide

= -25.3° (c 0.25, 1N-HClaq.)

mp : 237-243°C (dec.)

NMR (DMSO-d₆, δ) : 0.69 (3H, d, J=7Hz), 0.75 (3H, d, J=7Hz), 0.87 (1H, m), 0.96 (3H, t, J=7Hz), 1.20 (1H, m), 1.38 (1H, m), 2.20 (1H, m), 2.37 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.70-3.04 (6H, m), 4.53 (1H, m), 5.44 (1H, t, J=6Hz), 5.80 (1H, t, J=5Hz), 7.25 (2x1H, d, J=6Hz), 7.85 (1H, q, J=4.5Hz), 8.25 (1H, d, J=8Hz), 8.41 (2x1H, d, J=6Hz), 8.80 (1H, s), 10.45 (1H, s)

HPLC : 4.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=451 Example 17-8)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-[3-(piperidin-1-yl)propionylaminomethyl]succinyl]-L-4-pyridylalanine

methylamide = -26.3° (c 0.20, 1N-HClaq.)

mp : 227-232°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.87 (1H, m), 1.24 (1H, m), 1.30-1.58 (7H, m), 2.10-2.25 (3H, m), 2.27-2.54 (7H, m), 2.57 (3H, d, J=5Hz), 2.72 (2H, t, J=6Hz), 2.83 (1H, dd, J=13, 10Hz), 2.96 (1H, dd, J=13, 4Hz), 4.55 (1H, ddd, J=10, 8, 4Hz), 7.24 (2x1H, d, J=6Hz), 7.68 (1H, dd, J=6, 5Hz), 7.86 (1H, q, J=5Hz), 8.29 (1H, d,

J=8Hz), 8.38 (2x1H, d, J=6Hz), 8.74 (1H, br), 10.34 (1H, s)

HPLC : 4.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=519 Example 17-9)

N-[ (2R,3P)-3-(3-tert-Butylureιdomethyl)-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalamne methylamide

= -27.2° (c 0.22, 1N-HClaq.)

mp : 196-200°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.75 (3H, d, J=7Hz) , 0.88 (1H, m), 1.19 (1H, m) , 1.20 (9H, s), 1.40 (1H, m), 2.17 (1H, m), 2.35 (1H, m), 2.57 (3H, d, J=5Hz) , 2.73 (1H, m), 2.80-2.93 (2H, m) , 2.98 (1H, dd, J=14, 4Hz), 4.54 (1H, m), 5.35 (1H, dd, J=5, 5Hz), 5.72 (1H, s), 7.25 (2x1H, d, J=6Hz), 7.83 (1H, q, J=5Hz), 8.26 (1H, d, J=8Hz), 8.42 (2x1H, d, J=6Hz), 8.82 (1H, br), 10.46 (1H, s) HPLC : 5.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=479 Example 17-10) N-[ (2R,3R)-3-Acetoxyacetamidomethyl-4-hydroxyamino-2-isobutylsucemyl]-L-4-pyridylalanine methylamide

= -26.4° (c 0.25, 1N-HClaq.)

mp : 23C-236°C (dec. )

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) , 0.77 (3H, d, J=7Hz) , 0.87 (1H, ddd, J=12, 9, 3Hz) , 1.24 (1H, m), 1.39 (1H, ddd, J=12, 9, 3Hz), 2.08 (3H, s) , 2.22 (1H, ddd, J=1C, 10, 3Hz) , 2.43 (1H, ddd, J=11, 11, 3Hz) , 2.56 (3H, d, J=4.5Hz) , 2.71 (1H, ddd, J=14, 5, 4Hz) , 2.84 (1H, dd, J=14, 11Hz) , 2.89 (1H, m) , 2.97 (1H, dd, J=14, 6Hz) , 4.35 (1H, d, J=12Hz) , 4.40 (1H, d, J=12Hz) , 4.55 (1H, ddd, J=11, 8, 6Hz) , 7.25 (2x1H, d, J=6Hz) , 7.58 (1H, dd, J=6, 5Hz) , 7.86 (1H, q, J=4.5Hz) , 8.32 (1H, d, J=8Hz) , 8.40 (2x1H, d, J=6Hz), 8.80 (1H, s), 10.39 (1H, s)

HPLC : 4.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=548 Example 17-11)

N-[(2R,3R)-3-Carboxylacetamidomethyl-4-hydroxyamino-2-losbutylsuccinyl]-L-4-pyridylalanine methylamide

= -32.6° (c 0.22, 1N-HClaq.)

mp : 234-239°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.76 (3H, d, J=7Hz), 0.87 (1H, m), 1.23 (1H, m), 1.40 (1H, m), 2.21 (1H, m), 2.43 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.75-2.90 (3H, m), 2.96 (1H, dd, J=14, 6Hz), 3.06 (1H, d, J=15Hz), 3.11 (1H, d, J=15Hz), 4.56 (1H, m), 7.25 (2x1H, d, J=6Hz), 7.71 (1H, dd, J=5.5, 5.5Hz), 7.86 (1H, q, J=4.5Hz), 8.30 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.78 (1H, br), 10.37 (1H, s) HPLC : 3.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=466 Example 17-12)

N-[ (2R,3R)-4-Hydroxyamino-2-isobutyl-3-(methoxycarbonyl-aminomethyl)sucemyl]-L-4-pyridylalanine methylamide

= -27.1° (c 0.21, 1N-HClaq.)

mp : 226-230°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz) , 0.78 (3H, d, J=7Hz) , 0.87 (1H, m) , 1.27 (1H, m), 1.38 (1H, m), 2.17 (1H, m), 2.31 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.68-2.89 (3H, m), 2.95 (1H, dd, J=14, 4Hz) , 3.47 (3H, s) , 4.56 (1H, m), 6.57 (1H, dd, J=5, 5Hz) , 7.26 (2x1H, d, J=6Hz) , 7.85 (1H, q, J=4.5Hz) , 8.31 (1H, d, J=8Hz) , 8.40 (2x1H, d, J=6Hz) , 8.75 (1H, s), 10.32 (1H, s)

HPLC : 4.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=438 Example 17-13)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(methoxy-acetamidomethyl)sucemyl]-L-4-pyridylalanine methylamide

= -20.4° (c 0.35, 1N-HClaq.)

mp : 241-244°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.87 (1H, m), 1.26 (1H, m), 1.38 (1H, m), 2.24 (1H, ddd, J=10, 10, 3Hz), 2.45 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.62 (1H, ddd, J=12, 5, 4Hz), 2.83 (1H, dd, J=14, 11Hz), 2.90-3.05 (3H, m), 3.28 (3H, s), 3.71 (2H, s), 4.54 (1H, ddd, J=11, 8, 5Hz), 7.10 (1H, dd, J=5, 5Hz), 7.25 (2x1H, d,

J=6Hz), 7.85 (1H, q, J=4.5Hz), 8.36 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 8.81 (1H, s), 10.40 (1H, s) HPLC : 4.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=452 Example 17-14)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyI-3-(mesylamino-methyl)succinyl]-L-4-pyridylalanine methylamide

= -15.8° (c 0.35, 1N-HClaq.)

mp : 223-226°C (dec.)

NMR (DMSO-d₆, δ) : 0.75 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, m), 1.31 (1H, m), 1.40 (1H, m), 2.19 (1H, m), 2.35-2.48 (2H, m), 2.57 (3H, d,

J=4.5Hz), 2.68 (3H, s), 10-2.95 (1H, m), 2.85 (1H, dd, J=14, 11Hz), 2.94 (1H, dd, J=14, 5Hz), 4.51 (1H, ddd, J=11, 7.5, 5Hz), 6.72 (1H, dd, J=7, 5Hz), 7.29 (2x1H, d, J=7Hz), 7.88 (1H, q, J=4.5Hz), 8.33 (1H, d, J=7.5Hz), 8.46 (2x1H, d, J=6Hz), 8.83 (1H, s), 10.46 (1H, s)

HPLC : 3.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=458 Example 17-15)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-[3-(4-pyridyl)-ureidomethyl]succinyl}-L-4-pyridylalanine methylamide

= -44.6° (c 0.27, 1N-HClaq.)

mp : 223-229°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.90 (1H, m), 1.28 (1H, m), 1.41 (1H, m), 2.24 (1H, ddd, J=10, 9, 3Hz), 2.42 (1H, ddd, J=10, 10, 3Hz), 2.57 (3H, d, J=4.5Hz), 2.68-2.91 (2H, m), 2.76 (1H, dd, J=14, 10Hz), 2.96 (1H, dd, J=14, 5Hz), 4.57 (1H, ddd, J=00, 8, 5Hz), 6.10 (1H, dd, J=6, 6Hz), 7.26 (2x1H, d, J=6Hz), 7.37 (2x1H, br d, J=5Hz), 7.87 (1H, q, J=4.5Hz), 8.21-8.36 (2H, m), 8.33 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.87 (1H, br), 9.00 (1H, s), 10.45 (1H, s)

HPLC : 4.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=500 Example 17-16)

N-[ (2R,3R)-3-Benzenesulfonylaminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

= -19.9° (c 0.13, 1N-HClaq. )

mp : 233-237°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz) , 0.75 (3H, d, J=7Hz) , 0.90 (1H, m), 1.26 (1H, m), 1.42 (1H, m), 2.25-2.51 (3H, m), 2.47 (3H, d, J=4.5Hz), 2.56 (1H, dd, J=14, 7Hz), 2.71 (1H, dd, J=14, 7Hz), 2.86 (1H, m), 4.40 (1H, ddd, J=8, 7, 7Hz) , 7.04 (2x1H, d, J=6Hz) , 7.46 (1H, dd, J=7, 5Hz) , 7.49-7.58 (3H, m), 7.70 (1H, d, J=5Hz), 7.72 (1H, d, J=5Hz), 7.79 (1H, q, J=4.5Hz), 8.28 (1H, d, J=8Hz), 8.35 (2x1H, d, J=6Hz), 8.87 (1H, s), 10.49 (1H, s)

HPLC : 6.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 15:85, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=520 Example 17-17)

N-[ (2R,3R)-3-Glycoloylaminomethyl-4-hydroxyamino-2-lsobutylsuccinyl]-L-4-pyridylalanine methylamide

= -20.0° (c 0.38, 1N-HClaq.)

mp : 221-226°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz) , 0.78 (3H, d, J=7Hz) , 0.88 (1H, m), 1.26 (1H, m) , 1.38 (1H, m) , 2.24 (1H, ddd, J=9, 9, 4Hz) , 2.41-2.53 (1H, m) , 2.55 (3H, d, J=4.5Hz) , 2.71 (1H, ddd, J=13, 5, 4Hz) , 2.85 (1H, dd, J=14, 10Hz) , 2.91-3.08 (1H, m) , 2.96 (1H, dd, J=14, 5Hz) , 3.75 (2H, br) , 4.54 (1H, ddd, J=10, 8, 5Hz) , 5.46 (1H, br) , 7.11 (1H, dd, J=6, 5Hz) , 7.26 (2x1H, d, J=6Hz) , 7.85 (1H, q, J=4.5Hz) , 8.41 (2x1H, d, J=6Hz) , 8.85 (1H, s) , 10.47 (1H, s)

HPLC : 3.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=438 Example 17-18)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(phenoxycarbonyl-aminomethyl)succinyl]-L-4-pyridylalanine methylamide

= -34.5° (c 0.30, 1N-HClaq.)

mp : 222-226°C (dec.)

NMR (DMSO-d₆, δ) : 0.75 (3H, d, J=7Hz), 0.81 (3H, d, J=7Hz), 0.89 (1H, m), 1.29 (1H, m), 1.40 (1H, m), 2.22 (1H, ddd, J=10, 9, 3Hz), 2.36-2.53 (2H, m), 2.57 (3H, d, J=4.5Hz), 2.80 (1H, m), 2.82 (1H, dd, J=14, 11Hz), 2.95 (1H, dd, J=14, 4Hz), 4.60 (1H, ddd, J=11, 8, 4Hz), 7.11 (2x1H, d, J=7.5Hz), 7.19 (1H, dd, J=7.5, 7.5Hz), 7.22-7.32 (3H, m), 7.38 (2x1H, dd, J=7.5, 7.5Hz), 7.87 (1H, q, J=4.5Hz), 8.35 (1H, d, J=8Hz), 8.42 (2x1H, br), 8.82 (1H, s), 10.42 (1H, s)

HPLC : 3.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=500 Example 17-19)

N-[(2R,3R)-4-Hydroxyamino-3-(2-indolylcarbonylamino- methyl)-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide = -24.3° (c 0.30, 1N-HClaq.)

mp : 234-238°C (dec.)

NMR (DMSO-d₆, δ) : 0.75 (3H, d, J=7Hz), 0.82 (3H, α, J=7Hz), 0.92 (1H, ddd, J=13, 10, 3Hz), 1.30 (1H, m), 1.45 (1H, m), 2.39 (1H, ddd, J=10, 9, 3Hz), 2.46-2.65 (1H, m), 2.59 (3H, d, J=4.5Hz), 2.80 (1H, ddc, J=11, 4, 3Hz), 2.87 (1H, dd, J=14, 10Hz), 2.98 (1H, dd, J=14, 6Hz), 3.15 (1H, m), 4.59 (1H, ddd, J=10, 8, 6Hz), 7.02 (1H, dd, J=7.5, 7.5Hz), 7.05 (1H, s), 7.17 (1H, dd, J=7.5, 7.5Hz), 7.22-7.35 (2H, br), 7.42 (1H, d, J=7.5Hz), 7.60 (1H, d,

J=7.5Hz), 7.89 (1H, q, J=4.5Hz), 7.95 (1H, dd, J=4, 4Hz), 8.29-8.50 (2H, br), 8.43 (1H, d, J=8Hz), 8.75 (1H, s), 10.37 (1H, s), 11.48 (1H, s)

HPLC : 6.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=523 Example 17-20)

N-[(2R,3R)-4-Hydroxyamino-3-(3-indolylcarbonylamino¬methyl)-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

= -25.4° (c 0.25, IN-HClaq.)

mp : 218-222°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.92 (1H, m), 1.22 (1H, m), 1.44 (1H, m), 2.36-2.53 (2H, m), 2.59 (3H, d, J=4.5Hz), 2.88 (1H, dd, J=14, 10Hz), 2.90-3.15 (3H, m), 4.58 (1H, m), 7.08 (1H, dd, J=7.5, 7.5Hz), 7.14 (1H, dd, J=7.5, 7.5Hz), 7.26 (2x1H, d, J=6Hz), 7.41 (1H, d,

J=7.5Hz), 7.90 (1H, q, J=4.5Hz), 7.96 (1H, d,

J=2Hz), 8.11 (1H, d, J=7.5Hz), 8.32-8.45 (3H, m), 8.75 (1H, s), 10.38 (1H, s), 11.49 (1H, d, J=2Hz) HPLC : 3.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm, MeCN:0.05% TFAaq. = 20:80, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=523 Example 17-21)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(2-methoxyethoxy-carbonylaminomethyl)succinyl]-L-4-pyridylalanine methylamide

= -19.5° (c 0.30, 1N-HClaq.)

mp : 223-227°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.78 (3π, α, J=7Hz), 0.86 (1H, m), 1.26 (1H, m), 1.38 (1H, m), 2.17 (1H, ddd, J=10, 10, 3Hz), 2.43 (1H, m), 2.46- 2.60 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.76 (1H, m), 2.81 (1H, dd, J=14, 11Hz), 2.93 (1H, dd, J=14, 5Hz), 3.25 (3H, s), 3.47 (2H, t, J=4Hz), 4.00 (2H, t, J=4Hz), 4.55 (1H, ddd, J=11, 8, 5Hz), 6.63 (1H, dd, J=5.5, 5.5Hz), 7.25 (2x1H, d, J=6Hz), 7.86 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 8.76 (1H, s), 10.30 (1H, s)

HPLC : 5.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 254 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=482 Example 17-22)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(isobutoxy-carbonylaminomethyl)succinyl]-L-4-pyridylalanine methylamide

= -25.4° (c 0.31, 1N-HClaq.)

mp : 232-236°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.82-0.93 (1H, m), 0.88 (2x3H, d, J=7Hz), 1.26 (1H, m), 1.38 (1H, m), 1.82 (1H, tqq, J=7, 7, 7Hz), 2.18 (1H, m), 2.33 (1H, m), 2.36-2.61 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.77 (1H, m), 2.82 (1H, dd, J=14, 10Hz), 2.94 (1H, dd, J=14, 6Hz), 3.68 (2H, d, J=7Hz), 4.55 (1H, ddd, J=10, 8, 6Hz), 6.50 (1H, dd, J=6, 6Hz), 7.26 (2x1H, d, J=5Hz), 7.87 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.39 (2x1H, d, J=5Hz), 10.31 (1H, s)

HPLC : 5.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 15:85, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=480 Example 17-23)

N-[(2R,3R)-3-Cyclopropanecarbonylaminomethyl-4-hyoroxy-amino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

= -37.9° (c 0.29, 1N-HClaq.)

mp : 236-241°C (dec.)

NMR (DMSO-d₆, δ) : 0.52-0.66 (4H, m), 0.70 (3H, d,

J=7Hz), 0.75 (3H, d, J=7Hz), 0.85 (1H, m), 1.20 (1H, m), 1.38 (1H, m), 1.48 (1H, m), 2.20 (1H, ddd, J=11, 7, 7Hz), 2.39 (1H, ddd, J=11, 9, 3Hz), 2.54 (3H, d, J=4.5Hz), 2.70-2.82 (2H, m), 2.84 (1H, dd, J=14, 11Hz), 2.95 (1H, dd, J=14, 5Hz), 4.54 (1H, ddd, J=11, 8, 5Hz), 7.22 (2H, br), 7.65 (1H, dd, J=5.5, 5.5Hz), 7.84 (1H, q, J=4.5Hz), 8.28 (1H, d, J=8Hz), 8.37 (2H, br), 8.76 (1H, s), 10.36 (1H, s) HPLC : 4.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=448 Example 17-24)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(lsopropoxy-carbonylaminomethyl)succinyl]-L-4-pyridylalanine methylamide

= -27.1° (c 0.32, 1N-HClaq.)

mp : 230-236°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.86 (1H, m), 1.14 (2x3H, d, J=7Hz), 1.25 (1H, m) , 1.37 (1H, m) , 2.17 (1H, ddd, J=9, 9, 4Hz) , 2.42 (1H, m), 2.44-2.59 (1H, m) , 2.56 (3H, d,

J=4.5Hz) , 2.75 (1H, m), 2.81 (1H, dd, J=14, 10Hz) , 2.93 (1H, dd, J=14, 5Hz) , 4.54 (1H, ddd, J=10, 8, 5Hz) , 4.69 (1H, qq, J=7, 7Hz) , 6.37 (1H, dd, J=5, 5Hz) , 7.25 (2x1H, d, J=6Hz) , 7.84 (1H, q, J=4.5Hz) , 8.32 (1H, d, J=8Hz) , 8.40 (2x1H, br d, J=6Hz) , 8.75 (1H, s) , 10.29 (1H, s)

HPLC : 7.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05. TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=466 Example 17-25)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(2-pyrrolyl-carbonylaminomethyl)succinyl]-L-4-pyridylalamne methylamide

= -23.0° (c 0.21, 1N-HClaq.)

mp : 220-224°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.88 (1H, m), 1.25 (1H, m), 1.40 (1H, m), 2.33 (1H, ddd, J=10, 9, 4Hz), 2.38-2.50 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.77 (1H, m), 2.85 (1H, dd, J=14, 11Hz), 2.95 (1H, dd, J=14, 4Hz), 3.08 (1H, m), 4.55 (1H, m), 6.03 (1H, dd, J=3, 3Hz), 6.67 (1H, br), 6.81 (1H, br), 7.24 (2x1H, d, J=6Hz), 7.44 (1H, dd, J=5.5, 5.5Hz), 7.87 (1H, q, J=4.5Hz), 8.30-8.43 (3H, m), 8.73 (1H, s), 10.32 (1H, s), 11.32 (1H, br)

HPLC : 8.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=473 Example 17-26)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(pyrazin-2-yl- carbonylaminomethyl)succinyl]-L-4-pyridylalanine methylamide = -22.8° (c 0.25, 1N-HClaq.)

mp : 234-238°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, ddd, J=13, 10, 3Hz), 1.29 (1H, m), 1.42 (1H, m), 2.39 (1H, ddd, J=10, 9, 4Hz), 2.48-2.62 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.76-2.91 (2H, m), 2.96 (1H, dd, J=14, 5Hz), 3.26 (1H, m), 4.57 (1H, m), 7.26 (2x1H, d, J=7Hz), 7.87 (1H, q, J=4.5Hz), 8.25 (1H, dd, J=5.5, 5.5Hz), 8.37 (2x1H, d, J=7Hz), 8.44 (1H, d, J=8Hz), 8.73 (1H, br), 8.83 (1H, s), 8.88 (1H, d, J=2Hz), 9.17 (1H, s), 10.46 (1H, s)

HPLC : 6.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=486 Example 17-27)

N-[(2R,3R)-3-Ethanesulfonylaminomethyl-4-hydroxyamino-2-lsobutylsuccinyl]-L-4-pyridylaIanine methylamide

= -22.3° (c 0.24, 1N-HClaq.)

mp : 240-246°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.89 (1H, ddd, J=13, 10, 3Hz), 1.10 (3H, t, J=7.5Hz), 1.30 (1H, m), 1.40 (1H, m), 2.18 (1H, ddd, J=13, 10, 3Hz), 2.32-2.47 (2H, m), 2.57 (3H, d, J=4.5Hz), 2.70 (2H, q, J=7.5Hz), 2.79-2.98 (3H, m), 4.50 (1H, m), 6.73 (1H, dd, J=6, 5Hz), 7.27 (2x1H, d, J=6Hz), 7.88 (1H, q, J=4.5Hz), 8.31 (1H, d, J=8Hz), 8.45 (2x1H, br d, J=6Hz), 8.81 (1H, s), 10.44 (1H, s)

HPLC : 4.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.) MASS : M+H=472 Example 17-28)

N-[(2R,3R)-3-(3-Furoylaminomethyl)-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

= -25.0° (c 0.28, 1N-HClaq.)

mp : 225-228°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.89 (1H, ddd, J=13, 11, 2.5Hz), 1.27 (1H, m), 1.41 (1H, ddd, J=13, 11, 2.5Hz), 2.34 (1H, ddd, J=10, 10, 4Hz), 2.45 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.73 (1H, ddd, J=13, 5.5, 4Hz), 2.86 (1H, dd, J=14, 10Hz), 2.92-3.08 (1H, m), 2.98 (1H, dd, J=14, 4Hz), 4.57 (1H, m), 6.80 (1H, s), 7.28 (2x1H, d, J=6Hz), 7.69 (1H, s), 7.75 (1H, dd, J=5.5,

5.5Hz), 7.87 (1H, q, J=4.5Hz), 8.11 (1H, s), 8.30- 8.47 (3H, m), 8.72 (1H, s), 10.34 (1H, s) HPLC : 6.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=474 Example 17-29)

N-[(2R,3R)-3-(2-Furoylaminomethyl)-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

= -22.8° (c 0.23, 1N-HClaq.)

mp : 231-235°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.89 (1H, m), 1.27 (1H, m), 1.41 (1H, m), 2.35 (1H, ddd, J=10, 9, 4Hz), 2.43-2.55 (1H, m), 2.57 (3H, d, J=4.5Hz), 2.70 (1H, ddd, J=12, 5.5, 4Hz), 2.84 (1H, dd, J=13, 11Hz), 2.95 (1H, dd, J=13, 5Hz), 3.08 (1H, m), 4.56 (1H, ddd, J=11, 8, 5Hz), 6.60 (1H, dd, J=3, 2Hz), 7.05 (1H, d, J=3Hz) , 7.25 (2x1H, d, J=6Hz), 7.73 (1H, dd, J=5.5, 5.5Hz) , 7.80 (1H, d, J=2Hz), 7.87 (1H, q, J=4.5Hz), 8.36 (2x1H, d, J=6Hz), 8.40 (1H, d, J=8Hz), 8.77 (1H, s), 10.37 (1H, s)

HPLC : 7.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10.90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=474 Example 17-30)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(trifluoro-acetamidomethyl)succinyl]-L-4-pyridylalanine methylamide

= -24.9° (c 0.24, 1N-HClaq.)

mp : 223-227°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.84 (1H, m), 1.28 (1H, m), 1.39 (1H, m), 2.24 (1H, ddd, J=9, 9, 3Hz), 2.30-2.52 (2H, m), 2.57 (3H, d, J=4.5Hz), 2.81 (1H, dd, J=14, 11Hz), 2.89 (1H, m), 2.96 (1H, dd, J=14, 4Hz), 4.60 (1H, m), 7.29 (2x1H, d, J=6Hz), 7.88 (1H, q, J=4.5Hz), 8.29-8.45 (3H, m), 8.78 (1H, s), 9.02 (1H, dd, J=5, 5Hz), 10.41 (1H, s)

HPLC : 5.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=476 Example 17-31)

N-((2R,3R)-4-Hydroxyamino-2-isobutyl-3-[(S)-2-pyrrolidon-5-ylcarbonylaminomethyl]succinyl}-L-4-pyridylalanine methylamide

= -36.5° (c 0.22, 1N-HClaq.)

mp : 248-254°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.87 (1H, m), 1.26 (1H, m), 1.40 (1H, m), 1.83-2.30 (5H, m), 2.40 (1H, m), 2.55-2.65 (1H, m), 2.58 (3H, d, J=4.5Hz), 2.72 (1H, m), 2.87 (1H, dd, J=14, 11Hz), 3.00 (1H, dd, J=14, 5Hz), 3.91 (1H, m), 4.59 (1H, ddd, J=11, 8, 5Hz), 7.36 (2x1H, d, J=6Hz), 7.61 (1H, dd, J=6, 6Hz), 7.68 (1H, s), 7.90 (lh, q, J=4.5Hz), 8.35 (1H, d, J=8Hz), 8.44 (2x1H, d, J=6Hz), 8.74 (1H, s), 10.38 (1H, s)

HPLC : 4.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H=491 Example 17-32)

N-[ (2R,3R)-4-Hydroxyamino-3-(ιmιdazol-4-ylacetylamino-methyl)-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

= -28.1° (c 0.23, 1N-HClaq. )

mp : 234-242°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.76 (3H, d, J=7Hz) , 0.86 (1H, m) , 1.23 (1H, m) , 1.38 (1H, m), 2.21 (1H, ddd, J=9, 9, 4Hz) , 2.45 (1H, m), 2.55 (3H, d, J=4.5Hz) , 2.67-2.90 (3H, m), 2.95 (1H, dd, J=14, 6Hz), 3.30 (2H, s), 4.53 (1H, m), 6.90 (1H, s), 7.23 (2x1H, d, J=6Hz), 7.52 (2H, dd, J=6, 6Hz), 7.63 (1H, s), 7.85 (1H, q, J=4.5Hz), 8.31-8.43 (3H, m), 10.46 (1H, s)

HPLC : 3.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-H=488 Example 17-33)

N-[(2R,3R)-3-(3-Carboxypropionylaminomethyl)-4-hydroxy-amino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

_

= -32.4° (c 0.26, 1N-HClaq.)

mp : 215-221°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) , 0.77 (3H, d, J=7Hz) , 0.86 (1H, m ) , 1.22 (1H, m ) , 1.38 (1H, m) , 2.13-2.47 (6H, m), 2.57 (3H, d, J=4.5Hz) , 2.68-2.78 (2H, m), 2.83 (1H, dd, J=14, 11Hz) , 2.96 (1H, dd, J=14, 6Hz) , 4.57 (1H, ddd, J=11, 8, 6Hz) , 7.23 (2x1H, d, J=6Hz) , 7.47 (1H, dd, J=5.5, 5.5Hz) , 7.86 (1H, q, J=4.5Hz), 8.30 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.74 (1H, br), 10.31 (1H, s)

HPLC : 3.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=480 Example 17-34)

N-[(2R,3R)-3-(N-Acetylglycyl)aminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

= -18.7° (c 0.37, 1N-HClaq.)

mp : 225-233°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.86 (1H, m), 1.24 (1H, m), 1.39 (1H, m), 1.87 (3H, s), 2.20 (1H, m), 2.45 (1H, m), 2.54 (3H, d, J=4.5Hz), 2.73 (1H, m), 2.83-2.96 (2H, m), 2.85 (1H, dd, J=14, 10Hz), 2.96 (1H, dd, J=14, 7Hz), 3.60 (2H, d, J=6Hz), 4.53 (1H, ddd, J=10, 8, 7Hz), 7.23 (2x1H, d, J=6Hz), 7.44 (1H, dd, J=5.5, 5.5Hz), 7.84 (1H, q, J=4.5Hz), 8.09 (1H, t, J=6Hz), 8.26 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.79 (1H, s), 10.39 (1H, s)

HPLC : 4.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=479 Example 17-35)

N-((2R,3R)-3-[(2R)-Glyeeroylaminomethyl]-4-hydroxyamino-2-isobutylsuccinyl}-L-4-pyridylalanine methylamide = -7.6° (c 0.41, 1N-HClaq.)

mp : 214-220°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7riz), 0.78 (3H, d, J=7Hz), 0.87 (1H, m), 1.25 (1H, m), 1.38 (1H, m), 2.23 (1H, ddd, J=9, 9, 4Hz), 2.47 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.61 (1H, ddd, J=13, 5, 4Hz), 2.83 (1H, dd, J=13, 11Hz), 2.91-3.06 (1H, m), 2.95 (1H, dd, J=13, 6Hz), 3.45 (1H, m), 3.58 (1H, m), 3.83 (1H, m), 4.54 (1H, ddd, J=11, 8, 6Hz), 4.73 (1H, dd, J=6, 6Hz), 5.50 (1H, d, J=5Hz), 7.15 (1H, dd, J=5.5, 5.5Hz), 7.24 (2x1H, d, J=6Hz), 7.84 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.84 (1H, s), 10.43 (1H, s)

HPLC : 4.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05. TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=468 Example 17-36)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-[(3-methoxy-carbonylmethyl)ureidomethyl]succinyl]-L-4-pyridylalamnemethylamide

= -27.4° (c 0.31, 1N-HClaq.)

mp : 210-214°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.74 (3H, d, J=7Hz), 0.87 (1H, m), 1.20 (1H, m), 1.39 (1H, m), 2.21 (1H, ddd, J=10, 9, 4Hz), 2.38 (1H, ddd, J=11, 10, 2Hz), 2.54 (3H, d, J=4.5Hz), 2.71-2.92 (3H, m), 2.97 (1H, dd, J=14, 5Hz), 3.61 (3H, s), 3.75 (2H, d, J=6Hz), 4.53 (1H, m), 5.97 (1H, dd, J=6, 6Hz), 6.26 (1H, t, J=6Hz), 7.22 (2x1H, d, J=7Hz), 7.83 (1H, q, J=4.5Hz), 8.24 (1H, d, J=8Hz), 8.40 (2x1H, d, J=7Hz), 8.81 (1H, s), 10.45 (1H, s)

HPLC : 5.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=495 Example 17-37)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(3-methylureιdo-methyl)succinyl]-L-4-pyridylalanine methylamide

= -22.1° (c 0.36, 1N-HClaq.)

mp : 223-226°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.74 (3H, d, J=7Hz), 0.87 (1H, m), 1.20 (1H, m), 1.38 (1H, m), 2.20 (1H, m), 2.38 (1H, ddd, J=10, 10, 3Hz), 2.51 (3H, d, J=4.5Hz), 2.56 (3H, d, J=4.5Hz), 2.80 (2H, t, J=6Hz), 2.86 (1H, dd, J=14, 10Hz), 2.97 (1H, dd, J=14, 6Hz), 4.53 (1H, ddd, J=10, 8, 6Hz), 5.49 (1H, t, J=6Hz), 5.71 (1H, q, J=4.5Hz), 7.23 (2x1H, d, J=6Hz), 7.85 (1H, q, J=4.5Hz), 8.28 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.78 (1H, s), 10.43 (1H, s) HPLC : 4.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=437 Example 17-38

N-{(2R,3R)-4-Hydroxyamino-2-isobutyl-3-[3-(methyl-earbamoylmethyl)ureidomethyl]succinyl}-L-4-pyridylalaninemethylamide

= -26.2° (c 0.28, 1N-HClaq.)

mp : 233-237°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.75 (3H, d, J=7Hz), 0.87 (1H, m), 1.21 (1H, m), 1.38 (1H, m), 2.17 (1H, ddd, J=10, 9, 4Hz), 2.38 (1H, ddd, J=10, 10, 3Hz), 2.53-2.69 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.60 (3H, d, J=4.5Hz), 2.70-2.86 (1H, m), 2.84 (1H, dd, J=14, 10Hz), 2.99 (1H, dd, J=14, 5Hz), 3.53 (1H, dd, J=17, 6Hz), 3.58 (1H, dd, J=17, 6Hz), 4.54 (1H, ddd, J=10, 8, 5Hz), 5.80 (1H, dd, J=6, 6Hz), 6.17 (1H, dd, J=6, 6Hz), 7.25 (2x1H, d, J=6Hz), 7.74 (1H, q, J=4.5Hz), 7.85 (1H, q, J=4.5Hz), 8.25 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.80 (1H, s), 10.43 (1H, s)

HPLC : 4.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=494 Example 17-39)

N-{(2R,3R)-3-[(2S)-Glyeeroylaminomethyl]-4-hydroxyamino-2-isobutylsuccinyl}-L-4-pyridylalanine methylamide

= -33.2° (c 0.36, IN-HClaq.)

mp : 211-220°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=6.3Hz), 0.76 (3H, d, J=6.3Hz), 0.86 (1H, m), 1.24 (1H, m), 1.40 (1H, m), 2.23 (1H, m), 2.40-2.62 (1H, m), 2.54 (3H, d, J=4.5Hz), 2.70 (1H, m), 2.78-3.10 (3H, m), 3.46- 3.66 (2H, m), 3.85 (1H, m), 4.52 (1H, m), 5.00 (1H, br), 5.48 (1H, d, J=6.2Hz), 7.23 (2x1H, d, J=5.5Hz), 7.29 (1H, m), 7.81 (1H, q, J=4.5Hz), 8.28 (1H, d, J=8.1Hz), 8.39 (2x1H, d, J=5.5Hz), 8.85 (1H, s), 10.48 (1H, s)

HPLC : 4.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=468 Example 17-40)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(methanesulfonyl-acetylaminomethyl)succinyl]-L-4-pyridylalanine methylamide

= -26.0° (c 0.36, 1N-HClaq.)

mp : 247-252°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz) , 0.87 (1H, m) , 1.25 (1H, m) , 1.41 (1H, m), 2.20 (1H, m) , 2.41 (1H, m) , 2.56 (3H, d, J=4.5Hz) , 2 70-2.87 (2H, m) , 2.84 (1H, dd, J=14, 12Hz) , 2.96 (1H, dd, J=14, 5Hz) , 3.10 (3H, s) , 3.98 (2H, s) , 4.58 (1H, ddd, J=12, 8, 5Hz) , 7.24 (2x1H, d,

J=6Hz), 7.87 (1H, q, J=4.5Hz), 8.02 (1H, dd, J=6, 6Hz), 8.28 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.77 (1H, s), 10.40 (1H, s)

HPLC : 4.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=500 Example 17-41)

N-[(2R,3R)-3-(2-Acetoxyethoxy)carbonylaminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine

methylamide

= -19.8° (c 0.34, 1N-HClaq.)

mp : 223-228°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.86 (1H, m), 1.27 (1H, m), 1.38 (1H, m), 2.02 (3H, s), 2.17 (1H, m), 2.35-2.61 (2H, m), 2.56 (3H, d, J=4.5Hz), 2.76 (1H, m), 2.81 (1H, dd, J=14, 11Hz), 2.94 (1H, dd, J=14, 5Hz), 4.03-4.20 (4H, m), 4.56 (1H, ddd, J=11, 8, 5Hz), 6.70 (1H, dd, J=5, 5Hz), 7.24 (2H, d, J=6Hz), 7.85 (1H, q, J=4.5Hz), 8.32 (1H, d, J=8Hz), 8.38 (2H, d, J=6Hz), 8.75 (1H, s), 10.30 (1H, s)

HPLC : 8.2 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=510 Example 17-42)

N-[(2R,3R)-4-Hydroxyamino-3-(2-hydroxyethoxy)carbonyl- aminomethyl-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide

3 = -22.4° (c 0.32, 1N-HClaq.)

mp : 215-219°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.87 (1H, m), 1.27 (1H, m), 1.38 (1H, m), 2.17 (1H, ddd, J=9, 9, 4Hz), 2.43 (1H, m), 2.45- 2.60 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.70-2.84 (1H, m), 2.82 (1H, dd, J=14, 11Hz), 2.94 (1H, dd, J=14, 5Hz), 3.53 (2H, t, J=4Hz), 3.90 (2H, t, J=4Hz), 4.56 (1H, ddd, J=11, 8, 5Hz), 4.75 (1H, br), 6.52 (1H, dd, J=5, 5Hz), 7.25 (2x1H, d, J=6Hz), 7.86 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 8.77 (1H, s), 10.31 (1H, s)

HPLC : 4.4 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=468 Example 17-43)

N-{(2R,3R)-3-[(2S)-2-tert-Butoxycarbonylamino-3-hydroxy-propionyl]aminomethyl]-4-hydroxyamino-2-isobutylsuccinyl}-L-4-pyridylalanine methylamide

= -38.1° (c 0.38, 1N-HClaq.)

mp : 214-217°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.85 (1H, m), 1.23 (1H, m), 1.31-1.47 (1H, m), 1.39 (9H, s), 2.15 (1H, m), 2.41-2.70 (2H, m), 2.56 (3H, d, J=4.5Hz), 2.70-2.84 (1H, m), 2.81 (1H, dd, J=13, 10Hz), 2.97 (1H, dd, J=13, 5Hz), 3.53 (2H, br d, J=5Hz), 3.95 (1H, dt, J=8, 5Hz), 4.60 (1H, ddd, J=10, 8, 5Hz), 6.50 (1H, d, J=8Hz), 7.26 (2x1H, d, J=6Hz), 7.52 (1H, dd, J=5, 5Hz), 7.90 (1H, q, J=4.5Hz), 8.33 (1H, d, J=8Hz), 8.39 (2x1H, d, J=6Hz), 8.79 (1H, s), 10.36 (1H, s) HPLC : 5.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05. TFAaq. = 15:85, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=567 Example 17-44)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(methanesulfonyl-aminomethyl)succinyl]-L-3-pyridylalanine methylamide

= -19.4° (c 0.31, 1N-HClaq.)

mp : 230-233°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, m), 1.22-1.48 (2H, m), 2.17 (1H, m), 2.30-2.46 (2H, m), 2.55 (3H, d, J=5Hz), 2.70 (3H, s), 2.77-3.00 (3H, m), 4.47 (1H, m), 6.70 (1H, dd, J=5, 5Hz), 7.03 (1H, dd, J=7.5, 5Hz), 7.68 (1H, br d, J=7.5Hz), 7.85 (1H, q, J=5Hz), 8.30 (1H, d, J=8Hz), 8.39 (1H, br), 8.47 (1H, s), 8.82 (1H, s), 10.43 (1H, s)

HPLC : 4.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=458 Example 17-45)

N-[ (2R,3R)-3-Acetoxyacetylaminomethyl-4-hydroxyamino-2-lsobutylsuccinyl]-L-3-pyridylalanine methylamide

= -26.9° (c 0.25,

1N-HClaq.)

mp : 206-208°C (dec. )

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) , 0.79 (3H, d, J=7Hz) , 0.86 (1H, m), 1.25 (1H, m) , 1.38 (1H, m), 2.08 (3H, s) , 2.20 (1H, ddd, J=9, 9, 4Hz) , 2.42 (1H, ddd, J=10, 9, 2Hz), 2.47-2.60 (1H, m), 2.55 (3H, d, J=4.5Hz) , 2.75-2.90 (2H, m), 2.95 (1H, dd, J=14, 6Hz) , 4.34 (1H, d, J=15Hz) , 4.38 (1H, d, J=15Hz) , 4.51 (1H, m), 7.20 (1H, dd, J=7.5, 5Hz) , 7.56 (1H, dd, J=6, 6Hz), 7.63 (1H, br d, J=7.5Hz), 7.84 (1H, q, J=4.5Hz), 8.29 (1H, d, J=8Hz), 8.33 (1H, d, J=5Hz), 8.43 (1H, s), 8.78 (1H, s), 10.37 (1H, s)

HPLC : 5.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M-rh=480 Example 17-46)

N-{(2R,3R)-4-Hydroxyamino-2-isobutyl-3-[(2R)-5-oxo-tetranydrofuran-2-ylcarbonylaminomethyl]succinyl}-L-4-pyridylalanine methylamide methanesulfonate

= -13.4° (c 0.35, 1N-HClaq.)

mp : 197-204°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.88 (1H, m), 1.27 (1H, m), 1.38 (1H, m), 2.09 (1H, m), 2.15 (1H, ddd, J=9, 9, 3Hz), 2.28- 2.53 (5H, m), 2.30 (3H, s), 2.60 (3H, d, J=5Hz), 2.78 (1H, m), 3.07 (1H, dd, J=13, 11Hz), 3.22 (1H, dd, J=13, 5Hz), 4.60 (1H, m), 4.70 (1H, ddd, J=11, 8, 5Hz), 4.78 (1H, dd, J=8, 6Hz), 7.73 (1H, dd, J=6, 5Hz), 7.85-7.98 (1H, m), 7.91 (2x1H, d,

J=6Hz), 8.42 (1H, d, J=8Hz), 8.75 (2x1H, d, J=6Hz), 10.46 (1H, s)

HPLC : 4.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=492 Example 17-47)

N-[(2R,3R)-3-Hydroxyacetylaminomethyl-4-hydroxyamino-2-lsobutylsuccinyl]-L-3-pyridylalanine methylamide

methanesulfonate

= -17 -5° (c 0.30, 1N-HClaq.)

mp : 169-171°C (dec.)

NMR (DMSO-d₆, δ) : 0.75 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.89 (1H, m), 1.28 (1H, m), 1.38 (1H, m), 2.16 (1H, ddd, J=10, 9, 4Hz), 2.32 (3H, s), 2.35- 2.53 (2H, m), 2.60 (3H, d, J=5Hz), 2.85 (1H, m), 3.00 (1H, dd, J=14, 11Hz), 3.15 (1H, dd, J=14, 4Hz), 3.72 (1H, d, J=16Hz), 3.76 (1H, d, J=16Hz), 4.60 (1H, m), 7.05 (1H, dd, J=5, 5Hz), 7.85-7.96 (2H, m), 8.32-8.45 (2H, m), 8.70 (1H, d, J=5Hz), 8.78 (1H, s), 10.52 (1H, s)

HPLC : 4.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=438 Example 17-48 )

N-{(2R,3R)-4-Hydroxyamino-2-isobutyl-3-[(2S)-5-oxotetrahydrofuran-2-ylcarbonylaminomethyl]succinyl}-L-4-pyridylalanine methylamide methanesulfonate

⁼ -27.1° (c 0.27, 1N-HClaq.)

mp : 210-214°C (dec.)

NMR (DMSO-d₆, δ) : 0.77 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.87 (1H, m), 1.27 (1H, m), 1.38 (1H, m), 2.05 (1H, m), 2.19 (1H, ddd, J=9, 9, 3Hz), 2.30- 2.53 (5H, m), 2.32 (3H, s), 2.60 (3H, d, J=4.5Hz), 2.67 (1H, m), 3.07 (1H, dd, J=14, 12Hz), 3.23 (1H, dd, J=14, 5Hz), 4.71 (1H, ddd, J=12, 8, 5Hz), 4.80 (1H, dd, J=8, 6Hz), 7.82 (1H, dd, J=6, 6Hz), 7.88- 7.98 (3H, m), 8.43 (1H, d, J=8Hz), 8.75 (2x1H, d, J=6Hz), 10.43 (1H, s)

HPLC : 4.7 min. (Nucleosil 5C18, 4 mm Φ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=492 Example 17-49)

N-[ (2R,3R)-3-Ethoxycarbonylaminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-3-pyridylalanine methylamide

methanesulfonate

= -23.2° (c 0.31, 1N-HClaq. )

mp : 189-191°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz) , 0.78 (3H, d, J=7Hz) , 0.87 (1H, m) , 1.14 (3H, t, J=7Hz) , 1.25 (1H, m), 1.37 (1H, m), 2.10 (1H, ddd, J=9, 9, 3Hz), 2.22 (1H, ddd, J=12, 5, 4Hz) , 2.32 (3H, s), 2.38 (1H, m), 2.59 (3H, d, J=5Hz), 2.69 (1H, m), 3.00 (1H, dd, J=14, 12Hz), 3.15 (1H, dd, J=14, 5Hz), 3.93 (2H, q, J=7Hz), 4.61 (1H, m), 6.50 (1H, dd, J=5, 5Hz), 7.81-7.92 (2H, m), 8.29-8.43 (2H, m), 8.70 (1H, d, J=5Hz), 8.78 (1H, s), 10.35 (1H, s) HPLC : 6.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=452 Example 17-50)

N-[(2R,3R)-3-(N-tert-Butoxycarbonylglycyl)aminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine

methylamide

= -22.2° (c 0.20, 1N-HClaq.)

mp : 217-219°C (dec.)

NMR (DMSO-d₆, δ) : 0.72 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.87 (1H, m), 1.13-1.48 (2H, m), 1.38

(3x3H, s), 2.20 (1H, m), 2.45 (1H, m), 2.55 (3H, d, J=4.5Hz), 2.74-2.91 (3H, m), 2.96 (1H, dd, J=14, 6Hz), 3.45 (1H, dd, J=16, 5Hz), 3.50 (1H, dd, J=16, 7Hz), 4.56 (1H, m), 6.82 (1H, dd, J=5, 5Hz), 7.24 (2x1H, d, J=6Hz), 7.87 (1H, q, J=4.5Hz), 8.28 (1H, d, J=8Hz), 8.41 (2x1H, d, J=6Hz), 8.78 (1H, s), 10.35 (1H, s) HPLC : 8.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 15:85, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=537 Example 17-51)

N-[(2R,3R)-4-Hydroxyamino-2-isobutyl-3-(oxamoylamino-methyl)succinyl]-L-4-pyridylalanine methylamide

= -14.8° (c 0.38, 1N-HClaq.)

mp : 221-224°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.89 (1H, m), 1.28 (1H, m), 1.38 (1H, m), 2.22 (1H, ddd, J=10, 9, 4Hz), 2.32-2.52 (2H, m), 2.60 (3H, d, J=4Hz), 2.97 (1H, m), 3.05 (1H, dd, J=14, 12Hz), 3.19 (1H, dd, J=14, 5Hz), 4.67 (1H, ddd, J=12, 8, 5Hz), 7.79-8.00 (6H, m), 8.48 (1H, d, J=8Hz), 8.71 (2x1H, br d, J=6Hz), 10.46 (1H, s) HPLC : 4.5 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=451 Example 17-52)

N-[(2R,3R)-3-D-Gluconylaminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

methanesulfonate

= -3.9° (c 0.21, 1N-HClaq.)

mp : 180-185°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.88 (1H, m), 1.29 (1H, m), 1.37 (1H, m), 2.14 (1H, ddd, J=9, 9, 3Hz), 2.29-2.54 (2H, m), 2.32 (3H, s), 2.60 (3H, d, J=4.5Hz), 2.88 (1H, m) 3.07 (1H, dd, J=14, 12Hz), 3.22 (1H, dd, J=14, 4Hz), 3.41-3.64 (4H, m), 3.88-3.99 (2H, m), 4.70 (1H, ddd, J=12, 8, 4Hz), 7.12 (1H, dd, J=5, 5Hz), 7.90 (2x1H, d, J=6Hz), 7.93 (1H, q, J=4.5Hz), 8.42 (1H, d, J=8Hz), 8.75 (2x1H, or d, J=6Hz), 10.46 (1H, s)

HPLC : 3.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 10:90:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=558 Example 18

To a stirred suspension of N-[(2R,3R)-4-benzyloxyamino-3-ethoxyearbonylacetylaminomethy1-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide (243 mg) in methanol (5 ml) wasadded 1N aqueous sodium hydroxide solution (1.2 ml) atambient temperature. The mixture was stirred at the sametemperature for 4 hours. The solution was neutralized bydropwise addition of 1N-hydrochloric acid (1.2 ml). Theprecipitate was collected and washed with water to give

N-[(2R,3R)-4-benzyloxyamino-3-carboxyacetylaminomethyl-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide (216 mg).

= -38.3° (c 0.21, 1N-HClaq.)

mp : 246-250°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.77 (3H, d, J=7Hz), 0.80 (1H, m), 1.23 (1H, m), 1.37 (1H, m), 2.20 (1H, ddd, J=11, 9, 3Hz), 2.44 (1H, m), 2.55 (3H, d, J=5Hz), 2.62-2.91 (3H, m), 2.95 (1H, dd, J=14, 5Hz), 3.03 (1H, d, J=15Hz), 3.10 (1H, d, J=15Hz), 4.57 (1H, ddd, J=10, 8, 5Hz), 4.72 (1H, d, J=11Hz), 4.80 (1H, d, J=11Hz), 7.24 (2x1H, d, J=7Hz), 7.29-7.42 (5H, m), 7.77-7.93 (2H, m), 8.33 (1H, d, J=8Hz), 8.40 (2x1H, d, J=7Hz), 11.05 (1H, s)

HPLC : 5.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=556 Example 19-1

N-[(2R,3R)-3-(N-tert-Butoxycarbonylglycyl)aminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalamne

methylamide (130 mg) was dissolved in 10. hydrogen chloridem methanol (5 ml). After tne solution was stirred atambient temperature for 40 minutes, the solvent was

evaporated m vacuc. The obtained solid was triturated withethyl acetate, collected and washed with ethyl acetate togive N-[(2R,3R)-3-glycylaminomethyl-4-hydroxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide

dihydrochloride (86 mg) as a powder.

= -23.5° (c 0.28, 1N-HClaq.)

mp : 250-255°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.85 (1H, m), 1.26 (1H, m), 1.38 (1H, m), 1.95-2.15 (2H, m), 2.33 (1H, m), 2.62 (3H, d,

J=5Hz), 2.68 (1H, m), 3.06 (1H, dd, J=13, 12Hz), 3.28 (1H, dd, J=13, 4Hz), 3.35-3.60 (2H, m), 4.77 (1H, ddd, J=12, 8, 4Hz), 7.98 (2x1H, d, J=7Hz), 8.02-8.20 (4H, m), 8.49 (1H, d, J=8Hz), 8.75 (2x1H, d, J=7Hz), 10.45 (1H, s)

HPLC : 3.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 10:90:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=437 Example 19-2)

N-{(2R,3R)-3-[(2S)-2-Amino-3-hydroxypropιonyl]amino-methyl-4-hydroxyamino-2-isobutylsuccinyl}-L-4-pyridylalaninemethylamide dihydrochloride was obtained in substantially thesame manner as that of Example 19-1).

= -17.8° (c 0.28, 1N-HClaq.)

mp : 236-243°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz) , 0.84 (1H, m) , 1.27 (1H, m) , 1.36 (1H, m) , 2.01 (1H, m), 2.20-2.48 (2H, m), 2.63 (3H, d, J=4.5Hz) , 3.06 (1H, dd, J=13, 12Hz) , 3.28 (1H, dd, J=13, 4Hz) , 3.60 (1H, dd, J=11, 7Hz) , 3.67 (1H, dd, J=11, 3Hz), 3.77 (1H, m) , 4.79 (1H, ddd, J=12, 8, 4Hz), 7.97 (2x1H, d, J=6Hz), 8.07 (1H, q, J=4.5Hz), 8.15-8.28 (3H, m), 8.50 (1H, d, J=8Hz), 8.73 (2x1H, d, J=6Hz), 10.45 (1H, s)

HPLC : 3.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 10:90:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=467 Example 20-1)

N-[(2R,3R)-4-Benzyloxyamino-3-(2-hydroxyethoxy)carbonyl¬aminomethyl-2-isobutylsuccinyl]-L-4-pyridylalanine

methylamide was obtained from N-[(2R,3R)-3-(2-acetoxyethoxy)-carbonylaminomethyl-4-benzyloxyamino-2-isobutylsuccinyl]-L-4-pyridylalanine methylamide in substantially the same manneras that of Example 18.

= -16.2° (c 0.21, 1N-HClaq.)

mp : 237-240°C (dec.)

NMR (DMSO-d₆, δ) : 0.65-0.88 (1H, m), 0.70 (3H, d,

J=7Hz), 0.78 (3H, d, J=7Hz), 1.17-1.40 (2H, m), 2.14 (1H, m), 2.31-2.61 (2H, m), 2.55 (3H, d,

J=4.5Hz), 2.70 (1H, m), 2.81 (1H, dd, J=14, 12Hz), 2.95 (1H, dd, J=14, 5Hz), 3.45-3.58 (2H, m), 3.81- 3.98 (2H, m), 4.56 (1H, ddd, J=12, 8, 5Hz), 4.70 (1H, d, J=11Hz), 4.76 (1H, d, J=11Hz), 6.71 (1H, dd, J=6, 6Hz), 7.25 (2x1H, d, J=6Hz), 7.28-7.42 (5H, m), 7.86 (1H, q, J=4.5Hz), 8.36 (1H, d,

J=8H∑), 8.39 (2x1H, d, J=6Hz), 10.95 (1H, s)

HPLC : 4.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.) MASS : M-H=558 The following compounds were obtained in substantiallythe same manner as that of Example 20-1). Example 20-2

N-[ (2R,3R)-4-Benzyloxyamino-3-hydroxyacetylaminomethyl-2-isobutylsuccinyl]-L-4-pyridylalamne methylamide

= -33.8° (c 0.22, 1N-HClaq.)

mp : 239-244°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz) , 0.78 (3H, d, J=7Hz) , 0.82 (1H, m) , 1.26 (1H, m), 1.34 (1H, m), 2.23 (1H, ddd, J=9, 9, 4Hz) , 2.41-2.53 (1H, m) , 2.56 (3H, d, J=4.5Hz), 2.73 (1H, m) , 2.38 (1H, dd, J=14, 11Hz) , 2.90-3.03 (2H, m) , 3.75 (2H, d,

J=6Hz) , 4.54 (1H, m), 4.71 (1H, d, J=11Hz), 4.78 (1H, d, J=11Hz), 5.45 (1H, t, J=6Hz) , 7.21 (1H, m), 7.24 (2x1H, d, J=6Hz), 7.85 (1H, q, J=4.5Hz), 8.35- 8.44 (3H, m) , 11.09 (1H, s)

HPLC : 4.8 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=528 Example 20-3)

N-[(2R,3R)-4-Benzyloxyamino-3-hydroxyacetamidomethyl-2-isobutylsuccinyl]-L-3-pyridylalanine methylamide

= -38.8° (c 0.24, 1N-HClaq.)

mp : 253-256°C (dec.)

NMR (DMSO-d₆, δ) : 0.71 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.82 (1H, m), 1.25 (1H, m), 1.33 (1H, m), 2.22 (1H, ddd, J=9, 9, 4Hz), 2.47 (1H, m), 2.54 (3H, d, J=4.5Hz), 2.65 (1H, ddd, J=13, 5, 4Hz), 2.82 (1H, dd, J=14, 11Hz), 2.94 (1H, dd, J=14, 6Hz), 3.75 (2H, d, J=6Hz), 4.50 (1H, m), 4.71 (1H, d, J=11Hz), 4.77 (1H, d, J=11Hz), 5.43 (1H, t, J=6Hz) , 7.19 (1H, dd, J=5, 5Hz) , 7.23 (1H, dd, J=7.5, 5Hz) , 7.30-7.42 (5H, m) , 7.64 (1H, br d, J=7.5Hz) , 7.84 (1H, q, J=4.5Hz) , 8.30-8.40 (2H, m), 8.44 (1H, br s) , 11.09 (1H, s)

HPLC : 4.9 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O :TFA = 25:75:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=528 Example 21-1)

N-[(2R,3R)-4-Benzyloxyamino-2-isobutyl-3-(methyl-carbamoylacetylaminomethyl)succinyl]-L-4-pyridylalaninemethylamide was obtained in substantially the same manner asthat of Example 2-1).

= -46.2° (c 0.21, 1N-HClaq.)

mp : 257-260°C (dec.)

NMR (DMSO-d₆, δ) : 0.70 (3H, d, J=7Hz), 0.73-0.87 (1H, m), 0.77 (3H, d, J=7Hz), 1.23 (1H, m), 1.36 (1H, m), 2.18 (1H, ddd, J=10, 9, 4Hz), 2.44 (1H, m), 2.55 (3H, d, J=5Hz), 2.58 (3H, d, J=5Hz), 2.63-2.89 (2H, m), 2.83 (1H, dd, J=14, 10Hz), 2.90-3.03 (1H, m), 2.97 (2H, s), 4.58 (1H, m), 4.70 (1H, d,

J=11Hz), 4.80 (1H, d, J=11Hz), 7.25 (2x1H, d,

J=7Hz), 7.28-7.42 (5H, m), 7.77-7.93 (3H, m), 8.33 (1H, d, J=8Hz), 8.40 (2x1H, d, J=6Hz), 11.02 (1H, br)

HPLC : 5.0 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=569 Example 21-2)

N-( (2R,3R)-4-Benzyloxyamino-2-isobutyl-3-[ (3-methyl- earbamoylmethyl)ureidomethyl]sucemyl)-L-4-pyridylalanine methylamide was obtained in substantially the same manner asthat of Example 2-1).

= -28.2° (c 0.23, 1N-HClaq.)

mp : 244-249°C (dec.)

NMR (DMSO-d₆, δ) : 0.69 (3H, d, J=6.5Hz), 0.75 (3H, d, J=6.5Hz), 0.80 (1H, m), 1.20 (1H, m), 1.34 (1H, m), 2.19 (1H, m), 2.40 (1H, m), 2.56 (3H, d, J=4.5Hz), 2.60 (3H, d, J=4.5Hz), 2.71 (2H, dd, J=6, 6Hz), 2.84 (1H, dd, J=14, 11Hz), 3.00 (1H, dd, J=14, 5Hz), 3.53 (1H, dd, J=17, 6Hz), 3.63 (1H, do, J=17, 6Hz), 3.75 (2H, d, J=6Hz), 4.56 (1H, ddd, J=11, 8.5, 5Hz), 4.74 (1H, d, J=11Hz), 4.80 (1H, d,

J=11Hz), 5.90 (1H, t, J=6Hz), 6.14 (1H, dd, J=6, 6Hz), 7.24 (2x1H, d, J=6Hz), 7.31-7.44 (5H, m), 7.72 (1H, q, J=4.5Hz), 7.84 (1H, q, J=4.5Hz), 8.25 (1H, d, J=8.5Hz), 8.40 (2x1H, d, J=6Hz), 11.05 (1H, s)

HPLC : 4.6 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 25:75, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=584 The following compounds were obtained in substantiallythe same manner as those of Examples 12-1) and 19-1). Example 22-1

N-((2R,3R)-3-(2-Aminoethoxy)carbonylaminomethyl-4-hydroxyamino-2-isobutylsuccinyl}-L-4-pyridylalanine

methylamide from N-{(2R,3R)-4-benzyloxyamino-3-(2-benzyloxy-carbonylamino)ethoxycarbonylaminomethyl-2-isobutylsuccinyl}-L-4-pyridylalanine methylamide

= _19.5° (c 0.25, 1N-HClaq.)

mp : 201-206°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.79 (3H, d, J=7Hz), 0.86 (1H, m), 1.28 (1H, m), 1.38 (1H, m), 2.17 (1H, m), 2.43 (1H, m), 2.58 (3H, d, J=4.5Hz), 2.68-2.89 (3H, m), 2.95 (1H, dd, J=14, 4Hz), 3.20- 3.70 (2H, m), 3.88 (2H, t, J=6Hz), 4.57 (1H, m), 6.52 (1H, m), 7.26 (2x1H, d, J=6Hz), 7.87 (1H, q, J=4.5hz), 8.35 (1H, d, J=8Hz), 8.50 (2x1H, d, J=6Hz)

HPLC : 3.3 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=467 Example 22-2)

N-((2R,3R)-4-Hydroxyamino-3-[(4S)-2-oxoιmιdazolidm-4-yl)carbonylaminomethyl-2-isobutylsuccinyl}-L-4-pyridylalaninemethylamide methanesulfonate from N-((2R,3R)-4-benzyloxyamino-3-[(4S)-3-benzyloxycarbonyl-2-oxoimidazolidin-4-yl]carbonylaminomethyl-2-isobutylsuccinyl}-L-4-pyridylalanine methylamide

= -25.4° (c 0.33, 1N-HClaq.)

mp : 201-204°C (dec.)

NMR (DMSO-d₆, δ) : 0.73 (3H, d, J=7Hz), 0.78 (3H, d, J=7Hz), 0.85 (1H, m), 1.25 (1H, m), 1.37 (1H, m), 2.10 (1H, ddd, J=9, 9, 3Hz), 2.30 (3H, s), 2.32- 2.52 (2H, m), 2.55-2.70 (1H, m), 2.60 (3H, d, J=5Hz), 3.05 (1H, dd, J=14, 12Hz), 3.13-3.28 (2H, m), 3.46 (1H, dd, J=10, 9Hz), 4.00 (1H, m), 4.73 (1H, m), 6.28 (1H, br), 7.48 (1H, dd, J=6, 6Hz), 7.88 (2x1H, d, J=6Hz), 7.93 (1H, q, J=5Hz), 8.41 (1H, d, J=8Hz), 8.72 (2x1H, d, J=6Hz), 10.43 (1H, s)

HPLC : 3.7 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:H₂O:TFA = 10:90:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=492 Example 23

To a stirred suspension of N-[(2R,3R)-4-hydroxyamino-2-isobutyl-3-(methanesulfonylaminomethyl)sucemyl]-L-3-pyridylalanine methylamide (124 mg) in ethanol (1 ml) wasadded methanesulfonic acid (28 mg). The mixture was heateduntil a clear solution was obtained. The solution wasallowed to cool to ambient temperature and diluted with ethylacetate with stirring. The precipitate was collected andwashed with ethyl acetate to give N-[(2R,3R)-4-hydroxyamino-2-isobutyl-3-(methanesulfonylaminomethyl)sucemyl]-L-3-pyridylalanine methylamide methanesulfonate (142 mg) as apowder.

= -12.4° (c 0.32, 1N-HClaq.)

mp : 140-146°C (dec.)

NMR (DMSO-d₆, δ) : 0.74 (3H, d, J=7Hz), 0.80 (3H, d, J=7Hz), 0.90 (1H, m), 1.29 (1H, m), 1.39 (1H, m), 2.13 (1H, ddd, J=9, 9, 3Hz), 2.23 (1H, ddd, J=13, 5, 4Hz), 2.32 (3H, s), 2.37 (1H, m), 2.58 (3H, d, J=5Hz), 2.80 (1H, m), 3.01 (1H, dd, J=14, 11Hz), 3.13 (1H, dd, J=14, 5Hz), 4.56 (1H, ddd, J=11, 8, 5Hz), 6.72 (1H, dd, J=6, 5Hz), 7.85-7.97 (2H, m), 8.35 (1H, d, J=8Hz), 8.40 (1H, d, J=7.5Hz), 8.75 (1H, d, J=5Hz), 8.80 (1H, s), 10.49 (1H, s)

HPLC : 4.1 min. (Nucleosil 5C18, 4 mmΦ x 15 cm,

MeCN:0.05% TFAaq. = 10:90, 260 nm, flow rate 1.0 ml/min., at R.T.)

MASS : M+H=458

Claims

CLAIMS 1. A compound of the following formula :

R

in whicn R¹ is hydrogen or hydroxy-protective group,

R² is hydrogen or acyl,

R³ is hydrogen or lower alkyl, or

R⁴ is heterocyclic(lower)alkyl, and

R⁵ is lower alkoxy or lower alkylamino, or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1, wherein

R is hydrogen,

R² is hydrogen; oxamoyl; lower alkanoyl;

lower alkanesulfonyl; lower alkoxycarbonyl; (C₃-C₇)cycloalkanecarbonyl;

di(lower)alkylamino(lower)alkanoyl;

lower alkylcarbamoyl; di(lower)alkylcarbamoyl; N-[(lower)alkylcarbamoyl(lower)alkyl]carbamoyl; C₆-C₁₀ aroyl; C₆-C₁₀ arenesulfonyl;

C₆-C₁₀ arylcarbamoyl; heterocyclic-carbonyl optionally substituted by the group consisting ofacyl, lower alkyl, hydroxy and oxo;

heterocyclic-carbamoyl;

(C₆-C₁₀)aryloxy(lower)alκanoyl;

heterocyclic(lower)alkanoyl;

lower alkylcarbamoyl(lower)alkanoyl;

carboxy(lower)alkanoyl; protected

carboxy(lower)alkanoyl; hydroxy(lower)alkanoyl;protected hydroxy(lower)alkanoyl;

lower alkoxy(lower)alkanoyl;

lower alkoxy(lower)alkoxycarbonyl;

amino(lower)alkoxycarbonyl;

protected amino(lower)alkoxycarbonyl;

lower alkoxycarbonyl(lower)alkylcarbamoyl;

lower alkylsulfonyl(lower)alkanoyl;

hydroxy(lower)alkoxycarbonyl;

protected hydroxy(lower)alkoxycarbonyl;

lower alkanoyl substituted by the group consistingof amino and hydroxy; lower alkanoyl substituted bythe group consisting of protected amino andhydroxy; amino(lower)alkanoyl; or protectedamino(lower)alkanoyl;

said heterocyclic groups being

unsaturated 3- to 8-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s),

saturated 3- to 8-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s),

unsaturated 7- to 12-membered condensedheterocyclic group containing 1 to 4 nitrogenatom(s),

saturated 7- to 12-membered condensed

heterocyclic group containing 1 to 4 nitrogenatom(s),

unsaturated 3- to 8-membered heteromonocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),

saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 ritrogen atom(s),

unsaturated 7- to 12-membered condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),

unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),

saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),

unsaturated 7- to 12-membered condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),

unsaturated 3- to 8-membered heteromonocyclic group containing an oxygen atom,

unsaturated 3- to 8-membered heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s),

unsaturated 7- to 12-membered condensed neterocyclic group containing 1 to 2 sulfur

atom(s), or

unsaturated 7- to 12-membered condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), and

R⁴ is neterocyclic(lower)alkyl,

said heterocyclic groups being

unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s),

saturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s),

unsaturated 7- to 12-membered condensed heterocyclic group containing 1 to 4 nitrogen atom(s) ,

saturated 7- to 12-membered condensed

heterocyclic group containing 1 to 4 nitrogen atom(s),

unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),

saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),

unsaturated 3- to 8-membered heteromonocyclic group containing an oxygen atom,

unsaturated 7- to 12-membered condensed heterocyclic group containing 1 to 2 sulfur

atom(s), or

unsaturated 7- to 12-membered condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s).

3. The ompound of Claim 2, wherein R² is hydrogen; oxamoyl; lower alkanoyl;

lower alkanesulfonyl; lower alkoxycarbonyl;

(C₂-C-₇)cycloalkanecarbonyl;

di(lower)alkylamino(lower)alkanoyl;

C₆-C₁₀ arylcarbamoyl; heterocyclic-carbonyl optionally substituted by the group consisting of C₆-C₁₀ ar(lower)alkoxycarbonyl, lower alkyl, hydroxy and oxo, said heterocyclic group being unsaturated 5- or 6-membered

heteromonocyclic group containing 1 to 4 nitrogen atom(s),

saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s),

unsaturated 9- or 10-membered bicyclic heterocyclic group containing 1 to 4 nitrogen atom(s),

unsaturated 5- or 6-membered

heteromonocyclic group containing 1 to 2 oxygen atom, or

saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom;

heterocyclic-carbamoyl, said heterocyclic group being

unsaturated 5- or 6-membered

heteromonocyclic group containing 1 to 4 nitrogen atom(s),

unsaturated 5- or 6-membered

heteromonocyclic group containing 1 to 2 oxygen atom, or

saturated 5- or 6-membered

heteromonocyclic group containing 1 to 2 oxygen atom;

(C₆-C₁₀)aryloxy(lower)alkanoyl;heterocyclic(lower)alkanoyl, said heterocyclicgroup being

unsaturated 5- or 6-membered

heteromonocyclic group containing 1 to 4 nitrogen atom(s)

saturated 5- or 6-membered

heteromonocyclic group containing 1 to 4 nitrogen atom(s),

unsaturated 5- or 6-membered

heteromonocyclic group containing 1 to 2 oxygen atom(s), or

saturated 5- or 6-membered

heteromonocyclic group containing 1 to 2 oxygen atom(s);

lower alkylcarbamoyl(lower)alkanoyl;

carboxy(lower)alkanoyl; protected

lower alkoxy(lower)alkanoyl;

lower alkoxy(lower)alkoxycarbonyl;

amino(lower)alkoxycarbonyl; C₆-C₁₀

ar(lower)alkoxycarbonylamino(lower)alkoxycarbonyl;lower alkoxycarbonyl(lower)alkylcarbamoyl; lower alkylsulfonyl(lower)alkanoyl;

hydroxy(lower)alkoxycarbonyl; protected hydroxy(lower)alkoxycarbonyl; lower alkanoyl substituted by the group consisting of amino and hydroxy; lower alkanoyl substituted by the group consisting of protected amino and hydroxy;

amino(lower)alkanoyl; or protected

amino(lower)alkanoyl; and

R⁴ is heterocyclic(lower)alkyl, said heterocyclic group being

unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 9- or 10-membered bicyclic heterocyclic group containing 1 to 4 nitrogen atom(s),

unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s), or

saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s).

4. The compound of Claim 3, wherein

R² is hydrogen; oxamoyl; lower alkanoyl;

lower alkanesulfonyl; lower alkoxycarbonyl;

(C₃-C₇)cycloalkanecarbonyl;

di(lower)alkylamino(lower)alkanoyl;

C₆-C₁₀ arylcarbamoyl; heterocyclic-carbonyl optionally substituted by the group consisting of C₆-C₁₀ ar(lower)alkoxycarbonyl, lower alkyl, hydroxy and oxo, said heterocyclic group being pyrrolyl, pyridyl, pyrazmyl, pyrrolidinyl, imidazolidinyl, indolyl, isomdolyl, qumolyl, isoquinolyl, furyl, or oxolanyl;

pyridylcarbamoyl;

(C₆-C₁₀)aryloxy(lower)alkanoyl;

heterocyclic(lower)alkanoyl, said heterocyclic group being

imidazolyl or pyridyl;

lower alkylcarbamoyl(lower)alkanoyl;

carboxy(lower)alkanoyl;

lower alkoxycarbonyl(lower)alkanoyl;

hydroxy(lower)alkanoyl;

lower alkanoyloxy(lower)alkanoyl;

lower alkoxy(lower)alkanoyl;

lower alkoxy(lower)alkoxycarbonyl;

amino(lower)alkoxycarbonyl; C₆-C₁₀ ar(lower)- alkoxycarbonylamino(lower)alkoxycarbonyl; lower alkoxycarbonyl(lower)alkylcarbamoyl; lower alkylsulfonyl(lower)alkanoyl;

hydroxy(lower)alkoxycarbonyl;

lower alkanoyloxy(lower)alkoxycarbonyl;

lower alkanoyl substituted by the group consisting of amino and hydroxy; lower alkanoyl substituted by the group consisting of lower alkoxycarbonylamino and hydroxy; amino(lower)alkanoyl; lower alkanoylamino(lower)alkanoyl, or lower

alkoxycarbonylamino(lower)alkanoyl; and

R⁴ is pyridyl(lower)alkyl.

5. The compound of claim 4, wherein

R² is hydrogen;

oxamoyl;

C₁-C₆ alkanoyl optionally substituted by halogen; C₁-C₄ alkanesulfonyl;

C₁-C₄ alkoxycarbonyl;

(C₃-C₇)cycloalkanecarbonyl; di(C₁-C₄)alkylamino(C₁-C₄)alkanoyl;

C₁-C₄ alkylcarbamoyl;

di(C₁-C₄)alkylcarbamoyl;

N-[(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkyl]carbamoyl;benzoyl;

ber.zenesulfonyl;

phenylcarbamoyl;

pyrrolylcarbonyl;

pyridinecarbonyl optionally substituted by C₁-C₄alkyl;

pyrazinylcarbonyl;

pyrrolidinylcarbonyl optionally substituted by oxo;imidazolizmylearbonyl optionally substituted bythe group consisting of oxo phenyl(C₁-C₄)-alkoxycarbonyl;

quinolmecarbonyl optionally substituted by

hydroxy;

indoylcarbonyl; isoindolylcarbonyl;

furoyl;

oxolanecarbonyl optionally substituted by oxo;

pyridylcarbamoyl;

phenoxy(C₁-C₄)alkanoyl;

imidazolyl(C₁-C₄)alkanoyl;

pyridyl(C₁-C₄)alkanoyl'

piperidinyl(C₁-C₄)alkanoyl;

C₁-C₄ alkylcarbamoyl(C₁-C₄)alkanoyl;

carboxy(C₁-C₄)alkanoyl;

C₁-C₄ alkoxycarbonyl(C₁-C₄)alkanoyl;

mono- or di- or tri- or tetra- or pentahydroxy-(C₁-C₄)alkanoyl;

C₁-C₄ alkanoyloxy(C₁-C₄)alkanoyl;

C₁-C₄ alkoxy(C₁-C₄)alkanoyl;

C₁-C₄ alkoxy(C₁-C₄) alkoxycarbonyl¬amino(C₁-C₄)alkoxycarbonyl;

phenyl(C₁-C₄)alkoxycarbonylamino(C₁-C₄)- alkoxycarbonyl;

C₁-C₄ alkoxycarbonyl(C₁-C₄) alkylcarbamoyl;

C₁-C₄ alkylsulfonyl(C₁-C₄)alkanoyl;

hydroxy(C₁-C₄)alkoxycarbonyl;

C₂-C₄ alkanoyloxy(C₁-C₄)alkoxycarbonyl;

C₁-C₄ alkanoyl substituted by the group consisting of amino and hydroxy;

C₁-C₄ alkanoyl suostituted by the group consisting of C₁-C₄ alkoxycarbonylamino and hydroxy; amino(C₁-C₄)alkanoyl;

C₁-C₄ alkanoylamino(C₁-C₄)alkanoyl;

C₁-C₄ alkoxycarbonylamino(C₁-C₄)alkanoyl, is hydrogen or C₁-C₄ alkyl, or the formula :

R⁴ is pyridyl(C₁-C₄)alkyl, and

is C₁-C₄ alkoxy or C₁-C₄ alkylamino.

6. A process for the preparation of a compound of the

formula :

or a salt thereof, which comprises (a) reacting a compound of the formula :

or a reactive derivative at the carboxy group,

or a salt thereof with a compound of the formula : R¹-O-NH₂ III or a reactive derivative at the amino group,

or a salt thereof, to give a compound of the formula (I) or a salt thereof; or (b) subjecting a compound of the formula :

or a salt thereof to a removal reaction of the

phthalimido moiety to give a compound of the formula :

or a salt thereof; or (c) alkylating the amino group of a compound of the above formula (I-b) or a salt thereof, to give a compound of the formula :

or a salt thereof; or (d) acylating a compound of the formula :

or a salt thereof to give a compound of the formula :

or a salt thereof; or (e) subjecting a compound of the formula :

or a salt thereof to a removal reaction of the hydroxy- protective group to give a compound of the formula :

or a salt thereof; or (f) reacting a compound of the formula : R

or a salt thereof, with a compound of the formula :

or its reactive derivative at the amino group,

or a salt thereof, to give a compound of the formula :

or a salt thereof; or (g) subjecting a compound of the formula :

or a salt thereof, to a removal reaction of the carboxy- protective group on to give a compound of the

formula :

or a salt thereof; or (h) subjecting a compound of the formula :

or a salt thereof, to a removal reaction of the amino- protective group on

to give a compound of the formula :

or a salt thereof; or (i) subjecting a compound of the formula :

or a salt thereof, to a removal reaction of the hydroxy- protective group on to give a compound of the

formula :

or a salt thereof; or (j) reacting a compound of the formula :

or a salt thereof, with lower alkylamine, to give a compound of the formula :

or a salt thereof;

in which R¹, R², R³, R⁴ and R⁵ are each as defined in

Claim 1,

is hydroxy-protective group,

is acyl,

is protected carboxy(lower)alkanoyl, is carboxy(lower)alkanoyl,

is protected amino(lower)alkoxycarbonyl, protected amino(lower)alkanoyl,

lower alkanoyl substituted by protected amino and hydroxy, or N-protected lmidazolidinyl optionally substituted by oxo,

is amino(lower)alkoxycarbonyl,

amino(lower)alkanoyl,

is protected hydroxy(lower)alkoxycarbonyl, or protected hydroxy(lower)alkanoyl, is hydroxy(lower)alkoxycarbonyl, or

hydroxy(lower)alkanoyl,

is lower alkoxycarbonyl(lower)- alkylcarbamoyl or lower alkoxycarbonyl- lower alkanoyl,

is lower alkylcarbamoyl(lower)-

alkylcarbamoyl or lower alkylcarbamoyl lower alkanoyl,

is lower alkyl,

is lower alkoxy, and

is lower alkylamino.

7. A pharmaceutical composition which comprises a compound of Claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

8. A process for preparing a pharmaceutical composition

which comprises admixing a compound of Claim 1 or a pharmaceutically acceptable salt thereof with a

pharmaceutically acceptable carrier or excipient.

9. A compound of Claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

10. A compound of Claim 1 or a pharmaceutically acceptable salt thereof for use as an inhibitor of MMP or TNFα.

11. A use of a compound of Claim 1 or a pharmaceutically

acceptable salt thereof for manufacturing a medicament for treating and/or preventing MMP or TNF_α mediated diseases.

12. A method for treating and/or preventing MMP or TNF_α

mediated diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.