CA2483020A1 - Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same - Google Patents

Abstract

Compounds having a metalloproteinase inhibitory activity, represented by the formula (I), its optically active isomers, their pharmaceutically acceptable salts, or hydrates thereof.

(See formula I)

Description

DESCRIPTION
SULFONATED AMINO ACID DERIVATIVES
.AND METALLOPROTEINASE INHIBITORS CONTAINING THE SAME
Technical Field This application relates to sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same.
Background Art An extracellular matrix consists of collagen, proteoglycan, ete., has a function to support tissues, and plays a role in a maintaining of a cell functions , for example propagation, differentiation, adhesion, or the like. Matrix metalloproteinases (MMP) such as gelatinase, stromelysin, collagenase, and the like have an important role in degradation of an extracellular matrix, and these enzymes work for growth, tissue remodeling, etc. under physiological conditions. Therefore, it is considered that these enzymes participate in progression of.various kind of diseases involving breakdown and fibrosis of tissues, such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (for example, HIV
infection). At the present time, it is not clear which enzyme participates in the above diseases seriously, but it is considered that these enzymes at least participate in tissue breakdown. As metalloproteinase inhibitors of amino acid derivatives, for example hydroxamic acid derivatives of amino acids (JP-A-6-2562939), carboxylic acid derivatives of amino acid and/or their hydroxamic acid derivatives (W095135276), etc.
are disclosed.
Disclosure of Invention If it is able to inhibit the activity of MMP, it is considered that MMP
inhibitors contribute to an improvement and prevention of the above diseases caused by or related to its activity. Therefore, development of MMP inhibitors has long been desired.
In the above situation, the inventors of the present invention found that a kind of sulfonamide derivatives have strong activity to inhibit MMP.
The present invention relates to a composition for inhibiting metalloproteinase which contains a compound of the formula I_:

R~-R4-R3-SO2°N~COY
~2 R
wherein Ri is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; RZ is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, -(CHz)m-, -CH=CH-, -C = G-, -CO-, -CO-NH-, -N=N-, -N(R,A)-, -NFi-CO-NH-, -NH-CO-, -O-, -S-, -SOzNH-, -S02-NH-N=CH-, I5 or tetrazol-diyi; Rs is optionally substituted lower alkyl, optionally substituted Ca-Ca cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is -NHOH or -OH; and m is I or 2; provided Rz is hydrogen atom when Y
is -NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
Mentioned in more detail, the invention relates to the following a)-b), 1)-16), and A)-C).
a) A composition for inhibiting metalloproteinase which contains a compound of the formula I:
R5-R4-R3-SO2-N~COY _I

wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkgl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, -(CH2)m-, -CH=CH-, -C '--C-, -CO-, -CO-NH-, -N=N-, -N(RA)-, -NH-CO-NH-, -NH-CO-, -O-, -S-, -SOzNH-, -S02-NH-N=CH-, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted Cs-Ca cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is -NHOH or -OH; and m is 1 or 2; provided R2 is hydrogen atom when Y
is -NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is -CO-NH- or -NH-CO-, R3 is optionally substituted aryl or optionally substituted heteroaryl when Rs is optionally substituted arylene or optionally substituted heteroarylene and R4 is tetrazol-diyl, R5 is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or heteroaryl substituted by lower alkyl or optionally substituted aryl when Rg is optionally substituted arylene and R4 is a bond, both of R3 and R4 are not a bond at the same time, and R4 is not -O- when R3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
b) A composition for inhibiting metalloprnteinase as mentioned above, which is a composition for inhibiting type-IV collagenase.
Preferred embodiment of the present invention are as follows.
1) A compound of the formula I:

R5-R4-R3-S02-N~COY I_ R
wherein Rl is optionally substituted Lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Rg is a bond, optionally substituted arylene, or optionally substituted heteroarylene; Rø is a bond, -(CHz)m-, -CH=CH-, -C = C-, -CO-, -CO-NH-, -N=N-, -N(R,A)-, -NH-CO-NH-, -NH-CO-, -O-, -S-, -SOzNH-, -SOa-NH-N=CH-, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyelic grnup; RA is hydrogen atom or lower alkyl; Y is -NHOH or -OH; and m is 1 or 2; provided RZ is hydrogen atom when Y
is -NHOH, Rb is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is -CO-NH- or -NH-CO- (when R3 is phenylene and R4 is -CO-NH-, Rl is not methyl or phenyl and Rb is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R~ is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R~
is tetrazol-diyl, Rb is lower alkyl, aryl substituted with lower alkyl or optionally substituted aryl, or heteroaryl substituted with lower alkyl or optionally substituted aryl when R3 is optionally substituted arylene and R4 is a bond, both of R3 and R4 are not a bond at the same time, and R4 is not -O- when R3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
2) A compound of the formula II:
Rs Rt R' R6 ~ \ S02-N~COY

wherein R6 is -CH=CH-, -C '-- C-, -N=N-, -NH-CO-NH-, -S-, -S02NH-, or -SOz-NH-N=CH-; R' is optionally substituted aryl or optionally substituted heteroaryl;
R$ and R9 are each independently hydrogen atom, lower alkoxy, or vitro; R1, R2, and Y
are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
3) A compound of the formula III:
R8 R~
I
R' R1° ~ ~ SO2-N~COY
Rz R
wherein Rl° is -(CHa)m-, -CO-, -CO-NH-, -N(R,A)-, -NHCO-, or tetrazol-diyl; m is 1 or 2;
Rl, R2, R', R8, R9, RA, and Y are as defined above, provided R1 is not methyl or phenyl and R~ is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when Rl° is -NH-CO-, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
4) A compound of the formula IV:

R'-R" ~ ~ sot-nr'~coY
°R2 wherein Ril is a bond, -CH=CH-, or -C = C-; X is oxygen atom or sulfur atom, R1, R2, R7, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

5) A compound of the formula I_':
', R
R5~-R~~-R3~-S02-N~COY r_ r 2.
R
wherein R1' is benzyl, (indol-3-yI)methyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (1-acetylindol-3-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, (1-alkoxycarbonyl-3-yl)methyl (for example ethoxycarbonylmethyl), or i-propyl;
R2' is hydrogen atom, methyl, 4-aminobutyl, or benzyl; R3' is I,4-phenylene; R4' is -O-; R~' is phenyl or 4-hydroxy-phenyl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

6) A compound of the formula j'_':
R5"-R4"_R3"-S02-N~COY I_"
i 2"
R
wherein Rl" is 4-thiazolylmethyl, (indol-3-yl)methyl, (5-methoxyindol-3-yl)methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-biphenylylmethyl, 2,2,2-trifluoroethyl, 2-phenylethyl, benzyl, i-propyl, 4-nitrobenzyl, 4-fluorobenzyl, cyclohexylmethyl, (I-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-ffuoroindol-3-yI)methyl, (pyridin-4-yl)methyl, (benzothiazol-2-yl)methyl, (phenyl)(hydroxy)methyl, phenyl, carboxymethyl, 2-carboxyethyl, hydroxymethyl, phenylmethoxymethyl, 4-carboxybenzyl, (benzimidazol-2-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, or (1-ethoxycarbonylindol-3-yl)methyl; R2" is hydrogen atom; R~" is 1,4-phenylene;
R4" is a bond; R~" is phenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methylthiophenyl, 4-biphenylyl, 2-thienyl, benzoxazol-2-yl, benzothiazol-2-yl, or tetrazol-2-yl;
and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

7) A compound of the formula V:
R~ R~
R'-R12 ~ \ SO2-N~COOH V_ wherein R12 is -CH=CH- or -C '-- C-; Rl, R2, R7, R8, and R~ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

8) A compound of the formula VI:

R8 R1s O I ~
R'4-C-N ~ ~ SO2°N~COOH VI
_Rs Rz wherein R2, R8, and R9 are as defined above, Rls is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R14 is optionally substituted aryl, or optionally substituted heteroaryl; provided Rl~ is not methyl or phenyl and R14 is not 2-ehlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

9) A compound of the formula VII:
R$ Rt N N
R7 N. -' / ~ SOz-N ~COOH VII
N L~_ Rz Rs wherein R1, R2, R', R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

10) A compound of the formula VIII:
Rt R7 R" ~ p SOz-N~COOH '~Il Rz wherein R1, R2, R', and Rii are as defined above, its optically active substance, their I5 pharmaceutically acceptable salt, or hydrate thereof.

11) A compound of the formula VIII:
R8 R~

R? o ~ \ sot-N''~cooH
Rz R
wherein R1, R2, R?, R$, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

12) A compound of the formula X_:
R8 R' I
R7 R12 ~ ~ S02-N ~COOH
_1_ H _ wherein RIZ is -CH=CH- or -C = C-; Ri, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

13} A compound of the formula Xl:

O I
R14-C-N ~ \ S02-N~COOH XI
H _ _ _.

wherein R8, R9, R13, and Ri4 are as defined above, provided R13 is not methyl or phenyl and R'4 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

14) A compound of the formula III:

N N I
R7 N. ~' / ~ SO2-N~COOH ~II_ N 'v:~- H
Rs wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

15) A compound of the formula XI~:

R'-R11 I l So2_N~GOOH
S H
wherein Rl; R7, and Rll are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof 16) A compound of the formula HIV:
R8 R~
R7 O ~ \ S02-N'~COOH ITV
H
Rs wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
A compound of the invention is more specifically illustrated below:
A) The compound of any one of above 1) to 16), wherein Rl, Ri', RI", and RI3 are i-propyl, benzyl, or (indol-3-yl) methyl.
B) The compound of any one of above 1) to 4) and 7) to 16), wherein R5, R7, and Ri4 are phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.
C) The compound of any one of above 1) to 16), wherein a configuration of asymmetric carbon atoms bonding with Ra, Ri', Rt", and R13 is R configuration.
Further, this invention relates to a pharmaceutical composition , a composition for inhibiting metalloproteinase, and a composition fox inhibiting type IV
collagenase which contain the compound above 1) to I6) and A) to C) All of compounds of above 1) to 16) and A) to C) have strong metalloproteinase inhibitory activity, and the following compound is more preferable:
R~
R5-R4-R3-SO2-N~COY ~
R
1) A compound wherein Rl is i-propyl, benzyl, or (indol-3-yl) methyl, RZ is hydrogen atom, Rg is 1,4-phenylene, R4 is -C = C-, and R5 is optionally substituted phenyl.
2) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl) methyl, RZ is hydrogen atom, Rg is optionally substituted 2;5-thiophen-diyl, R4 is -C = C-, and R5 is optionally substituted phenyl.
3) A compound wherein R' is i-propyl, benzyl, or (indol-3-yl)methyl, R2 is hydrogen atom, R3 is 1,4-phenylene, Rø is tetrazol-diyl, and R5 is optionally substituted phenyl.
The term "alkyl" herein used means Cx-Cio straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tart-butyl, n-pentyl, i-pentyl, neo-pentyl, tent-pentyl, and the like.
The term "lower alkyl" herein used means Ci-Cs straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tart-butyl, and the like.
The term "Cs-Cs cycloalkyl" herein used is exemplified by cyclopropyl, eyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term "aryl" herein used means monocyclic or condensed ring aromatic hydrocarbons. Examples of the aryl are phenyl, naphthyl, and the like.
The term "aralkyl" herein used means the above mentioned alkyl substituted by the above mentioned aryl at any possible position. Examples of the aralkyl are benzyl, phenethyl, phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (a-naphthylmethyl), anthrylmethyl (9-anthrylmethyl), and the like. Benzyl is preferred.
The aryl part may optionally be substituted.
The term "heteroaryl" herein used means a 5 to ~ membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring and may be fused with a carbocyclic ring or other heterocyclic ring at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 2-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4- imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyi (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 3-furyl), benzofuryl (e,g., 3-benzofuryl), thienyl (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. The aryl part of the above heteroaryl is optionally substituted.
The term "heteroarylalkyl" herein used means the above mentioned alkyl substituted with the above mentioned heteroaryl at any possible position.
Examples of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g., 5-thiazolyl-2-ethyl), indolylmethyl (e.g., 2-indolylmethyl), imidazolylmethyl (e.g., 4-imidazolylmethyl), benzothiazolylmethyl (e.g., 2-benzothiazolylmethyl), benzopyrazolylmethyl (e.g., I-benzopyrazolylmethyl), benzotriazolylmethyl (e.g., 4-benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 2-pyridylmethyl), and the like. The aryl part of the above heteroaryl is optionally I5 substituted. _.
The term "arylene" herein used is exemplified by phenylene, naphthylene, and the like. Mentioned in more detail, it is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, and the like.
The term "heteroarylene" herein used is exemplified by thiophen-diyl, furan-diyl, pyridin-diyl, and the like, in more detail, by 2,5-thiaphen-diyl, 2,5-furan-diyl, and the like.
The term "non-aromatic heterocyclic group" herein used means 5 to 6 membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and may bind at any possible positin. Examples of the non-aromatic heterocyclic group are morpholino, piperidino, pyrrolidino, and the, like.
The term "alkoxy" herein used means alkoxy of which alkyl part is the above mentioned alkyl. Examples of the alkoxy are methoxy, ethoxy, propoxy, butoxy, pentyloxy, and the like.
II

The term "lower alkoxy" herein used means alkoxy of which alkyl part is the above mentioned Iower alkyl. Examples of the lower alkoxy are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tart-butoxy, and the like.
The term "halogen" herein used means fluoro, chloro, bromo, and iodo.
The term "alkylthio" herein used means alkylthio whose alkyl part is the above mentioned lower alkyl. Examples of the alkylthio are methylthio, ethylthio, and the like.
Substituents for "optionally substituted alkyl", "optionally substituted Ca-Ca cycloalkyl", and "optionally substituted non-aromatic heterocyclic group" are hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitrn, cyano, haloalkyl (e.g., trifluoromethyl), substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl, benzyloxy, and the like. These substituents are able to bind them at one or more of any possible positions.
Substituents for the aromatic ring of "optionally substituted aryl", "optionally substituted aralkyl", "optionally substituted heteroaryl", "optionally substituted heteroarylalkyl", "optionally substituted arylene", and "optionally substituted heteroarylene" are, for example, hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy) substituted or unsubstituted amino (e.g., methylamino, dimethylamino, diethylamino, and benzylidenamino), guanidino, alkyl (e.g., methyl, ethyl, n-propyl, i-prapyl, n-butyl, i-butyl, sec-butyl, tart-butyl, n-pentyl, i-pentyl, neo-pentyl, and tent-pentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), alkanoyl (e.g., formyl, acetyl, and propionyl), acyloxy (e.g., acetyloxy), acylamino, alkylsulfonyl (e.g., methylsul~onyl), phenyl, benzyl, an azo group (e.g., phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally substituted ureido (e.g., ureido and phenylureido), and the like. These substituents are able to bind to it at one or more of any possible position.
Best Mode for Carrying Out the Invention Compounds (Ia) and (Ib) of the invention are able to be synthesized from the corresponding a-amino acids represented by the formula (XV) by means of the following 6 synthetic methods. Generally, it is possible to produce the compounds of the invention by means of the method A. Each classified type of the compounds is possible to be produced by means of methods the B to F. However, these methods are only examples to produce the compounds represented by the formula I. A
compound represented by the formula I produced by any other method is included in this invention.
Method A: A general synthetic method of the compound represented by the formula I.
Method B: A synthetic method of the compound wherein and R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is -C=C-, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method C: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, Rø is a bond, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method D: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R~ is -CO-NH-, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method E: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is tetrazol-diyl, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method F: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is -CH=CH-, and R~ is optionally substituted aryl or optionally substituted heteroaryl.
Details of these methods are explained as follows.
(Method A) R~ R~
Process -1 R5-R~-R3-SO2-Hai R2 XV Ia-~
R' Process 2 Ia-1 --~ R5-R4-R3-S~2-N~CONHOH ~--__ ~2 R
Ib-1 R' Process 3 Process 4 R5-R4-R3-SOz-N CONHOR~s- -XVI
wherein RI, R2, R3, R~, and RS are as defined above, Rl~ is hydrogen atom or a carboxy protective group, Rls is a hydroxy protective group, and Hal is halogen.
Conversion of compound (X'~ to compaund (Ia-1) is sulfonation of an amino group of the compound (X~ (process 1). If necessary, after this reaction, N-alkylation, deprotection of a carboxyl protective group, etc. are carried out. Conversion of compound (Ia-1) to compound (Ib-1) is to obtain hydroxamic acid derivatives from carboxylic acid derivatives (process 2). To obtain compound (Ib-1) from compound (Ia-1), compound (Ia-1) may also be reacted with hydroxylamine having a hydroxyl protective group or its acidic salts to give compound (XVI) process 3), followed by and deprotection (process 4). Conversion to sulfonyl derivatives and hydroxamic acid derivatives are able to be carried out according to an usual method. For example, an amino acid represented by the formula (X~ is reacted with a sulfonating agent such as sulfonyl halide represented by R3-R4-R3-SOzIial (R.3, R4, and R5 are as defined above;
and Hal is halogen) and then hydroxylamine. Each process will hereinafter be described in more detail.

(Process 1) Some of amino acids represented by the formula (~ or its acidic salts (e.g., hydrochloride, p-toluenesulfonate, and trifluoroacetate) which are starting materials are commercially available. The other are able to be synthesized in accordance with a method described in Zikkenkagakukoza, vol. 22, IV (nihonkagakukai), J. Med.
Chem.
38, 1689-1?00, 1995, Gary M. Ksander et. al., etc. some of sulfonating agents are commercially available and the other are synthesized in accordance with a method described Shin-zikkenkagakukoza, vol. 14, 178?, 1978, Synthesis 852-854, 1986, etc.
A carboxyl protective group is exemplified by esters (e.g., methyl ester , tert-butyl ester and benzyl ester). Deprotection of this protective group may be carried out by hydrolysis with acid (e.g., hydrochloride and trifluoroacetic acid) or base (e.g., sodium hydroxide) depending on the type of the group, or by catalytic reduction, e.g., under 10% palladium-carbon catalyst condition. To obtain a compound (Ib-1), the esters may directly be converted to hydroxamic acid by the method of process 2. When a I5 compound (XV) is an amino acid wherein R15 is hydrogen atom, preferable solvents for this sulfonylation are dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, or mixed solvents thereof. When a compound (XV) is an amino acid wherein R15 is a protective group such as an ester, a solvent for this sulfonylation is exemplified by the above solvents and mixed solvents of water-insoluble solvents (e.g., benzene and dichloromethane) and the above solvents.
A base to be used in this sulfonylation is exemplified by organic bases such as triethylamine, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and the like. Usually this reaction can be carried out at ice-cooling to room temperature. When R1, R3, R4, R5, or R15 of compound (Ia-1) contains a functional groups) possibly interfering this sulfonylation (e.g., hydroxy, mercapto, amino, and guanidino), it can previously be protected in accordance with a method described in " Protective Groups in Organic Synthesis" ( Theodora W.
Green (John Wiley & Sons)) and then deprotected at an appropriate process. When R2 is not hydrogen atom, compound (Ia-I) wherein R2 is hydrogen atom is further reacted with haloalkyl (e.g., methyl iodide, and ethyl iodide) or haloaralkyl (e.g., benzyl chloride, and benzyl bromide) in dino.ethylformamide, tetrahydrofuran, dioxane, and the like at a temperature range of ice-cooling to 80 ~, preferably ice-cooling to room temperature, for 3-10 hours, preferably 10-20 hours to give the desired N-R2 derivative.
(Process 2) A hydroxylamine is reacted with compound (Ia-1) or its reactive derivatives to give hydroxamic acid derivatives (Ib-1). A hydroxylamine is usually used as its acidic salts (e.g., hydrochloride, and phosphate, sulfate: commercially available) in the presence of a base. A base to be used in this reaction is exemplified by organic bases such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc.
When compound (ta-1) is used as a starting material of conversion to hydroxamic acid, this reaction is carried out in the presence of a peptide condensing agent (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonyldiimidazole, or a mixture of one of the above agents with 1-hydroxybenzotriazole, N-hydroxy sucinicimide, etc.). A salvent for this reaction may be dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, and mixed solvent thereof. This reaction is carried out at -20 ~ to 40 °~, preferably ice-cooling to room temperature, for 1 to 16 hours.
Acid anhydrides (especially, mixed acid anhydrides), acid halides, acid azides, and esters can be utilized in this reaction as a reactive derivative of compound (Ia-1).
These reactive derivatives are produced by usual methods. For example, the acid anhydride derivatives can be produced by a reaction of compound øa-1) with acid halide derivatives (e.g., ethyl chlorocarbonate) in the presence of a base (e.g., triethylamine), and acid halide derivatives can be produced by a reaction of compound (Ia-1) with a halogenation agent (e.g., oxalylchloride, and thionylchloride).
Ester derivatives may be inactive or active. Sulfonyl derivatives converted from a compound (X~ wherein R1~ is a carboxyl protective groups (e.g., methyl, tert-butyl, and benzyl) at process 1 can he used as inactive esters without deprotection.
Active esters can be produced by a reaction of compound (Ia-1), carbodiimide reagents (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and hydroxy derivatives corresponding to the active ester residue such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, or the like. A reaction condition of conversion of the reactive derivatives of compound (Ia-1) to hydroxamic acid may be the same as that of conversion of compound (Ia-1) itself to hydroxamic acid .
The reactions of processes 1 and 2 are able to continuously be carried out in one-pot reaction.
(Process 3) A protected hydroxylamine to be used in this reaction includes O-benzylhydroxylamine, O-(p-methoxybenzyl)hydroxylamine, O-(tert-butyl)hydroxylamine, or the like. This reaction condition may be in the same manner as that of process 2.
(Process 4) This process for deprotection is_carried out by catalytic reduction, treatment with conc. hydrochloric acid, or treatment with trifluoroacetic acid to give the desired compound (Ib-1). The compounds of this invention (Ia-1) and (Ib-1) can be isolated and purified by usual separation methods and purification methods (e.g., chromatography, crystallization, etc.).
(Method B) 1?

R' _ Ri Process 1 ,~ - Process 2 H2N COORS '~" (Hai-~R'~ S02-H COORS --~-XV X~V
R' R' Process 3 R~ C=C-R'7 S02-H COOR'S --~ R7 C=C-R'7 SO2-N2 COOH
R

Process 4 ~--'' R'-C=C-R1~ SO~-N~CONHOH

Ib-2 wherein R1, R2, R7, R15, and Hal are as defined above, R17 is optionally substituted aryl or optionally substituted heteroaryl.
Conversion of compound (X'~ to compound (XVII) is performed by sulfonation of an amino group of compound (X~ (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XVII) to compound (XVIII) is performed by Heck reaction (K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 4467(1975) etc.) wherein halogen of Ri7 is utilized to insert a triple bond (process 2). Conversion of compound (XVIII) to compound (Ia-2) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 3), which can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-2) to compound (Ib-2) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 4), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(Process 1) This process may be carried out in the same manner as that described in process 1 of method A.
(Process 2) Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an ethynyl group such as ethynylbenzene in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(PhsP)zCl2), a divalent copper reagent (e.g., CuI), and an organic base (e.g., triethylamine, and diisopropylethylamine) to give a desired compound (XVIII) (Heck reaction). This reaction is carried out at room temperature to 100 'C, preferably room temperature to 80 'C. This reaction is completed for 3 to 30 hours, preferably 10 to 20 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of " Protective Groups in Organic Synthesis " ( Theodora W. Green (John Wiley &
Sons)), and then deprotected at an appropriate step.
(Process 3) This process may be carried out in the same manner as that described in process 1 of method A.
(Process 4) This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
(Method C) R~ R1 (Haf-)R"S02-N~COOR'~ Proces~ R~ RWS02-N~COOR,S
H H
XVII XIX

Process 2 ~ Process 3 -~--~- R' R"S02-N COON ~- R~-R"SO~-N~CONHOH

1~ Ib-3 wherein RI, Rz, R~, R15, R17, and Hal axe as defined above.
Conversion of compound (XVII) to compound (XIX) is performed by Suzuki reaction (M. J. Sharp and V. Shieckus, Tetrahedron Lett., 26, 5997 (1985) etc.) wherein halogen of R'~ is utilized to introduce aryl or heteroaryl (process 1).
Conversion of compound (XIX) to compound (Ia-3) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 2) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-3) to compound (Ib-3) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 3), and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(process 1) Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having a B(OI~2 (otherwise B(Et)z) group such as phenylboronic acid in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(PhsP)a) and a base (e.g., potassium carbonate, calcium carbonate, triethylamine, sodium methoxide etc.) to give the desired compound (XIX) (Suzuki reaction). This reaction is carried out at room temperature to 100 °C, preferably room temperature to 80 ~.
This reaction is completed for 5 to 50 hours, preferably 15 to 30 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of " Protective Groups in Organic Synthesis " ( Theodora W. Green (John Wiley & Sons)) and then deprotected at an appropriate step.
(Process 2) This process may be carried out in the same manner as that described in process 1 of method A.
(Process 3) This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
(Method D) R~
R' Process 1 ~, Process 2 H2N COOR~5 -"(OWN )R17 702 H C~~R~5-- . -XV XX
R' R' O
(H2N-)R1~ SO2-N~'COOR~5 PrOCeSS 3 ~ R7_C-N-R'7 SO2-N~COOR15 H H
XXI XXII

Process 4 R7 o-N-R17-S02-N~COOH Process 5~
'2 la-4 R

R' C-N-R~~ S02-N~'CONHOH

wherein Ri, R2, R7, R15, Rm, and Hal are as defined above.
Conversion of compound (X~ to compound (X~ is sulfonation of an amino group of the compound (X~ (process 1) and this process may be carried out in the same manner as that described in process l of method A. Conversion of compound (XX) to compound (XXI) is reduction of a vitro group of Ri7 to an amino group (process 2) and this process can be carried out by catalytic reduction or other reduction using hydrochloric chloride - Fe, hydrochloric chloride - Sn, etc. Conversion of compound (XXI) to compound (XXII) is performed by usual amide bond formation reaction wherein an amino group of Rz7 is utilized (process 3). Conversion of compound (XXII) to compound (Ia-4) is N-alkylation, deprotection of a carboxyl protective group, etc.
(process 4) of compound (XXII) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-4) to compound (Ib-4) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 5) and this process can be carried out in the same manner as those described 2i in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(process 1) This process may be carried out in the same manner as that described in process 1 of method A.
(Pracess 2) Compound (XX) is treated with hydrogen in a salvent such as methanol, ethanol, ethyl acetate, acetic acid, etc. in the presence of a catalyst (e.g., Pd-C, Pt02, Raney Ni etc.) , under a no-pressure ar pressured condition to give the desired compound (XXI). This reaction is carried out at a temperature under ice-cooling to 80 ~, preferably room temperature to 50 °C, and is completed far 1 to 10 hours, preferably 2 to 5 hours.
(Process 3) Compound (XXI) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an acid halide (otherwise an active ester) group such as benzoyl chloride in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, xylene, toluene, benzene, dichloromethane, etc. in the presence of a base (e.g., triethylamine, N-methylmorpholine, potassium carbonate etc.) to give the desired compound (XXII). This reaction is carried out at a temperature under ice-cooling to 100 ~, preferably room temperature to 60 ~, and is completed for 3 to 30 hours, preferably 10 to 25 hours.
(Process 4) This process may be carried out in the same manner as that described in process 1 of method A.
(Process 5) This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
(Method E) R~
Rt Process 1 ~ Process 2 H2N~COOR~S ~ (CH2=CH-)R'7-S02 H COOR~5 R' _ R' (OHC-)Rw_S02-N~COOR~S Proce~ R7 S2 N-N-C-R~~ SO2-N~COOR~s H H
R~
Process 4 N'N ~ Process 5 R~ N,N~R~7 S02-H COOR15 N=N N=N
R? N, ~Rt~ S02-N~'COOH P'~~ R? N, ~--R~~ S02-N~CONHOH

I
wherein R1, R2, R7, R15, R~~, and Hal are as defined above.
Conversion of compound (X~ to compound (XXITI) is performed by sulfonating an amino group of the compound (XV) (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XXIII) to compound (XXI~ is done by the reduction wherein an ethenyl group of Rl~ is converted into an aldehyde group (process 2). Conversion of compound (XXT~ to compound (:KXVI) is performed by a tetrazole ring formation reaction (processes 3 and 4).
Conversion of compound (XXVI) to compound (Ia-5) is N-alkylation, deprotection of a carboxyl protective group, etc. of compound (:KXVI) (process 5), and this process can be carried out in the same manner as that described in process 1 of method A.
Conversion of compound (Ia-5) to compound (Ib-5) is that of carboxylic acid derivatives to hydraxamic acid derivatives (process 6), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(process 1) This process may be carried out in the same manner as that described in process 1 of method A.

(Process 2) A compound (XXIII) is treated with ozone in a solvent such as dichloromethane, ethyl acetate, methanol, etc. to form an ozonide, and then a reagent such as zinc-acetic acid, triethylphosphate, dimethylsulfide, etc. is added to this reaction mixture for reduction to give the desired aldehyde derivatives (XXI~
The reduction can also be carried out by catalytic hydrogenation. This reaction is carried out at -100 ~ to room temperature, preferably -78 'C to a temperature under ice-cooling, and is completed for 0.5 to 10 hours, preferably 1 to 3 hours.
(Process 3) A compound (XXI~ is reacted with benzensulfonylhydrazide in a solvent such as tetrahydrofuran, ether, etc. mixed with a solvent such as methanol, ethanol, etc. to give the desired compound (;~. This reaction is carried out at a temperature under ice-cooling to 80 °C, preferably room temperature to 50 ~, and is completed for 3 to 30 hours, preferably 10 to 20 hours.
(Process 4) Optionally substituted aryl or optionally substituted heteroaryl having amino group such as aniline is dissolved in a mixed solvent such as alcohol (e.g., ethanol) and water. To this mixture cone. hydrochloric acid and a diazotizing agent such as a sodium nitrite aqueous solution are added at -20 '~ to 10 ~, preferably 0 'C
to 5 ~, to give a diazonium salt. The reaction time is 5 min to 1 hr, preferably 10 to 30 min.
This reaction mixture is added to a pyridine solution of compound (:~ and allowed react for 1 to 10 hr, preferably 2 to 5 hr, at -30 °O to 50 °O, preferably -15 °C to room temperature to give the desired compound (X~~~'VI). When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of "
Protective Groups in Organic Synthesis " ( Theodore W. Green {John Wiley & Sons)), and then deprotected at an appropriate step.
(Process 5) This process may be carried out in the same manner as that described in by an usual method, in a solvent such as toluene, xyleae, tetrahydrofuran, ether, dimethylformamide, etc. at -100 ~ to room temperature, preferably -?8 'C to ice-cooling for 1 to 20 hours, preferably 1 to 5 hours, to give the desired compound (XX~VII).
When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of " Protective Groups in Organic Synthesis " ( Theodora W. Green (John Wiley & Sons)), and deprotected at an appropriate step.
(Process 2) This process may be carried out in the same manner as that described in process 1 of method A.
(Process 3) This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
The term " compound of the present invention " herein used includes pharmaceutically acceptable salt or hydrate of the compound. The salt is exemplified by a salt with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, mallein acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid). These salts can be formed by the usual method.
The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.
The compound of the present invention has an excellent activity for inhibiting metalloprateinase, especially activity for inhibiting MMP, and inhibits matrix dissolution, as described in the following test example. Therefore, the compound of the present invention is useful to treat or prevent diseases which are caused by MMP
and relative enzymes such as TNF-a converting enzyme, etc.
Definitely, the compounds of the present invention are useful in the prevention or treatment of diseases such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., HIS, arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, and gastric ulcer.
When the compound of the present invention is administered to a person for treatment or prevention of the above diseases, they can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, and liquid medicine, or by parenterai administration such as injections, suppository, percutaneous formulations, insufllation, or the like. An effective dose of the compound of the invention is formulated by being mixed with medicinal admixture such as excipient , penetrant, disintegrators, lubricant, and the like if necessary.
When parenteral injection is prepared, the compound of the invention and an appropriate carrier are sterilized to prepare it.
An appropriate dosage varies with the conditions of the patients, an administration route, their age, their body weight and the like and should be determined by a physician in the end. In the case of oral administration, a daily dosage can generally be between 0.1 - 100 mglkglday, preferably 1 - 20 mg/kg/day. In the case of parenteral administration, the daily dosage can generally be between 0.01 -10 mg/kg/day, preferably 0.1 - 1 mg/kg/day. The daily dosage can be administrated in one to several divisions.
The following examples are provided to further illustrate the present invention and are not to be constructed as limiting the scope thereof.
Abbreviations described below are used in the following examples.
p-TsOH : p-toluenesulfonic acid DMSO : dimethylsulfoxide Me : methyl tBu : tert-butyl Example 1 (Method A) ~I ~I
Process 1 H2N~COOH ' \ / \ S02-N~COOH
~/ H
Ia-1-1 Process 2 / \ / \ g02-N~CONHOH
~J H
To a suspension of (R)-(+)-phenylalanine (compound XV-1, 1.65g (10 mmol)) in 50 ml of dimethylformamide and 35 ml of water was stirred and treated with 2.78 ml (20 mmol) of triethylamine under ice-cooling. Then, 2.52g(10 mmol) of 4-biphenylsulfonyl chloride in 10 ml of dimethylformamide was added dropwise to the mixture over 5 min. After the reaction mixture was stirred for 2 h at the same temperature, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 2.1 g (11 mmol) of 1-ethyl-3-(3-dimethylaminopmpyl)carbodiimide hydrochloride, 3.47 g (50 mmol) of hydroxylamine hydrochloride, and 7 mI (50 mmol) of triethylamine were added to the mixture. After being stirred for 16 h at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 2N HCI, 5% NaHCOa, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCIa I
MeOH = 4011 to 20/1 were collected to yield 1.70 g of compound {Ib-1-1) as a foam.
Yield 43%.. mp. 169-170.
Elemental analysis (%) CziHzoNz04S

9.

Calcd. : C; 63.62, H; 5.08, N; 7.0?, S; 8.09 Found : C;63.61, H; 5.12, N; 6.98, S; 8.06 IR v max (cm-1) (Nujol) : 3365, 3295, 3266, 16?4, 1320, 1159.
NMR (8 ppm) ds-DMSO : 2.61 (dd, J=8.6, 13.4Hz, 1H), 2.80 (dd, J=6.0, 13.6Hz, 1H), 3.80 (m, 1H).
[ a JD: +18.5 ~ 1.2 (c=0.503 %, 25~.:, DMSO) Example 1' Another synthetic method of compound (Ib-1-1) p-TsOH = _ Process 1~
H2N~C~~CH2Ph ~ ~ ~~SO2-H~'CO~CH2Ph XV-1, Ia-1-1' a Process 2 ~ ~ / \ ~ Process 3 ~S02-H COOH ~- -1-1 -~ Ia-1-1" /
Process 4 ~ l Process 5 S02-N~CONHOCH2Ph ~.l ~J H

Process 1 To a solution of (R)-phenylalanine benzyl ester tosylate (compound XV-1', 2.5 g (5.85 mmol)) in 60 ml of dichloromethane was added triethylamine (1.8 ml, 12.8?
mmol) and 4-biphenylsulfonyl chloride(1.63 g, 6.44 mmol) under ice-cooling.
After being stirred for 2 h at room temperature, the reaction mixture was washed with 2N
HCl, 5% NaHCOs and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCIa / MeOH =

to 2011 were collected and crystallized from dichloromethane / hexane to give 2.32 g of a i~

compound (Ia-1-1'). Yield 84.1%. mp. 130-131.
Elemental analysis (%) CasH2sN04S
Calcd. : C; ? 1.32, H; 5.34, N; 2.97, S; 6.80 Found : C; 71.05, H; 5.41, N; 3.00, S; 6.81 IR v max (cm~i) (Nujol) : 3352, 1732, 1341, 1190, 1163.
NMR (b ppm) (CDCIs): 3.06 (d, J=5.8Hz, 2H), 4.30 (dt, J=6.0, 9.OHz, 1H), 4.89 (s, 2H), 5.12 (d, J=9.OHz, 1H), 6.98-7.81 (m, 14H).
[a]n: -I6.4~ 1.1(c=0.506 %, 25~C, MeOH) Process 2 A solution of compound (Ia-1-1') (2.28 g) which was obtained process 1 in 50 ml of mixed solvents of methanol I ethyl acetate =IIl, was hydrogenated using 10 % Pd/C
(200 mg) for 25 min. The reaction mixture was filtered off, and the filtrate was concentrated in vacuo. The residue was recrystallized from dichloromethane /
hexane to give 1.83 g of compound (Ia-1-1"). Yield 99.1 %. mp. 146-14790.
Elemental analysis (%) CziHi9N04S
Calcd.: C; 66.12, H; 5.02, N; 3.67, S; 8.41 Found: 0;65.97, H; 5.06, N; 3.61, S; 8.48 IR v max (cmn) (Nujol) : 3408, 3305, 1751, 1325, 1161, 1134.
NMR (b ppm) (CDCIs): 2.97 (dd, J=7.0, 13.8Hz, 1H), 3.14 (dd, J=5.2, 14.OHz,1H), 4.13 (m, 1H), 7.03-7.78 (m, 14H).
[a]n: -4.0~0.4(c=1.000 %, 25'0, MeOH) Process 3 To a solution of compound (Ia-1-1", L0 g (2.62 mmol)) which was obtained process 2 in dichloromethane (20 ml} was added 0.33 ml (3.93 mmol) of oxalyl chloride and one drop of dimethylformamide. After being stirred for stirred for 1 h at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 10 ml of tetrahydrofuran. A solution of hydroxylamine hydrochloride (911 mg (13.1 mmol)) and NaHCOs 1.54 g (18.34 mmol) in lOml of tetrahydrofuran and lOml of water was stirred for 5 min under ice-cooling. To the mixture was added the ~ .a above solution of acid chloride in tetrahydrofuran and the resulting mixture was stirred far 30 min. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with 5°r6 NaHCOs, and water, and concentrated in vacuo to give compound (Ia-1) (969 mg). Yield 93.3 %.
Process 4 To a solution of compound (Ia-1-1'", 2.0 g, 5.24 mmol) which was obtained process 2 in dimethylformamide (20 ml) was added 1-hydroxybenzotriazole hydrate (0.? g, 5.24 mmol), N-methylmorpholine (2.9 ml, 26.2 mmol), 1-ethyl-3-(3-diisopropylamino) carbodiimide hydrochloride (8 mmol), and O-benzylhydroxylamine hydrochloride (1.67 g, 10.48 mmol}, and the resulting mixture was stirred for 6 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCOs, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHzClz I hexane = I/l were collected and recrystallized from dichloromethane / hexane to give 2.04 g of compound (XVI-I).
Yield 80 %. mp. 171-173.
Elemental analysis (%) CzsHzsNz04S
Calcd.: C; 69.I2, H; 5.39, N; 5.76, S; 6.59 Found :C; 68.85, H; 5.46, N; 5.76, S; 6.78 IR v max (cm-1) (Nujol) : 3248, 1661, 1594, I333, 1163.
NMR (8 ppm} (CDCIs): 2.85-3.60 (m, 2H), 3.86 (m, 1H), 4.77 (ABq-Apart, J=11.4Hz, 1H), 4.82 (ABq-Bpart, J=11.4Hz, 1H), 5.00 (m, 1H}, 6.95-7.70 (m, 19H).
[ a' ]D: -40.2 t 1.6 (c=0.505 %, 25'L, DMSO) Process 5 A solution of compound (XVI-1) (1.97 g) which was obtained process 4 in a 60 ml of mixed solvents of methanol / ethyl acetate =1/1 was hydrogenated using Pd-C (200 mg) for 3.5 h. The reaction mixture was filtered off, and the filtrate was concentrated in vacuo. The residue was recrystallized from dichloromethane /
hexane to give 1.35 g of compound (Ib-1-1). Yield 84.4 %.

Example 2 - 91 The compounds which were shown in Tables Z to 22 were synthesized in a manner similar to those described in Example 1' Table 1 ~ N = C~7 O ~ pip IV ~ OD n N
tV -~j N N - ~ g N = 0 ~rj N Z N
_~_ _z Z ~ n Z ~r ao p, ~ $ O x r r ~ = II
O
G' ~ !V Np N N ~ N O IV N ate"; N r T3 i ~~ z~? o a ~r ~~° r=N ~~ r ~Z t'~
r 'd' N Z_ ,~r In Z h" N n ~r O N ~ = N = _ ~ N N
t~ ~j 0 ~ N N ~ O =
~; N ~O ~ ~t 'C r = ~ r ~ E C) '~ T N
r. Z ch N '~ ~ pj r C~ N ~ ~p 'a O GD
II
a0 ~ t0 a0 N O N ~ ~j ~ tp N r t0 '7 N 7 CO CD ~ CV to ~ ~ .Q N' CV ~ ~O II ,Zy N '7 ~....
M
r.
f~~. ~ tC7 ~ l'Oh C'N~ ~! 3 COp r r ~ r ' r v ~ Oi W th r 0 O N
? 1~C~0 (per ~ ~~ O ~tD 00 O~
W r tO r Gg r r r ~ O '~ N r N C'9 r T ~ r T N r r h. N N t~ Ch r N O~
tN ~ ~ M ~~ Mr ~ ~ c'~~T 4jcr ~r Z
Z
U a ea c~ r co ~.~ * n o N at c~c sM.
M N ~ r r r r r s~- O N M ~ N
N r r r~ r r ac# '~~~a'~~~'a,'~. x I
I~ !~ I~ I~ I~ I~ I~ w Ir I f I I I I I m r r r r r r r Z N
Z U S N
N U N U = N
V =Z / \ V ~ = Uo' U
l \ / \ I r cn / \ ~ U I
o I
U r z a z N M
>e I I 1 I ! I I

Table 2 T c~9 Z
N
O Z N N '!7 ''~Ov.. N ~ OC'~D N
_t~_ ~ Nip ~u~.j ~N ~ ~M_ N=
Z2 ~ zv,= N~ ~!~ ~ cv= TP_ P
N tn P ,C =
o» E E ~ -~ E ~° r- ri ,- r~ cc ~-N_ N~ _~ _~' _ _~?_ V PP e0 G'7 tn _f'9 M N _~ __ ~ N. N
"~r MN = NM..:
=N N ~~N '~I r= r=N I~~r ~C N O ~ 2 N O r' ~ P ~ ~ P = ~ ~j N
c~x ~"~ ~= O H o~S ~_ ~Z'~ Nice 07 N O ,.
P
C~j ~ ~ ~ ~ tl OTp = ~j ~ T' IV ~ ~N', O
fV ~ O ~ ~ - ~ N 'C t- O = ~ r. P~ O~f 'C
t0 .p' ~ P P .V ~f! ~ ~ II
N ~ 09 ~ CO CV t~7 ~ = O = ~ ~ - O !~. ~ ep N = CD
N !~ n, ~ _t'. N '~9 ~ II = II ~ N r !9 N '7 P N 7 ...
C tN~. _ N
c~
P
tsr ~M W ~~ O C'N~ M N
N M M T O O ~ CO P9 C9 r P .- .- r r-NN NN Of~ Or r _ ,p ~ O N M tD f0 N tp _tn N (G ci OP
~/ ON rM ~T ~T ~T N'~
N,n- OeP mO Is et t0N c0f~. Nr ct0 Nc~9 Nf~ NfN Nc~~ N~ ~r M T CAS P (~ T (~ T ('' P (Y~ P
T' U ~ N n ~ M ~ ~ w ~~ * O i1 r C~ T 1~ !~ T r T
U
Cfl OD '~ CO In N tt O r ~ r ~ r r N O, '- '°
.>E x r~ x ~ ~ ~ ~ '~
o ~ ~ ~ ( o 0 0 0 0 0 I~
N

N
Z Z I U = w Z U
U U ~ U U = U =Z
N o rx I o ' .~, ~ ( o U z / \
ti ~ i ~ l \
U
O
c~
Z
a~
C .-~ N c~'~ d' tI~ c0 C
~z x W

Table 3 tai °' = n~ o E ~ oyd' °9 ~ °~ c°
i-. N r N t~ Qy et ~ _N p N 7 _ tl N ~
~ r N ~~,- ~C Q~ T 'O
r ~ r ~ r ~ ~t = ~ = tf7 ~ 1I7 ~ ~
n, C7 -N M N _~r _Oj= M=~
r= N= '~ N ~r r cc= ~ ni E~ tech ~°~ t~=0 ado=V
amo '? ~ o -'- of ~ ''- ri z T Ch'C= C~j$ OII= ~rU ~~-r ~ N ~ ~ N O N ~ r ~ CO ..~ ~ 4l7 ~
N ~ M ~ _ ~ ~ GV ~ N ~ ~
N "7 '~ O
N
~p m r r ~ ! r r r ~ r _~ N
O~ ~ ~~ NN t_p~ .ar _~~
~ ..?v ~~ I r ~_M ~~ ~~ O~ Otn C9 r (h r er C9 N ~
NN U'OD~ CAD t~~ O~ Nr Nr ~. ~° ~ ~ ~ r (~ r O Mr c'o~
Z
Z
O y O
* ~ T '' _~ _OOf O
' ~ ~ CO n N
!~' r r ~/ (n r Ca, '' '' ~ N
I~ \ y r ~ r r r r I ~ . r Iw I~ i~ i~ Iw (\ z o r r r r r N
U U N U I Z N N
zZ U Z~ =U-Q V
w -'~ ~ I ~ r r / \ / \ I , / \ i ~ ~ ~ I ~ I
z CO 3~ O .-i N M er i.f7 O
.-r .-. N N N N N N
W

Table 4 II
Z ~ N
~ Q n r ~ ~ ~ _ .V N n u7 c0 V
N= ~c,~=O ~aD~~ N_IU N_r Nnp~ _ ~= N~ _..: = E
° W= =rm~ r'~ rr NO Z=~ N~ Nip ~ e~i = E °~ in ~ ~ s c~ ~ ~ ~ _~°? ~ ~ e?
- p~'ao n co rN~~ ~ '~ Nm O M _~ aD r r ~ r r O N rc9C= Is~= II O N O N
r N
'CSD o~pi=cNO__ ~__~' ~~O ~N
tai -~ N z o .o ~, n co '? tj ~"~
'D r ~ ~ r '~M ~c=oNniWv°~n: -.raccU ~co O~ t_i=~ N<~= Cf~ ' ml'.
N ~j ~ ~ aC N c9 aC ca~IN N I~ Z N '7 O
n m mr N r M
~D
N r O r r N M~ i ~ ~ r r '~ M ~ ~ d N O ~ ~ N ~
r y.?r O ~ O GO ~' CO N r f'~ r OM O~' Nr Nr r(p Nth Nr Ols O~ Or ~m ~M ~r ° C~ r ~ r cn~~ T
O
_ U ~ _ c~ N
cg ~-~ ~ h O O fp ~C ~ O ~ ~ N ~ ~ 4 z N CL r r '~' ~ ~ ~ W ~1 x I ~ I / I / I .~ I / I ~- I / I
Z
u. o ~ i I .- I ,~ I / \ I
CV N
U U N U O U U
U ' _ _ /
cx / / O V O U \ I =Z -\ I ° o = / v \i o°
x cD C~- 00 07 O .--i N M
O
x Z N N N N ~'7 M C9 M
W

Table 5 T
/~
N
N
'C
N
G?

N
N
h co ~, O
~O
O N
N~

O~
(~ Y
A Y
Z b ~'~, ~ r' Z ''' d' N C, x t s' m .,, U U
- Z
'~.' =Z ZT
a~

m m x W

Table 6 ~N,-_ .°
o~ _ ~° cMrr _ p ~o ti ~ ,- a t = N '" ~ t7~ t'' n, = M ~ ap E '~ t~7 .; O _.. M ~ p - o 'fl '~ nj=~~ ~_~ t~ ~ljj M= T= ~'j o, zE°-~l°,N zE° ~.., _" zE E~ _= n;' r. , = r r r .C r ~ N ~ ~ ~ N O r m N ~ = N ~ t!f .~. N ~ 6n ~" pate p~:= t'~ ~_~= t~'~L_'~ et~_rj ~= r ,~-=r = M=~ M= i~: tN07 ~et N r ~ r T N Z ll "~ O ~,j = O p t,,~ ~ '~~ nj 11 1~~ nj = - r N '7 N ~
~~=7 ~O~ ~ It ~~' at t'=9 N OZ NN
~O ~~r ~ ~ = OO
~,~~.-nj~ 'Cr - C'Z brr bra (~jpj ~CD ~f~j'~
in -uj' c0 ~ O = tC~ r ~ In 00 ~ ~ ~ O' 11 M - O r _ fi~p~ ~m n"~ ~lt~ w ~~f? ~~ ~= W ~
N '7 .,.... It ~ t1j ... r II z l' II ~p ,N tr1 r ~- r E
CV 7 ~~. C~ '3 r CV 7 v CV 6W ..
O M O eF 1~
M ~ N
r Z w ~ r ~ ~ ~ M
V N
M" ~ M
r r_ O ~ ~ ~ N ~-_._ - o f0 (~ CO ~ r U ~O
O ~h O CO ~ M CC tt7 ~' r ~ r r r0 O O) t0 CO M r- t!7 r O ~ ~a' f~ CO O ~ Q) ~ M
... i-r N ~ M v~~ O '~! M r ~ C9 N N N ~ C9 r Mr Mr Mr Otn Q M~ MC'' N~ M~ N~
_ U ~
r o~ Ire v ~ C~O N W N N r !T O
d .~ C1 tv r ~ t'7 ..n T N 00 O N ~ t~ O
r r r C_D
i~ ~ '~ '"~ x x ~ x .- .~ .~ i ~ i i w i x z i ~ i ~ ,.~ ( ~ w ~ y y -~ ~ i w w a r i i Z N
U Z ' N
N U N U ~ = N
=z / \ U W z = v 04 .Z.J TZ ~ / \ / \ ~ ~ V W
</ J co vo /
U
Z
_d w Table T
_ _ N ~ ~ r = N r r e., N r ~ C~ ~ N = _ nj r Z_ E ~ ~_ ~ _ '°rn ra U 'N z 7 N ~ C~ ~O ~ O ~ !~ = M et '4 ~ M i' 'O = t"7 'C '~ e A N.M-~ ~rj=~ l~ =C~ ~ N= N N
D ~ CC N = N CO ~' ~ E N ~ E
ai z E ~.- co n ~z cn=o N'' ~= cvi~ o00 E ._'~' ;? ~ T- sz ej _~ M ri y c? t!i t0 et N ~ ~rj ~ ~ N O ~ m CD N
CO r- O ,- d CO O N N OD N M
N M 'a' n' aij !~ O CD N ~,j GV "7 Q7 d O _tn0 C00! C_~JO ~ nP C~7 Pr PP r Pte' Y 1" P T
_ P_ .- r .- .- r r (» N tC) N (yI7 .-H et OD et st CO tD et T N M ~ M !- 01 L
N_tn r_N ODN O~t CrJr rt- ~a ptn r- T M T ~ r C91~ Of t~S OQ OD O
P4' t? tn ~1 Ci O> 1t1 N N M C9 N s? ~ T c0 .-r ct N O r~ CrJ t'~'~ CD M r C~3 ,- M r O tCl r-M ehrn Cnc') ~det Nt'~0 M '_' M '' N '°' M '' ~ ~ O O p ~ N ,-Q Mr MP N~
Q
U ~
M ID ~ MO O T In O
Z ~ '~ N ~ OD r. ,N- N
d i ~v~ r m O n ~ O
N r r r N r r ~_C
li it !~ I~ ii li i~ ii x ~i 'i ~i I~ !~ !~ ~I ~I
_ Z ~ N
N
Z V U _U = U
U
o U ti z =z =z U z I i ! / \ / \ i ~ va / \ _ / \
N li.
Q
M ~' ~ tD t~ 00 O
C
c~ z ... r, ..., ., ..., ...~ cv cV
w Table 8 7 ~ M h N u'1 _ C~ 0 ~.. N ~ ,II ~_ Y O = _ _ '~ _ ~ r Z _E W
~Y
a' Y N T O r" CO Y CO N
I Z ,; N N N N CD N ~ II N Cn ~
r r ~ ~ ~ = N ~ 6'9 =
A N .Z~..~ ~ _ ~ _ ' ~ = N ~ ~ d' T = fj M ,.~ ~ ~ N N O nj = O ~j = ~ r ~ h n x ~ _ ~ _ ~° 'd' a ~r' E '° oa ao ~ o~ _ ~ ~t' o~
N ~ N ~ 6p ~ ~ O -9 N il N '? ('.j II
O Z ~ ~ r ~ Y ~ ~ T ? ~ ~ ~ T
r- N Q9 et ~ O ~ O M ~ ~!' ~ ~ h O ~ Q7 ~
CV '7 r ~ N M '7 CD M ~ ~!' CV 7 OD
tN0 CMD
N Ltd CQ (D '- '- M
O r N v- r ~ M M MM ~~ ~O
_ r r r ,- MN Mc'~ O
~ f_9 ' M h '~' ~l7 C9 ~ LCS O) O O Q M O C~?
_ ~ CNr ~Z ~r0 .h-Or O~ O~
M .- M r M ,_ Mr ~ ~ 6Mn IJ o~ Or fr7c~ M~- Chr Nr ON O~
Mr M T MT Mr NN NN MCO
NC9 NC9 ~r O
U
p~~ * ~'" eo a~ c~ h r CV ~ ~ N Qy O
N
r ~_ lf5 N ... T f;! T ~ N
.>E ~ ~ Ix x x x x Iw iw Iw Iw Iw Iw Iw x wl wl wl to (o to wl N N
Z U U
_ =U o W f~ = U o / I
~ ~ O U O w ~ U Z o U
o z z wI o z _~
N ~'~7 CO 07 O ~-a N
C
~ ~.r N N N N M M C~7 x Table 9 -o _ "a N
r ~ II
_ '~ r _ ~o v~ = coo ~ et '.. ~ ~'? o Z
A '~_,_ N
r r II ~ E
~ r ~ P~.
~ r CO r II =
M 9 r O 1~.
r r L
v t~.i OJ r .C
C7 r ~r OCp '/ r r Mr NN Ot'~~
NM
Mr Nr Z
U ~
ca co N r d ly N r a0 oc '' ~

N N
U U
Z
4L~ =Z Z
_n~
a' ~° m d m x W

Table 10 ~o o°>Nm c°~'r~°
cc r~ cc c6 of of ire i~ iri iri ui ti~
'A °as oo po:-' co sci cc cc p v pZZ pzz Uzz i I zoo =~0 1 I I ~a°n°~
~ Sri Sri ~ Sri ui yri ui d ~=S :'__ ~ pZ=
~r9sn ~oc~ o~r~
~r.o. o00 ~o>c~
ZcNDCNe ZcNO.m Z°ic°a NU U <<""U U ~U U
= v c Z ~ c Z ti c UUti UU~ UU~
~r .- .~ ~ ~t c~ ~ o o a: eo co n. st m yn cc o u~ a7 ~ omn er a9 n u~ v o co v y~, M T tn T It7. T In T C~ in 1- (p f II) !-T r T T T '1o T 1~ f T T T T T T
N ~ P ~ ~ ~ ~ M M N ~ t '-' NN f90 00 NN OD CD NP. et0 rM
W h. M t~. et W N P~ f0 ~G ~- t~ M 1~ f~ P M
H T T T T 1~ T r T T 1~ 1~' T T T 1'~ T
r I~
_~ 007 C~~ O~afP7 O °',~° ~ ~ o°~ ~ Q CPO
!' T i Y T T
?a P»
O
sc a (/ I I/ (\ i/ w / ( _ /
s / /
/ ( ',- ( ( / o I / ( / ( / ( /
w ~ O ~ U cn /
_ = z N ~ N
i V ~ ~ U U U U U
Z
_ N _ O _ _ _ _ U
C~ c~ Z U Z =Z =Z ~ =Z ZZ ~ =Z i~~
Z
U
\ / \ / \ S \ ~ ~ ~ \ / \
_a~
0" c0 C- CO 07 O .-., N M
C
1 M ~'7 cY7 C9'7 cr d' d' V' W

Table lI
N O~
r ((~
r0 ~ l~ M~ CND
OD CD n 1~ ~ N CC CO
(~ fn fn il3 C7 07 Cn f~
!'~~ N M M ~ OS
.-,~' M C9 6'~5 t9 Z ~ N CV
C ZZ ZZ etao zz I I ti: ii f I = N o M~cc Mui~ci toy ~~~ri ozz ozz ~'" ozz Sri ui ~a~oa'to ~~~ Zz ~.rno W O ~ ~ O c~°o c~°o ~..- r.
O cc o5 z .. .. z .. .. orr zmm ~~,UU NUU Z~~ ~jUU
~ zcn ~' ~ ~m UU
UUti UUti ~~y ~ UUti U U ti ~m ~ n ~i~D r~3 ~ ~ N
Mr Iwr M tCr M M M M
rr rr r rr r r r r > eY CC e! et O aD le Qi et ~ T N u7 01 O C7 N N M N P. d' r et t0 CS tp N tn In In I~ M rw M (D r f~~ M r tD r t~ r f~ r f"1 r r r r T 1~ r r r r r r r r r r "'y~1 Gf et 115 n d' ca GD N
r N r r r r r N

O r V ~°. ~' ~ ~t ,i ~ ~ aMO aMO
r N r r r r r N
~"~
z dE P,' P.,' Per t~' Ct~ ~ P'r iY, O
ao I
I~ (r (~ Ir i~ I~ it r r i x I r I r I .~ I ~ I w ! s I ~ r r r U O U O r m w I eL z u. z z w I
, , , , N N
U U U U U U U U
N N N N N _N
M M io M 07 M
U U U U U U I , I i ~r m cc ~ 00 0~ o .., k Z ~ ~r tr ~r d~ m ~n W

Table 12 N f~
lI5 d' cD ~O ef eF ~ f~'J
r r r r M F3 ~O ~G ~ N
OzZ ~ZZ
w i i z c~ i ~ ~M~ ~c~V
N ~ t!> O dw? ~ et M
a~ Q = = N= = 0 et ~
O m tLi N GC CG
Z ti') tn z ~f! ~ ~ ~ tl NU U °°U U z_ r.: n.
Z ~ c 2 ~ c U
UUv° UUii Z ~ c~
U U li ~ c~'o ii c~~~ o .Nrn c°o M
C'9 Ln r Ip r (~ G~ C~ ~ r n r r r r r r r r r r rr ? In CO r O ~ f'~ <O e1' C1 tn CO r V~ C9 r Is N
~D Gfl O~ tn ~' N et ~O et c0 -_ __ ~'Q V' N
~r ~~ ~ ~r (ar ~r ~~ ~~!"
r r r r r r r r r r r r r r r O N tn O O O M
co T o9 a~ r a~ ~t r r r r r N N
b 47 r ~ ~ ~ Pe ~ N
r ~. ~ O O O N
z P: P: C~ c~ P~ ~, O
/ ! ~ I / ~ / y ~~ i y w w ~ ~ / I
I/ I (/ I/ U ~ /
/
U
Z Z Z
v Z ~ u7 N N
Z ~ ~ _ U U ~ V U
U U U U _ O _ x w w ~ ~ =z xz - ° z =z -I / p p U _ _ - -\ / \ / ~ ~ \ /
N M ~Y' ~ c0 t~ 00 cn C
x ,~., tt) tn ~ ~ tt~ tt7 tf~ t17 W

Table 13 'wC O '~O,V tJ '~0....~ nj 'gyp... ~ ~ ~ tt'j CPO
M ? Z . Cs N ~ N N 1~ CV n ~ N Z .~- N
a _~~ _~ _~ ~ _~ r:Zv~ =a E
r r ~"' ep Tl1 N f~~. ~ N ~ _ ~ _r = f;D _ ~7 ~t N .r IMO. CO
M ? ~ C~ ~ ~ = N _~ _ ~ (Cj = e~. (h _ ~ _ O r '_fl t~ N
$n' ~ r ~ M
r r r ~G ~ ~D
t- N ~ ° N °' z '°- r°.'' i N
°° ~ ~ ~ a sr m = a r~ ~ ~ ~ -~ n ~
? .~ _ ? ? ~ r M M ~ ? d' ~ c? _ r 'C r r ~ 'd r 1~ ~ ~ r P' _ _ ~r ~ C ~ ~ O ~ m N c0 O ~ O ~7 ~ _N ~ v_ ~O N
mm~ ~~~ P~M PN PO~ M=P P
II it Z N ~ P ~ M N ' '~ CV r C9 nj -7 <G N ~~
N ~ Ot~ N "~ r N
P N vt N d~ N et N sf N' M
M ~ 1I~ K ~ t tar MM
tn r ,,r r ~ r ,- rr rr rr ~,In- (MOB ON PN ~N
C'7 M f9 f0 M
r rr rr rr rr rr ~' CV r N t~? <O tn t1D t0 '~'t O tf) 8~ P~~'CO ~ t'N' Om O ~_f5 ON mCh rN O~ rpp rr Mr Mr ~~ ~.~- ~r c~tt C~ r C~~7 ~
Z
_ U ~ M r _ r Z .~~ o ~ I m I I I I
.. ..- v N GL ~' r x x ~ x Iw Iw Iw Iw Iw Iw Iw Iw i i ~ s i i i 0 0 0 ~ 0 0 0 0 wl w! wl wi l~ I~ I~ I~
_N _N
z V U Z
U U U M
U
U U ~ xz -. v x 1 ~ =z xz ti ~_z / \ xz ~ ~
/ \ ..- / \ / ~ / \
U
d o.-iNC~dmncot~

ca co co co ~ cc ca ca W.

Table 14 i '~C~m= ~ o.~ ~ W ~ r ~ W
~ 'n N o co r ao ~" ~ = z E _ao r ~!~~ c~?r=-.g Z '~~ N c''? CD Z S
r = v. f~ r N
W
c, ~ ? ~ °~ ~ oa ~ ~° ~ = E E
oMO :'~ ~ °- r~ ~ ri N
...~ to~'?co N~_'?= ch =_.p Z ~ ~? ri = N ~"~ N OD
r r CO r z Z N N 1~' O = _ ..~ O
~C ~ N .~ N S = E '~ O = 0,9 r N =
C9Z= h=COD E pj ON~ rte- it1 N
~ c'~ _ ~ ~ Or ~ r n 'p r ~j W ~ N c0 ~D ~'° c0 = II M W Z
CV~W ODN= ~'7 Often NM M? ~~ r t~ n. pp t0 W W nj N ~ 1~
CV ~ CD CV '7 ~ N ~ ~ _ ~ et M l11 ~ N
M r N CD
M
cu~''~ ~' ° aWO cMO ~ ~ m~ o~
c~ m ,~n° ~ ~ ~ v I,n v .- m r rZ r r r r rr rr ~ r e! CV CV N N M tri M N eF f~ ~t N W OD oD CO rfi N ~ W h.
iw M ~ 1~ r tn f0 ~ r 1~ r 1L7 r ,~~, '', r r r r r r r r r r r v~ 00 mr ~N Or ~aD ~"'f~ tflt;C NN
h. M N I!7 N t47 N 01 C~ W N W et et O O N M P: r t~~ N I~ r N r h r- f~ C7 h"~ ~T ('f'r rr rr rr ('r rr rr NN et CO ~r ~r triQj ~pr r('~ LnW 1~M OM rN WCD
d, r' cC ~ C~~ M r c,Ni,~ T ~ M st Cr7 N LA
Nr r Mr Mr U
,..~ o ~ ~ ~ c~
r I i I N
N ~ ~ O CO O
T' l'r' N
_ab c~ x c~ x \ (\ ~\ ~\ ~\ ~\ ~\
s / / / / / / / /
N
N N
U U = V _U U co U
Z
U _ _ UN M _ =Z U
\ =Z ~ U ~_z / \ t ~
/ / \ / \ -- / \ / \
U _ $ L-( U
o ~ cv m yn co e~ z co ca co cca co ca c~ co t~

Table 15 (o r N
N N
r !~
Cj T
I M ~ I
d N= I
oOhO~
W Z t~pn. ~
N<3 U
c UUu°.
.~ ON Mr M
tMf7 N f V i.a r r r r r On.
T ~ M r'~ r r r r r r r r O
I I
tL *
O
OC
I , w w i~ I~

I ~ ~ w I~ I~

z _N ~ _N
U Z
U U Cj U
_ N _ O
- O O
x =z ~z Uz v o ~ o v o ~z x W

Table 16 _ __ Z m~U
N ~ r 0 V IV ~ W N ~ NV
.:-, x~x E =m~.
m m NQN
I i CO O~ tf1 :n. ~D N
N ~ N oo cu ~~ o =
a o~i= ~_~ N - o?I:m C4 p - -,~ - n p r W
M = ch ~. h "N~ N NZ9 ~r =O'~ I
N PI P x ~ _ ~ I r .- Q
Em ,~', ~~~ _~~ on ~ii~
N "N C~ C7 x 1~ x _N n ~
e~Om~ fO~r Il r x~~
tp CV ~ 11 N V E r ~i_ __ ..~r'~C ~ E ~.
O N N
0~D ~ r~°° ~ ~ C~0 = N
E x o cei x C n ~ C tV CD tV E Ip c~j h O N
r COO W ~ NO .S? tN lOl1 ... ~ r I O N I
ooc~ o~ ~V oc~
W.. N .C'7- N ~ p N~ N M
_ N r N r N
x C9r Mr ~N C'~r p M
r U °' ;~ _ T co Q _ _ x b ~ °~ .o .n 1 ~ I
N O
N C1.
p x !~ ! ~ °_ I~ I
t x tx N U U
z U U ! i O
p U
N N
N N () _ U U U U
=Z / xZ
i ( i ~ i l \ ~ ! l d ...
a' .~r N tYJ Wit' tf~ cD
C
h n N N n n W

Table 17 c~ Z
P r., O
P ~ ~
_ CV '~ ~j Of C9 4i ~. ='~D~~ N_ G ~' p. tf7 rQ U~ = CO r N m ~
~ ,~., et ~_ ~7 = ~ r f'~ _ "O st N u:
,~ P r 6O th ~ r tn pj In r f~5 O
CO = ~D to ~
~~~_ ~_~
~ r ~ N ~r N
O ~ ~t N '~ CD ~.. ~ O
N O M
N O
r P1 M~
L r L
r .a ~, O N O aNf7 ~ O N r '-' ~,' N r N s O
O N O ~
M~ ~r Z
z U O
~~ * O ~. ~ O
Z .d CO W ~
O
N !3~
N
x N
Z
U
U U _ SZ
_d °' ~ oo a~
d ~Z n ~ n x W .

Table 18 ,-~D r. _ ~ ;-~ -i'~ ~ ni 1~ ~rj ~~i = ~_., x ~ n1 wN~- cvi~U ~xU xr ~c'!~- -~xr CV x N ~ W a = ~ LCD ~ ~ 'O ~ r ,N~'~U r6r7~ ~" .. a 11N ~(~ N
N~aD N~ NaDZ =~~ ~i ~~ 101 pail ~ P
pj II E '~ x .:d O_ tA ~ '3 °7 ~ V' I -"D r Rj r ~ x ~ M
o, m u'° ~.t E o?= T~~ Nc~r G1 t~ ~ ~ ~ CV N ~ Is fp ~ C'7 = x x .~~. O ~ ~ r Q ~ .-r C'r~ m .:
coG ~o= ~_z~ ~N~ ~=E t's= z== ,x,.o 0 N ..~ N. _!~ '~ '' N COD, r d N N ef- I' ; C- C-,~ N = x=x =x ~p~~_~p ~p~ ZEN rZ= ri ~CO
_=N MOD ~ !~'Y°~.p r 11 °'_ ~'~~~.ju7 N'"r I~j M pj CD N C"7 IV N O r x '7 h =x0! ~.r_~ x~= t~~jr- ~~'= nj~~ Ilx~ G)M
nom ~d r r ~ 'V II r 0a~~ ~~r ~ $ ~;
II ~ _~ r' r E = X11~ V Q? ~ 1I yt ~p 'D M O OvD ~r ~O~ ~~x ~et1! N~~ O~~ ~ '~~~f tDM'~
r w Cr9 v ~ (p P7 ~ J '~O r CO
O~N ~~ r~
C ~ ~T_ O t~ Cx0 O 'CJ x N N N N N N II p y..l T
_ ~ ~ ~ ~ N ~ !H
N
N O ~ S? ~ ~ r r tC9 CO
s~~ M O ( 7 x ~ : - O C~ sf f~ -_ -. M~ tN ~ N M
,~ U O r OD tf1 C) tn s_' '_~ v ._~
00 ON ~~ TT rr O~- ON M N
~ M ~ .~~- O In N N ,M- ~ O ~ ~~r c0~1 H
_ _ _ _ O M_ O ~' M ~" M r C9 r O I!'1 O r .~.r LO
Nr x Cph OM ~~ NC7 Nr N.M- Nr Nr U ~
N
x ~~ r - ~ ~ ~ i i v z ~,~ r 'o ~ N
N ~ N ~p A ~O
r E_D
t9 x N
~ Z
a / N N (n z V
,~ « , , z o Ie wl U U
U U
N N fV
x x r x 2 T ~ U U ~ Z U
_ U U U _ _ U U _ x w w w xz xz i a xz I ~ I ~ ( ~ / \ / \ ~ I ~ I / \
~ ,.-~ c~ m ~r cc c~. oo cn d kZ ~ r' ~ ~ N
W

Table I9 ,- co so ~n eri iri m n. o~
O~~
I I ~ ~ ~ I I
v U
Qv~v Q'U f7 ~i UUu°.
~ yn .- c~ m w ,-T T T r T T 1~ T
P
T r P" 1'~ T 1~ T T P~ !~
v p d ~ _~ N
O b ~ ~ A N Q
U o. .- r- cv ,-.
~!
Z
Z ~ t1,' ~ a; f.~ C
N
~_ / \
a ti o o z' o z' cn f \ / \ / \
m N N N N
N U U U U
Z
U _ _ _ LL' ~ =Z =Z =Z J SZ I
_ ~ -\ / \ / \
_a~
A' p .-r N M d' C

k W

Table 20 N ~ O N =af ccr = N
~ r ~ '~" Z
CNO~~'.= ~ ~~ ov'~
r ~ II
NZ~ NOMDCO ~aiv a Z ~ ~ C~ v Z ~
r N _ N
= O h N CO 00 cV ~
t0 ~ CO Z v n; = m Z
M = f~ tf) M = ~i H, Oj ~rj = r ~ N
N _ ~j ~ p o~
CO r., ,7~= W==O t~iZZ
_~ _ c~ iii ~ ~ ~ ~ E n v~°r NC~C'~ fOr~ unyl~~
N in O
M
M ~ O
M CrC N frD M
~'. ~ ~' r ~ e- (~7 if7 a, O('~~ Or N r N r O e_t OcM~ O~
P~ P~ Nr M M r O et P tD
Mr Z
_ O ~ O N P
(L---~ * ~ .. ~ P N
N CD f0 r P COV
N Cv I\ ~\
Z
ac Z Z ~ S
Z=
Z
\~
Z Z Z
_ U U U
I
/ / \
a~
c.' m ce r.
d era z o0 0o cc x W

Table 21 ~..:~ ~ri~z v~~= ~~r a rn '0 M M
II fj O O _ ~.r tp 7 = Qy frj r N O
GV 'C r C~7 ~ Cn '~a O r ~ CO ~ N ~ Z
ø,~ N~7 rv~ =~O
=O('O~
Q"'' A rj = 1t9 O M ~ T " aj ~ r CO C~ ..~ .~.~ Is 'fl _ N r ~ Z M eh Z
rO
r r r Ch N
II =
r r L~ r O~ ? T
~ tf7 ~ '~ t' ~ N C~
I° .o ni u~ ~~?r N
lO
O
N t0 M
O
r Or r ~ r r .Q r ~ Q~ O ~r r V O ~ n°' ('~
Mr (~rr ''' ~ Mr OM ONO
N IMO. CO~ N (~G
OC~1 N'" NM,°
V'(O
Nr U
~~
v ~ r ~ N
d N v ~. O O
r N
W_ (\ \
/
z °_' 2 Z zx c~ z .- I
zx ~w /
Z Z
U U U
y ~a i i i Q' m :a c co co w Table 22 ~ca u~
~o p .,~ p P r r e~ r ca efi tIj cf) M 4'~ N N p .a.
r r r r i. ~ L
1N~' P
m In In ~ 09 CO O apQ' O
.~ZZ zZZ ~c.~t~
C'7 r r m ~ °~'~'- ~~c~o UOOC~
a a so co p ui ui ,~
Nx x Nx x O C7 In ~ M M ~!n 1n i~ M C?
W O~~ O~a ~~x z u7 u7 Z ~n tc7 0 ~ tND.
NU U NU U z x gj C x Lj C ~' st ~
~~ a m~ o °'UU
UUu. UUtL = ti UUti v~
r rr r rr ~ N t~ c'~il N tpp C~~ N
t~ N t~. f3 h r P~ C~
~r rr rr rr O ~ r r r f~ CO
U
r x z o ~ x x x cc ~i ~i ~i ~r x zx UO Zx Z
Zx tn0 ~x w \ ~~ ~ .
m' N
N
U
N N
fx xZ
U U
\ %
_a~
a. o~ ~ c ..-.
d ~ Z ao co cr: o:
W

Example 92 (Method B) HCl = Process 1 ( ( n Process 2 iw. - Br~S02-N COOMe --H2N COOMe S

Me0 ~ ~ - ( ~S02-N~COOMe Process 3 S H

V
Me0 ~ ~ - ( ( S02-N~COOH
_S_ H
Ia-2-1 Process 1 To a solution of D-valine methylester hydrochloride (XV-2) (755 mg, 4.5 mmol) in dichloromethane(12 ml) was added N-methylmorpholine (1.49 ml, 3 X 4.5 mmol) and 5-bromo-2-thiophensulfonyl chloride (1.24 g, 1.05 X 4.5 mmol) was added under ice cooling. After being stirred for 15 h.at room temperature, the reaction mixture was washed with 2N HCl, 5% NaHCOs, and water. The organic layer was concentrated in vacuo, and dried over Na2S~4. The residue was subjected to silica gel column chromatography and the fractions eluting with ethyl acetate / hexane = 1/3 were collected and washed with n-hexane to give 1.32 g of the desired compound (XVII-1).
Yield 82 %. mp. 109-110.
Elemental analysis CioHiaBrNC4S2 Calcd. : C; 33.71 H; 3.96 Br; 22.43 N; 3.93 S;1 8.00 Found : C; 33.75 H; 3.89 Br; 22.43 N; 3.96 S; 17.86 [ c~ ]n : -34.5 t 0.7(c=1.012 CHCla 25°C) IR(CHCls, v max cm-1) 1737,1356,1164,1138 NMR (CDCIs, b ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz, 3H), 2.00 (m, 1H), 3.60(s, 3H), 3.83(dd, J=5.2, 10.0 Hz, 1H), 5:20(d, J=10.0 Hz, 1H), 7.04(d, J=4.1 Hz, 1H), 7.32(d, J=4.1 Hz, 1H) Process 2 To a degassed solution of 400 mg (1.12 mmol) of compound (XVII-1) in 5 ml of dimethylformamide was added 222 mg (1.5 x 1.12 mmol) of 4-methoxyphenylacetylene and 21 mg(0.1 x 1.12 mmol) of copper iodide (I) under an argon atmosphere.
Then 39 mg (0.05 x 1.12 mmol) of bis(triphenylphosphine)palladium dichloride (II) and 0.4? ml (3 x 1.I2 mmol) of triethylamine were added to the reaction mixture. The resulting mixture was degassed and stirred overnight under an argon atmosphere at 50 °C.
The reaction mixture was diluted with ethyl acetate. The organic later was washed with 1N HCl, 5 % NaHCOs, and water, dried over NazS04, and concentrated in vacuo.
The resulting residue was column chromatographed on silica gel. The fractions eluting with n-hexane / ethyl acetate = 2l1 were collected and recrystallized from ethyl acetate / n-hexane to give 392 mg of the desired compound (XVIII-1). Yield 86 %. mp.
131-132'C .
Elemental analysis CisHziNOsSz ~ 0.2 Hz0 Calcd. : C; 55.51 H; 5.25 N; 3.41 S; 15.60 Found : C; 55.80 H; 5.I9 N; 3.38 S; 15.36 IR(KBr, v max cm-1) : 3268,2203,1736,1604,1524,1348,1164.
NMR(CDCls, b ppm) : 0.90(d, J=6.6 Hz, 3H), 1.00(d, J=?.0 Hz, 3H), 2.00(m, 1H), 3.60(s, 3H), 3.84(s, 3H), 3.86(dd, J=5.0, 10.2 Hz, 1H), 5.21(d, J=10.2 Hz, 1H), 6.90(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).
Process 3 To a solution of 407 mg (1 mmol) of compound (XVII-1) in 8 ml of tetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH. The resulting mixture was stirred for 6 h at 60 'O. The reaction mixture was concentrated in vacuo to remove an organic solvent, and the residue was diluted with ethyl acetate.
The mixture was acidified with aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over NaZS04, and concentrated in vacuo to give 373 mg of compound (Ia-2-1). Yield 100%, mp. 14?-148°C .
IR (KBr, v max cm-i) : 1710,1604,1351,1216.
Elemental analysis C18H19N~5S2 a 0.2H20 Calcd. : C; 54.45 H; 4.92 N; 3.53 S; 16.15 Found : C; 54.39 H; 4.93 N; 3.79 5; 15.96 Example 93 - 156 The compounds which were shown in Tables 23 to 30 were synthesized in a manner similar to those described in Example 92.

Table 23 mo nco ~ ~r mm mm mm v~ cry b~ vi ire ira 'm ~ ~ c'~o, aNO m r°~~
,Wn cri ~ ui ca co ZZ OZZ OZZ
I ~~ i f I 1 =N~ = o~
'~ef~ ~etsf ,n; ~'~ ~ ~'°o rn '*M ~
W Oiri~ri O'~~ O~'c mo 2 .. .. Z .. .. Z .. ..
<<""U U NU U ~;,U U
UUt° UUti UUti o cn ~n co rr oM cap MM
i cN°~ c~~a ii n~ ~~ oc_o c~_~
V r r r-_ r rr rr r_r rr d'O OM ~~ ll~M mO
Och ehM NM C9 t0 rN N1~ O~ thN
tnr I~r ~.r ~r I~f' 1~(' hM 1~C9 H rr rr 1~r rr rr rr rr rr v Z ~ ~ N N rte- COO O p r r ~ P
M i_p N
O N N r ~ O
r P t- r a T
~E p', G~ P.' p.,' W' Q'. 0~ A', O
cc w ~ .~ ( / ~ ~ ~ \ ~ ~ ( i U /

U U U III (~ U
y III / U
U ~ ~ s /
\~ O \~ \I \I \I
z z V ~ O ~ Z
Z Z
= r Z 2 S Z I Z
U U U U U U U U
f,L =Z =Z ZZ ~ =Z ~ =Z =Z s =Z ~ =Z
~i ~e ~l ~i ~i ~i ~i ~i o M ~ ~o c~ r. oc o~ a ca Z a~ c~ a: o~ a~ a~ a~
x .a w Table 24 et P M us om~ rn a~
to cc n: ri _ i~ in cri fri ~°~ o O ~ r co co co r:
OZZ OZ~
=o~o~ I i 1 I =~M I I
N d. cY ~- es '~
o== oZ
Omco Oerrs Zc,PC.~o Z~~
NUU ~UU
_ti _ti N cC Q ~ c0 O
U U t~ U U u.
CO ~ ~' et OD 09 P CO CD tf9 h P cD N
In UJ et tn P P tp 07 CO th st M
j"WD P (~ tf7 P h P ((~ P tp P
P Y P P P P P~ P P P P P
_a tD GD an O N CV O t0 tn P ~ et W N AD N
M O M C9~ C~7 t~ O M O C~ P et N t~ N 1~
hC9 r.M h.tr3 COM hM PC~ PM PP
H P P P P P P P P P P P P P P P P
i~ M °- ~ ~ ~ coo V ~ N N N E P N r P
1~ O ~ O ~ P
v N M ('~
N N N N ~ ~ N
~~
Z
# F~' f~ !x 4~' R~' R~ ~,' R;
O
ao it I / I /° ( / z I '- I ~ I r I
\ \ \
N
U ~U U O IU IU IU IU U
U U U U U U U IU

w I w I w I w I \ I o. I s I
Z IU N O O N Z
g = = O
U U U U
N N N N
fx =z =z =z =z U U U U
0 0 o r o a o i a, ~ cV e~ mn ct~ P op ~z ~ ~ o c o ~ 0 0 x .~ .~ .~ .-. .~ '-.~ r, ,-, W

Table 25 et N
~.. h h r tn tn N c~
O O C~ Gh ~~ ZZ
M~
ZZ ~v~
i i =o0 1 I I Oiiu: I
l'~~O NhOQ
= M C' d r==
' c~ ~O M eh ~
_ ~ M M O
W Q of Ci U3 Z "~? ~!r? 0 eh co _c""UU Zvv ~U U
UUu°..
UUt°i tD tn tn W CO 00 O h r t~7 ~' N h N
tn cp sn en N o0 c0 tn t0 O m O N7 (~ r r ~ (~ (~ r (~ T (~ r rr rr rr rr rr rr rr r > '~ O Cn ~! t0 ~ O C1 N ~ tf9 CD P. Ln t~ Oi CD N
Nr NCD rOln ChN M!f Nt9 N~ Nh h (h N~ M h CO r h C9 h. M h M h M h r I"y rr rr rrr rr rr rr rr rr w I~
r tNp ~7 M ~ m m r ~ r r r r r U''~ ahoroo~i ~aMOm r r r r r r r oC-z z ~ ~ x x x x w x x N
W_ ( ~ ~ I I I ( ~ ~ y / I/ / I/ s 111 U ~~ ~ Wii U
U p U U U U iV U
wI ~I wI wI wl wl ~I wl U O Q O U O
Z Z Z
I
I U Z Z Z I
U" U U U U
M
G~ U U U U I / I / I /
co Z
U
a~
C, C C7 ~ N M d' ~ CG
~z .-I r. r-, r.. .. .., .., w Table 26 r O
rr Il1 ~
c0 M M
OZZ
= ON7 ~
N~~
w Z vc1 tn °' U U
Z ~j C
~~ O
UUu.
~m C~~~ r~ N1! ~T cNOr tnD~ ~N
V O r O r C~ In r rr_ rr r r r_r r r r r r r > O O '~ CO tn C~ tn O et CD r M O) O p'r NrN(pCOInO'~OMNMNafi t0 h t~3 t~ M u7 r to C9 ~O M 1~ M t~ c~ 1~ M
r"i rr rr rr rr rr rr rr rr a a°'o:f c°'c oaNO'~v ~ r r r r r V'v~'~:-coo I I o°mw r r r r r r ~~
Z
Z aF i~ tx C~' F.~' tY f~ f~ C~
O
ao \ \ ~ tn .-, ~ U1 / fn U ~ IU U tU
IU tU U U U pi tU U
(x U I t I iti N U
O
y i ~ U ~ I z y .i ! y w I
\ ~ \
U ~' O U O
Z ~ S tL Z Z
T Z Z Z x Z
U U U U U U
_ U _ _ _ U
N N
=Z =Z =Z i =Z ZZ =Z Z
U U
/ ~ / ~ / ~ /
t~ 00 Q~ O ~-i N M
N N N N N
~z .., .-~ ..-~ .-.
w Table 27 M P
P N

r T T P
fn U3 fl3 Cn N ch M !9 ZZ
ai ch c7 M
ozz ozz zr° I i ~'v I a ~ I t I
C, N tn In N ,W t ~xx ~xx ~o ~ ~ O ~ C~e» !~ G~
o CO h o Of ~ Cn ~ ~
WUU ~tUU
z ~0 00 c wn z ~ = u. .. ..
UUu UUti U U ti y°n rnc'~o ii N ~o V ~ ~ r- M_ _C9 _~C _r-N ~ O tti tci d' O O d-!P I I I
~- r r r P r~ t r r-w n tn tf1 1n ~O tCD
T T T T T
o '~W i ~ ~ r us I I I
U cc an r P r ~~. a x x x c~ x x x x ac cn ,.- N ~ = cn -~ cn ~' ,~' i \ ' zN
U
tUUtntVUi~~s U in U V W V
U
V / U ~U , iie l U
\~ ! \I \) ~ ~ /
\ \ ( ~ ~ = V i t1. ~ Z LL x x Z Z = Z Z ~ Z
U U U U U U U U
N N
U U ~ \ ~ \ ~ \ ~ \ y y % / / ~ ~ /
d is, m co N aQ o: o r., N
N N N N N M M M
k ~ ~-n .~ ~ .-r .~ .-~ ..s W

Table 28 G
i I I i I I I i a a !~
a w I I I I I I I I
...
s~
I i I I I 1 I i i~
Z
z ~ x rx x ~ c~ sx t~ x O
_ao w \ ..-' 6n / ....- ~. s \ Z 4 ~ w Cn t//~
s I -~ U= U= U
U ~U U= U= ~U eU '~j ~U
R.° m U U
U y ~
Z \
U \ \ \ \
io ~ Q
U ~ u. sn U
z Z Z Z Z Z Z Z Z
U U U U U U U U
\ \ \ \ \ \ \ \
ø, ~ M ~' tf~ Cp h GO Q7 O
M M M M M M M
rr .-~ .--~ .-n ..~ .-~ .--i .--n W

Table 29 m .,., m is C
m I I I I I I I I
d i~
_a>
W
I I I I I I i I
..
ice' cc a.
o .-.
t I i I i I I I
..
x z ~ x t~ x x x tx x N
r i i ..i ~ \ ~ \ ~ ...r \ \ ~ \ \
U U
UUUm,C,~,U,V~V
y ,ti y U U ,~ U
el ~ ~I ~/ I ~ I ~I
( U U
° ~ O 0 w ~ x i i i i i i z z U U U U U U U U
I i I i I I ~ I
i i i i i i ~ i d p, ~-, N M C" t!7 CO h. 00 m Z ~ ~' ~f' a' C 'd' C' ~f' X .~ ,.-i .-, ,~ ~ ,--~ .-y ,-i W

Table 30 t t I t I t t t a a~
w ..
i I ( I i I I t ..
'~ Ci.
I~
o ..
~ ,~~ i i i i i I i i .r z 0.'f~t~P~P'.~0.'~.
O
cn r-W- ~ --v U U
n n ~U ~U 'U U U
U U U U ,U !U
~- ~ r ~ ~ ~ ~ r ~ r N
m U U U U U U U U
a ( ~ ~ ~ y y r r r r , r i r Or C: O .~w N M ~' t1) c0 C' tf~ lf~ Lf7 tf~ in tl~ tD
.-~ ..-~ .~ .-r ~-~~ ,-t .--i ,, Example 157, 158 Me0 ~ ~ - ~ ~SO -N~COOMe Pr°~ss 1 ~
~S 2 Fi -XVIII-~
Me0 ~ \ - ~ I S02-N"~COOH
Ia-2-66, a-Ia-I 2-6767 Process 1 (Rz = CHs) To a solution of 150 mg (0.33 mmol) of compound (XVIII-2) in 2 ml of dimethylformamide which was synthesized the same manner as those described in Example 96 was added 227 mg (5 x 0.33 mmol) of potassium carbonate and 0.1 ml (5 x 0.33 mmol) of methyl iodide, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over NazS04, and concentrated in vacuo to give 373 mg of N-methyl derivative as an oil. Yield 91%.
Elemental analysis C24H23NO5S2 Calcd. : C; 61.39 H; 4.94 N; 2.98 S; 13.66 Found : C; 61.22 H; 5.18 N; 2.93 S; 13.2?
Further, a solution of 140 mg of the above oily compound which was obtained the above process in 2 ml of methanol was added 0.6 ml of 1N NaOH, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was acidified with 2N HCI and extracted with ethyl acetate. The organic layer was washed with water, dried over NazS04, and concentrated in vacuo to give 105 mg of compound (Ia-2-66) (R= Me). 'Yield 77 %. mp. 185 - 186'C.
Elemental analysis CzsHziNOsS

Calcd. : C; 60.64 H; 4.65 N; 3.07 S; 14.08 Found : C; 60.56 H; 4.84 N; 3.01 S; 13.94.
IR (KBr, v max cm~i) : 3600-2300br, 3426, 2203, 1710, 1604, 1503, 1344, 1151.
NMR (ds-DMSO, b ppm) : 2.88(s, 3H), 2.93(dd, J=12.0, 10.2 Hz, 1H), 3.19 (dd, J=14.2, 5.6 Hz, 1H), 3.81(x, 3H), 4.74(dd, J=5.4, 10.2 Hz, 1H), 6.99-7.04(m, 2H), 7.20-7.35(m, 7H), 7.52-7.56(m, 2H), 6.90(d, J=9.0 Hz, 2H), ?.44(d, J=9.0 Hz, 2H), ?.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).
The compound (Ia-2-67) (RZ = CHaPh) was synthesized in the same manner as those described in Example 157,.
IR(KBr, v max cm-1) : 2200,1722,1340,1151.
NMR (ds-DMSO, 8 ppm) : 2.94(dd, J=7.6, 13.8 Hz, 1H), 3.19(dd, J=7.2, 14.4 Hz, 1H), 3.83(s, 3H), 4.29(d, J=16.2 Hz, 1H), 4.62(d, J=16.2 Hz, 1H) (Only characteristic peaks are shown.) Example 159 (Method C) V
Process 1 Br I S ~ S02 H COOMe i- Me0 S S02-H COOMe Process 2 ----~~~ Me0 ~ ~ ~ S ~ S02-N~COOH
H
Ia-3-1 Process 1 To a solution of 500 mg (1.4 mmol) of compound(XVII-2) which was obtained Example 96 in 12 ml of dry tetrahydrofuran was added 387 mg (2 x 1.4 mmol) of powdery potassium carbonate, 319 mg (1.5x1.4 mmol) of 4-methoxyphenylboronic acid and 81 mg (0.05 x 1.4 mmol) of tetrakis(triphenylphosphine)palladium. The resulting mixture was stirred under argon atmosphere for 48 h at 75~. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1N HCI, 5%
NaHCOs aq., and water, dried over NaaS04, and concentrated in vacuo. The residue a was column chromatographed on silica gel. The fractions eluting with n-hexane !
ethyl acetate = 3I1 were collected and recrystallized from n-hexane to give 44? mg of the desired compound (XIX-1). Yield 83 %. mp. 122-123.
Elemental analysis C17H21NO5S2 Calcd. : C; 53.25 H; 5.52 N; 3.65 S; 16.?2 Found : C; 53.26 H; 5.50 N; 3.69 S; 16.63 [ a ]D -21.? ~ 0.6 (c=1.000 DMSO 25'C) IR (KBr, v max cm-1) : 1735,1605,1505,1350,1167,1136 NMR (CDCIa, b ppm) : 0.90(d, J=7.0 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 2.10(m, 1H), 3.54(x, 3H), 3.85(s, 3H), 3.8?(dd, J=5.0, 10.2 Hz, 1H), 5.20(d, J=10.2 Hz, 1H), 6.94(d, J=9.0 Hz, 2H), ?.52(d, J=9.0 Hz, 2H), 7.11(d, J=4.0 Hz, 1H), 7.49(d, J=4.0 Hz, 1H).
Process 2 To a solution of 390 mg (1.01 mmol) of compound (XIX-1) in 8ml of tetrahydrofuran and 8ml of methanol was added 5.1 ml of 1N NaOH, and resulting mixture was stirred at 60'C for 6 h. The reaction mixture was concentrated in vacuo to remove an organic solvent. The resulting residue was diluted with ethyl acetate.
The mixture was acidified with aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over NazSO~, and concentrated in vacuo to give 373 mg of compound (Ia-3-1). 'Yield 100%. mp. :
1?4 176°C
IR(KBr, v max cmw) : 1735, 1503, 1343, 1163.
Example 160 - 1?5 The compounds which were shown in Tables 31 to 32 were synthesized in a manner similar to those described in Example 159,.

Table 31 _ O cG T T p~ O) N ~ ~ ~ N N
Cn U3 op5 O V! CO
°' a~D O
ICJ t0 ~ N ~ (~?
~ZZ NN ZZ
I ~c'~'°,~~ ~ ~ Otn~C! ~O
p p ~t ~ Z In CO et t0 eoZ = T std p W ~oc~ Q~fd; ~~p ~in~ 'r~~ Z'pd'~
c°vUU Zooi °'UU
.. ..
ti '~ d' cS
UU
UC?ti ~~ ~ UUti UUU°.
= n. a~ wn P co r~ M sr ao v ~ M t9 O~ CD ~h O ~O ~ O c0 N
~ ~ !7 C'h ~ T t? sn P ~f% 1n P Cp r !~ P T P 1~ T T T P
> h0 OvR tar ln0 tnC~ M_~ NN Is0 T
cOp~ t~OOr ~c~ ~~ n~ t~.~ Ohm ~:n r T f~ P T 1'~ r T T 1~ r' 1~ P T t~ 1~
CO ~ r. ~ m h t~ p ~ ~ r r N P r~ r O ~ ~ CO t~ 07 m ~ p lD 1~.
0 w O tp <O N f~ m ~ O
' T N T t~ T 1~
Q"~ #
\Z
Z~ WC~ 0.'P',A;P~0.' N
O
m_ /\ / /\ /\ ~, /\
W ~ ' ~ / ~ \ ~ ~.
x ~ \ \ ~ I \ \ I
° ~ i ( ° ° ~ ..~ ~ °
° °
O U cn O U cn Z Z tL I Z ~ ti S
Z Z Z I
U U U U
_ U U U U
t~ SZ =Z~ =Z ZZ = Z Z Z
U U U U
a ~ e!r a i a i O. O ~ N M 'Ct' Lf7 cD h~
cp O c0 cD tp cfl O Cb .-, ,~. .-, I W I ~ I i ~ L I I

Table 32 N '~t CD CO
r e-~N X000 ~~ 00 !n tn 1f~ tf1 (n fn N N
rr rr ~~ NN
fn !n fn VJ et tD Cn fn ~ CO ~ O N t'~9 Ch fM t'~ ~
ZZ ZZ Oco OZ2 i I i I
~f p d' et O O N et it ~ 17 m Cn M h ~ ~' f~ ~ tn p W C9 w ~ 1WI ~ ~7 t~j Cn = ~ ~ ~ L
Z Z ~ N C9 Z
~UU ~'UU Zctitc °'UU
u»
N l6 p N n3 p ~~ U N c0 Q
UUti UUu. ~c9 ~ UUt~
UUt,°~
~m m~ ~~ ~M
r r_ r_ r r r r I I I I
In p _C~'J CO r In O O Lf) v h M t~. M n CO r V' r rr rr rr rrr r CL
O ~
O d ~ co et c~%s I I I I
O v tD lD h. O
r r r N
cc--~ x z Z~~ ~C~Q'cY~0.'0.'~CL
O
m r\ ~" r\ , r\ r In ~ ~ (n flJ Cn v 't m I/ ~/ ~\ I/
Z = 11. Z I ~ ti 2 Z = Z Z Z r Z Z
U U U U U U U U
x W I w ~ w W I w W W W
/ / r i i i i a . oo a~ o .-~ c~ cr; v~ ~n ~z ~ ~ h r ., .. ,-~ ..., .-a .-. ., w Example 176 (Method D) HCl = Process 1 / ~ ,~ t Process 2 H2N~COOtBu "° OzNS02-H COO Bu ~-~-XV_3 XX-1 ~/
H2N ~ \ S02-N~COOtBu Pr°cess 3;
H

MeS ~ \ O N / \ SO2-N~COOtBu ~r°cess 4~
~/ H

O
MeS ~ \ N ~ \ S02°N~COOH
H
Ia-4-1 Process 1 To a solution of 10 g {47.68 mmol) of D-valine tent-butyl ester hydrochloride (XV-3) in 100 ml of dichloromethane was added 15.7 ml (3 x 47.68 mmol) of N-methylmorpholine and 14.1 g(1.2 x 47.68 mmol) of 4-nitrobenzenesulfonyl chloride under ice-cooling. After being stirred for 5 h at room temperature the reaction mixture was washed with 2N HCl, 5% NaHCOs, water. The organic layer was dried over NazS04 and concentrated in vacuo, and the resulting residue was recrystallized from dichloromethane / n-hexane to give 13.38 of the desired compound (XX-1).
Yield 77.8%. mp. 89-90~.
Elemental analysis CisHzzN20sS
Calcd. : C; 50.27 H; 6.19 N; 7.82 S; 8.95 Found : C; 50.04 H; 6.10 N; 7.89 S; 8.84 [cx]D -2.9-~-0.8(c=0.512 DMSO 23~) IR(KBr, v max cm-1) : 3430br, 3301, 1722, 1698, 1525, 1362, 1348, 1181, 1174, 1159.

Process 2 A solution of 13.29 g (37.08 mmol) of compound (XX-1) in 200 ml of methanol was hydrogenated using 10% Pd/C (lg) for 2h at room temperature. The reaction mixture was filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized from acetone / n-hexane to give 11.5g of amine derivative (XXI-1). Yield 94.4%. mp. 164-166'0 Elemental analysisCisHz4N20~S
Calcd. : C; 54.86 H; 7.37 N; 8«53 S; 9.?6 Found : C; 54.84 H; 7.33 N; 8 63 S; 9.50 IO [ a Jn +10.3 t 1.0(c=0.515 DMSO 23'0) IR(KBr, v max cm-1) : 3461, 3375, 1716, 1638, 1598, 1344, 1313.
NMR(d-DMSO, b ppm) : 0.80(d, J=6.8 Hz, 3H), 0.82(d, J=6.6 Hz, 3H), 1.23(x, 9H), 1.83(m, 1H), 3.30(m, 1H), 5.86(s, 2H), 6.56(d, J=8.8 Hz, 2H), 7.36(d, J=8.6 Hz, 2H), 7.47(d, J=9.6 Hz, 1H) Process 3 To a solution of 328 mg (Immol) of compound (XXI-I) in 10 ml of dichloromethane was added 0.33 ml (3 x 1 mmol) of N-methylmorpholine and 280 mg (1.5 x 1 mmol) of 4-(methylthio)benzoyl chloride under ice-cooling. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added ethyl ether and precipitation were collected and washed with ice-water and ethyl ether, The solid were recrystallized from acetone / ethyl ether to give 433 mg of the desired compound (XXII-1). Yield 90.5%. mp. 235-23890.
Elemental analysisCzsHsoN2OsSz Calcd. : C; 57.72 H; 6.32 N; 5.85 S; 13.40 Found : C; 57.63 H; 6.28 N; 5.86 S; 13.20 [a]n +5.7~0.9(c=0.512 DMSO 25~) IR(KBr, v max cm-1) : 3366, 3284, 1713, 1667, 1592, 1514, 1498, 1341, 1317.
NMR(ds-DMSO, s ppm) : 0.82(d, J=6.6 Hz, 3H), 0.84(d, J=6.8 Hz, 3H), 1.22(x, 9H), 1.91(m, 1H), 2.55(s, 3H), 3.32(s, 3H), 3.44(dd, J=6.2, 8.6 Hz, 1H), 7.40(d, J=8.6 Hz, 2H), 7.73(d, J=8.6 Hz, 2H), 7.90-8.01(m, 5H), 10.48 (s, 1H).
Process 4 To a solution of 405 mg (0.85 mmol) of compound (XXII-1) in 3 ml of dichloromethane was added 3.3 ml (50 x 0.85 mmol) of trifluoroacetic acid and resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was washed with ethyl ether to give 340 mg of the desired compound (Ia-4-1). Yield 94.? %. mp. 231-234'0 IR(KBr, v max cm-1) : 1748, 1655, 1592, 1323, 1161.
Elemental analysis C19H22N2OSS2 ~ 0.lCFsCOOH
Calcd. : C; 53.14 H; 5.13 N; 6.46 S; 14.78 Found : C; 53.48 H; 5.31 N; 6.57 S; 15.06 Example 177 - 208 The compounds which were shown in Tables 33 to 36 were synthesized in a manner similar to those described in Example 1?6.
?3 Table 33 0o n n~ cTn ~~ '~'° taco Nr Or '~ '~'tC .fn U7 NO
efl cti t0 cC cD c0. eG ct1 m ,Ma, :u :V
Cn fn Cn tn C~ ~ (/j fn N
~m N~ _.. ~~ n~ ijCOC Zz p0 OO OO
~ZZ Ozz OZZ Ozz _.t_et ~zz ~O)O NetN NmM ~cOO> ~ ': L:
xNt~ xcoN Zit T ~ /,~, °' ~xn : x= °_= inNCs omo N=Z
Do~o~ ~s~n~ i ~'a'n~ Ocaoo gist ~uo~~cc~~o~
W ~,ccai O~d; O goo ~=s Own Z tn In Z In U7 z ~ ~ O r M
g,C?CU NUU '~''UV Zrr ~°''UC) = ci c x c x c x ti ~ ' ~ ~ Z c N f6 Q ~t V J t0 V Q N ~ ~ p ~ V 7 N cL3 Q N lC p N U U N Rf p UUU. UUu. UUti UUu. ~~ c~ UUu.
U U u°.
c~ cn n co a~ rn co c~ o~ to n ao co c~ c~
~ st t0 t!7 n t~3 sf N O !n M tn N <D r 10 N
V y~ Cfl r Cfl t Sp r t0 r CD r CD f'' iD 07 CO C~
r r r t r t r r r t r r r r r r ci .= co co ri ..: vi o cv of ~ .= o i: o sr aci ci c>
t~7~1' NN Nm rd' MO-._. __M~O N071f~ N~in ne~~ nc~ nch nco nc~ nint wnr nunr H rr tt rr rt tr rrt trr trr td °' n .~. ao M co ~ oo a~
0 ~ N C~ r r M d' r et' N N N N N N N
O d ~ tn Ch CD r ~O O In d' O r r c~~
N N N N N N N N
x Z~x~~t~f~C~P;i~C~G~
N
O
x I\ \ \ I~ \ ~\
\
I w ~ ( / I ~ ~ / ~ / /
zx zx zx zx I zx _ zx Zx UO ~j0 UO UO UO Z UO
'~ UO / ~ ~.~ I / I \ I / ~ ~ O / I
\ ~ \ \
I z V w ~ U U, ' U
x O ~ x Z
Z Z Z Z Z Z Z Z
U U U U U U U U
xz xz xz xz ~ xZ xZ xZ xz \ / \ / \ / \ / \ / \ / \ / \ /
d a, n o5 0~ o -., cJ c~ ~r n N oD x o0 00 00 r, ~ .~ r. r, .-. .-, W

Table 34 NN
m tG M t M t0 m ,~ tt) tn _ O N M P~ h U) Cn ~ ~ . t0 h. ~O t Cl) V) M C~ ~. N U) Cn i~ P~ tG CD CD 1~ 'a' 1~ pw n, r r in lJ7 1n !'n (n VJ ~. ~ ~ ~ = Vj C!) M M
CO c0 t0 ~ M M = N 1n O CO p O N m t0 m tt OOL OCOL. ZZ MM
ZZ c~eo ~ca O~nac~ etm epqp ~t ZZ
CO h. (~ O M O !Y In 07 O
OD1~ ZZ ZZ MZZ O(VCV ZZ ~ZZ NM
Or~r~ ~~ oo Uc°w_~ Ott cc_M Ua~~o- ~v ap O N tL lL
N tL Il ~ et v 'eh M et ~ ~ m m M M 0 ',t et N
zT ZZ °z= tLN~ z= N=S
C~dv ~~~ ~N~ ~~~ ~r)c' ~sca0o ~07P.. ~'ef W ~~~ ~oo ~~ad ~nr. N,== ~ricvi O'nn Oinco Z~m Zyn Z~~ po~co Zm~ '°~~ OrN..
Za~ac ~UCJ ~UU n°,UU zcor~ NUU Z,VU Zoio>
= ci c = ti ~ = cs c '' w ~ _ ~ ~ S c tL wn O O N- O N- O d1 .. .. co~- O tU
NUU ~m o Nca o Nc~ o o~UU No o Nay o UU
z ~ c t,)-Uti UUti UU~ UUti. UUu. = cv c UUu°. UUti UUu°.
tM tN Nh CDtn OM mt0 h~ ~-et In ~7 tn N 1~ N en N h~ M N Of ~O cp M In N
y t0ch t0M t0 t9 COM cDM tou'!t cpM ~DM
tr rt tt tr tt rtr rt rt > ~ OMt Mgt OMO CONC7 M~-1~ Ni0'd' Nr-r tsC00 MOCO NOCO t01f3 ~O>tf! ~C>t0 tI>1nN et0»D MOCO
htDt h.Mv- f~t0t l~Int l~Ot 1~~OM t~.t0t l~lnt p".~ t t r' t t r" t t t P t t t 1'~ t t t t t t t T t t V /~
!t7 O O tf1 M ~t M O
z$~~NN,t-N NNN
p [~ ~ ~ i p~0 etN NNC_0 () a ~ N N r N N N N
z x x x c~ x x x x O
m_ w w w y Ir p w I I/ I~ y i ~2~ Z= I s_' Z= ZT
G~ UO UO UO Z UO UO UO
/ ( / UO ' / I UO
W w w I i ( W W w W
. ~- O N m' O
N
U Z I Z Z = I Z
_ U U U U U U U
c~ zz ~, w ~ w w w w \ / I ~ I / I / ~ i'~ I ~ I ~ I /
a, ~r: ca ~. ~ a~ o ~., cu co 00 00 ~ o~ a~ a~ a;
r. ... ... r, ... r, W

Table 35 c~ ago rn° i°°., V! Cn ~ (n O C1 T T ~ o N ~ et IL) CO I
,~r. ~ ~ M
ZZ xZZ ON rQ O~~t x~~ rV II CMOMG
T N Q M O ~O CO P P. V ~C t0 O O Z P. 1~ t0 t~.
OMr a OZZ OZZ ~ZZ 00~ OZZ OZZ
es! 1~ I~ U~P- 1~ NO ~ N("~ O U M r U~~ tf~ NOD tp Nr- CO
x th tfJ x h~ lD P r M Il LL LL = C~ ~ = 1!f ~
V U U ~yri ~ci N _ui ~ti iri ~ci U_ v ~ '" 1I7 Lf~ ~! tn In e~~i~v °~~ ~~N ~ ~ vix= ov~'~ ins= N~ex~~
~,=x p~''i' ~a>c; Nr~ tn== p~-o ococe O d' O7 O In tn N <O Cfl N tCa t!7 O M M ~ tC N N 1n 1t? N tn tn M CO M M r N Z Z Z in lC~ O CD CD Z Z
NU U N(,j U Z M ~ c°vrU V
U .. .. U ._ .. ~ti ~ ~ti ~ I ~ c ~~~ ~ti ~ ~ci ~
Z v ~ _ ~ c UU~i UUu~. tj~j~ x ty c UUu~. UU~
N RS Q N Ctf Q
UUti UUti UU~
W M t0 N N M th t0 t9 tn t9 ~O 1~ O ~- P
h N CD t~3 t(7 N tn N tn N N 01 ~O ~O .-~~, Cfl M Ct! O'J ~O th CO M t0 M Iw if> ~- ~O !9 t0 !0 TT YET TY PT 1~'T 1~l~P TAT 1~T
>'~ ~hNCO lnNO CDOr ~Nr CpNr O~CON Cprd7 tprUn NQfln N17~t0 d~O~ID ~fOI~C ~MtD ~cGN NG>47 OOfIn t~~ tI> r h. tl7 r t~~. In r- P. In r- t~ 119 r 1~ CO f7 N. t0 r- Cp tn N
PrT T1~1~ l~Tr t~l~r . TTr TPr 1~TP 1~P1~
v x $ ~ N N N N N N N N
O
(] ~ N N N N N N N N
CL
x # G.' P.~' ~' P~ a; R~ C~ 0.' O
ao I w i .- I ~ i ~ l / i w \ I /
~~
zx z= zx zx ~ zx zx VO UO _ UO C70 UO ~o Zx UO
I ,r UO
\ z \ z \ \ I \ ( \ I / I \ I
\ O
U z /I
\ ~ Z x Z Z
_ U U
N N N N N N
\ .~ c~ i~ t~'~ M '~'t~J c7 ~, ( / U U U U U U
d M V' Lf~ c0 I~ 00 Q7 O
O B: O) O: W O~ G7 O
.-., .--t ., ,-i .1 n7 Table 36 N c0 ~ M
t0 tG _ ~ ~V N ~ 1~ M O O ~ ~ ~ C~
h h ~ ~ 1~ t~- ~ ~ 1~ h 1~ t~ _ Cn fn ~j uj tn fl3 = V3 N Uj ~ U~ tn O O tn O
CD O ' Zo Z td) in o ~ N W 1~ ~ h~~
0 0 t p CMp 0 0 U r r 09 ~ ~ 08 p OZZ cm~:cc OZZ ~ZZ ZZ ZZ
~, =c~°p,,~ ,_ ~ ~ =a'~oo ~~c°> ~°n~ ~~ I I
'a' er ef ~ Cd oO '~ ui cc N d. ~ ~~ er et ~
c~~m ~?_= oz= __ =z O ct ~ ~~ N NO O bN ~ ~~ 1t09 W ~oo ~__ ~cccc O~°~ ~aioo yri~ri Z u? ua p co er Z en ~ 'd' m an Z ~r? !r? Z in ~n ~UU ~"'~fl NUU o.... o_,UU °'UU
Zeo° ~ m~'f o-° ~ =__ti ~ _ ~ ~ ov ~
UUti ~UU UUu "'~ Q UUu°. UUu°,.
U U u.
t7Uti OD P. M o3 r 01 M h~ N 07 t17 07 ~ N
c1 CO r C~ In h M !~ C9 CIO r ~ r V x" ~C C9 <O M t!7 r ~O C9 ~D M <O t0 ~D M
rr r rr rr rr rr rr I
? ~ ~pr(p tClNO O9 CO f~QN ~tfl0 Mltt1' CV CVln N W t0 N Cn In tn r N C7 ~D r O (p CQ O 1~ M O tn P. tn r t~ tf1 r 6D f9 IWC7 r I'~ tn r f~. In r I~ In r rrr rrr rr rrr rrr rrr rrr to N O _CD h tt~ ~ O
x $ ~ ~ M M 1w r N N N N N N N
O U~ _st CO N et Iv I
(J ~ N CN~A N N N N N
ct-~ x x Z ~ ~ 0; G'~ i~ P: t~ GY i~
O
_a~
\ \
(/ Is I/ I/ I\ Is 1/ is zx zx Zx zx / zx zx UD UO UO VO Z= IZx VO UO
UO
/ / I ~Z UO Zx /
[' ~..-\ I \ I \ z. I r I ~O i I \ I
U \
o ~ Z ~ Z
o m = x = m i U U U U U
' N N _fh t0 M M
U U ~? J J J I
G, ~-V N M V' t1~ ~p ~ . pp O O O O O O O O
N N N N N N N N
7?

Example 209 (Method E) HCl = Process 1 ~ ~ w Process 2 H2N~'COOtBu -> ~ S02-H'~COOtBu --->
XV_3 XXIII_1 Process 3 OHC ~ ' SOZ-N~COOtBu ------>
H
XXI'V-1 02 H H l o ~ t Process 4 S-N-N=C S02-H COO Bu >

N=N ' Process S
MeS / ~ N,N , ~ S02-H~COOtBu -->

N=N
MeS ~ \ N~N ~ ~ S02_H'~~'COOH
Ia-5-1 Process 1 To a solution of 20.94 g (99.8 mmol) of D-valine tert-butyl ester hydrochloride (XV-3) in 200 ml of dichloromethane was added 22 ml (2 x 99.8 mmol) of N-methylmorpholine and 20.27 g (99.8 mmol) of p-styrenesulfonyl chloride under ice-cooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HCI, 5% NaHCOa, water. The organic layer was dried over Na2S04 and concentrated in vacuo, and the resulting residue was column chromatographed on silica gel. The fractions eluting with ethyl acetate / n-hexane I chloroform =
1/3/1 were collected and washed with n-hexane to give 28.93 g of the desired compound (XXIII-1).
Yield 85 %. mp. 118-120'C.

IR(KBr, v max cm-1) : 3419, 3283, 1716, 1348, 1168.
NMR(CDCl3, 8 ppm) : 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 1.21(s, 9H), 2.04(m, 1H), 3.62(dd, J=9.8, 4.5 Hz, 1H), 5.09(d, J=9.8 Hz, 1H), 5.41(dd, J=0.5, 10.9 Hz, 1H), 5.84(dd, J=0.5, 17.6 Hz, 1H), 6.72(dd, J=10.9, 17.6 Hz, 1H), 7.49(d, J=8.4 Hz, 2H), 7.79(d, J=8.4 Hz, 2H).
Process 2 Ozone gas was buhbled through a solution of 5.09 g (15 mmol) of compound (XXIII-1) in 300 ml of dichloromethane for 15 h at -78°0: To this solution was added 22 ml (20 x 15 mmol) of methylsulfide, and the reaction mixture was allowed to warm to room temperature gradually over 80 min and concentrated in vacuo to give 6.03g aldehyde derivative (XXIV-1).
IR(CHCIa, v max cmu) : 3322, 1710, 1351, 1170.
NMR(CDCla, 8 ppm) : 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.9 Hz, 3H), 1.22(s, 9H), 2.07(m, 1H), 3.69(dd, J=4.5, 9.9 Hz, 1H), 8.01(s, 4H), 10.08(s, 1H).
Process 3 To a solution of 6.02 g{15 mmol) of compound (XXIV-1) in 60 ml of ethanol and 15 ml of tetrahydrofuran was added 2.72 g (1.05 x 15 mmol) of benzenesulfonyl hydrazide at room temperature. After being stirred for 2 h, the resulting mixture was concentrated in vacuo. The residue which was obtained by concentration in vacuo was column chromatographed on silica gel and the fractions eluting with chloroform ethyl acetate = 1/4 were collected and recrystallized from ethyl acetate to give 4.44 g of the desired compound (XXV-1}. Yield from process 2 60 0, mp. 163-16490.
Elemental analysis CzzHzsNsOsSz Calcd. : C; 53.32 H; 5.90 N; 8.48 S; 12.94 Found : C; 53.15 H; 5.87 N; 8.32 S; 12.82 [a]n -1L6~ 1.0(c=0.509 DMSO 23.5°0) IR(KBr, v max cm~l) : 3430, 3274, 1711, 1364, 1343, 1172.
NMR(CDCIs 8 ppm) : 0.84(d, J=6.9 Hz, 3H), 0.99(d, J=6.6 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 3.63(dd, J=4.5, 9.9 Hz, 1H), 5.16(d, J=9.9 Hz, 1H), 7_50-7.68(m, 5H), 7,73(s, 1H), 7.78-7.84(m, 2H), ?.96-8.02(m, 2H), 8.16(brs, 1H).
Process 4 To a solution of 0.14 ml (1.11 x 1 mmol) of 4-(methylmercapto)aniline and 0.3 ml of conc. hydrochloric acid in 3 ml of aqueous 50% ethanol solution was added a solution of 78.4 mg (1.14 x 1 mmol) of sodium nitrite in 1 ml of water at 0 to 5 'C of the internal temperature and the reaction mixture was stirred for 15 min at the same temperature. To a solution of 496 mg (1 mmol) of compound (XXV-1) in 5 ml of dry pyridine was added the above reaction mixture over 8 min at -25~. This reaction mixture was stirred for additional 4 h at -15'C to rt, poured into water, and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5 % NaHCOs, and water, dried over NaaSO4, and concentrated in vacuo. The residue was column chromatographed on silica gel and the fractions eluting with chloroform /
ethyl acetate = ll9 were collected to give 374 mg of the desired compound (~~XVI-1). Yield 74 % .
Elemental analysis C23H29N5O4S2' O.3H2O
Calcd. : C; 54.27 H; 5.86 N; 13.76 S; 12.60 Found : C; 54.25 H; 5.77 N; 13.87 S; 12.52 IR(KBr, v max cm~l) : 3422, 3310, 1705, 1345, 1171.
NMR(ds-DMSO, b ppm) : 0.83(d, J=6.9 Hz, 3H), 0.86(d, J=7.2 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 2.59(s, 3H), 3.54(dd, J=6.3, 9.6 Hz, 1H), 7.56(d, J=8.7 Hz, 2H), 8.00(d, J=8.6 Hz, 2H), 8.10(d, J=8.7 Hz, 2H), 8.33(d, J=9.6 Hz, 2H), 8.34(d, J=8.7 Hz, 2H).
Process 5 A solution of 353 mg of compound (XXVI-1) in 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid was stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was washed with ethyl ether to give 308 mg of compound (Ia-5-1). Yield 98%. mp. 194 - 195.
IR(KBr, v max cm-1) : 1720, 1343, 1166.
Elemental analysis C19H21N5O4S2 ° l.lHzO
Calcd. : C; 48.83 H; 5.00 N; 14.99 S; 13.72 Found : C; 49.13 H; 5.25 N; 14.55 S; 13.34 Example 210 - 251 The compounds which were shown in Tables 3~ to 43 were synthesized in a manner similar to those described in Example 209.
~1 Table 37 n N CO =
'a r CD tn N ~ v~

N II N
~ ~

~ = CD
~p O

O. (p CD
O N r r M ~Z
r Y

r N
M nj Q

",h, e~ Z N
p. W

II r P
N
~ L~ 1 'p ,..
~ N r a N

N~M

N !5 S
CD ~

~

"' ~ ( D
~ r LT

.n _.
V i r _ ~ O 1~
.fl p'., N r O~
O G~

h tD

Z

Z

C
t .d ~ tt v N CL r / /
s zZ z Z ZZ

, , N
U

_ U
tx =Z

d o o ,~
y~C N N
z W

Table 38 a N

N ~ ~

_ ~ O) II

S~ = L7 ~ !~. = M
ip Cl~

yr I N

~ ~
CO
~

e'r9 _ _ xi O~ r N

~ ~ ~

_ 6~. 'D
Ch =

N ~ tC7 w MO

M~

-w ~ 'N w ' r-~1 C~

G~
I - w ~./ o Y~1 v Nw ~ N
I

Z ~~ iii N yr D

O

\ \
m L~ Z.ZZ Z,ZZ

\ \
~

N
U

_ U
t~ =Z

a~
o o -, %z . N
N

Table 39 ~w et n ell ~ N tn N n CO n n f'9 O O
M YO ~ (~ Ps O ~ f0 C8 O C'7 '~ O r Sri ui n ,~ n. n: n n ui Sri ~ sc c~ co vi c~ co r f~ cri i~ t~ v5 i~ vi in tai vi y 'yf ~ ~ '°' W 00 N O (O W N N Cb O N Cf O n f0 ~ yn Z Z eo co n n rs r~ c~ mn ui r Q r r r r r r r r r r aZZ muy ZZ ZZ OZZ OZZ ZZ
Q' O j, C~ M M 'p' C'O O N ~y ~ N O) O tn CO
LJJ 'O tGl ~ (,L LL O r OD OD ~ ~ ll9 In = N f'~ O r r ~ lfD sf ~ N n tf7 1d7 ~' et ~O °~' !~ N ~ d' N ~
d o== etc~c~ ~_ _= oT= o== =z=
tbo o~cr~ tnry~ W oco got- ~nco ono ~T' ~ U7 ~ ~ ~O 1~ ~C'9 M ~n <O ~O ~ ~r N
W -~c°oc°o yn~' ~,~s~n ours ~cNOCNO ocNncro ~
O
NUU zr~M.'~ ZC7C7 ~IJU M,iJC7 Z,UU NCjU
Z _~ c u_ !n ~? Z ~ c Z ~ c = ~ c Z ~ c = ~ c c~U ~ o> ~ co- ~ ao- ~ co- ~ ,n N t0 Q cC Q ftf Q N t0 Q N l0 Q N f6 Q
UUu. ~c, a UUci UUu. UUti UUti UUu_ U U u°.
n co wo era n dno _c~co c~N
r~ c~ a> n o~ n co a>co so o co M ~ P ~ r ~ ~ ~ r n M
r r rr_ rr r rr rr rr n~ n~r° nee cory n~ nM nc~~ nerd r r r r r r r r r r r r r r r r r v n N W t N t0 ~ n N N N N r N N r r a~ O ~ N tp c0 6p O ~ O CV O N et' O N r (J ~ r N N N r N N r oc'-~ *
x ~ x \ \ \ \ \ \ \ \
I~ I~ I~ I~ I~ I~ I~ I~
zv zv z~ zv zv zv za zv ii Z n Z ii Z ie Z ii Z ii Z n Z n Z
Z.Z Z_Z Z_Z Z_Z Z.Z Z.Z Z_Z Z_~
\I \I \I \I \I \~ \I \I
N
z c~J N N U =
_ _ U
LL' U Z U =Z U ~ xz ~ I ~ / \ V =Z U
_ ~ Z - ~ / \
U v \ / ~ ~ U \ / \
I~
a, N m er m cn r.. oo a~
k z N N N N N N N N
W

Table 40 m n ~ ~r ca ec °r°~ ~:~ or o~ i~bi efl cti n: ~ r: n: r: r: ~r° nm vi iri sr~ cri iii ire iri iri ~: ri r r i0 O n N n N r r y N O O n ~tt r ~ r' Z Z
CD ~G CO (~ tf3 tf7 in tn tn N
r r r w- r r r r r ZZ ZZ OZZ OZZ
iC NN Od Zc0~9~ I NO C') ~ :: :_ I I
= ry r C et er s87 ct) ~ tc~ tn ~ an tn = m 00 °' _= ZS oSS ~__ °°~0~0 '~W n ~~l~r~ 'np.~- ~en~r QMCh W ~~~ ~°dvst ~CMC~ O v==
N,U U Z,U U M,f7 U mU U
Z ~ a Z ~ c Z ~ c u~- ~ o>- a o- ~ o- ~
N fLS Q t$ p N !LS Q N ftS Q
UUti UUu.. UUtL UUci _ cy c °° ~ o U U ti = rn ~ e~ eo c~ o r N v m ~ co r cp rn n v~ n o co o ~t ~~ n r (~ r (~ r (~ r (~ (~ ~ n V r r rr r T r r r r r rr ~M L~d NCn~ ~p~p ~N COr ODD hr n co n r~ n r~ n c~ n ~ c°'c :=
rr rr rr rr PP r rr p n n ~ n CD n tt7 O O O N O O
v ~ r N N ~ CV N N
~ .~ tP~ ct ~ V ~j n d' M
U ~ ~ N N r ~ ~ N N N
~~
Z
~E P'r Q', C~' Q'r R'e P-'W' Q'r O
m I i ~.. 1 s I .~ I i I s I ~ I w i ~Z Z ~Z Z vZ ~ ~Z Z ez z ~Z
-Z z vz 'z z.z -z " .z z ~z Z.z z wl ~I ~I ~I wl ~I wl I
O
z O s z m' z N N
U U
Z ~ U U U U
c~
tx =Z U ~ ~ io io '~ =Z V
U U V U U
Z Z
U U
m a. o ~-~ N c~ yn cD r~
N N N N N N N N
N N N N N N N N

Table 41 N e'~
OrD O ~ ~O
t0 ~G M tn tp 1~ ~G m r N 07 h. (O N
f~ (O tG SD ~ fn N fn ~ h N t~ ts7 tt7 u5 c0 f/j fn o~D, CAD. ~ ~ '~~j ~ ~ ~C CC cD
r ~ M M '~ ~ ~' '~ 'a' ~ M O ~ O
.., ~ ~- r r r r ~ M n, ~ r O
a~ Z Z co cc Z Z Z Z ~r ~. ri c~~ ,W
r p1 r r C' N n N r r r r r r °0 pZZ or- rN ~Z~ OZZ OZZ
N 00 N eS" tf' O f~; 1~ N ~ ~ N N 1(! N d ~O
~ f'~ f~ ~ L1. LL N(j (~ Z et = CD M = O r-r t~7 ~ ~ M = of 07 = r 0 N d. e~' ~:
tOlf) . _= NCO QO~~ r== r== .M==
d ~c~~'? mm~ ~~ COeI' ~Ojc~ fnetM ~r~ ~~1NC~
N = _ ~, ~ ~ o~ '~ v ~'o~ o O = ~ ~n,n m ~
Z .. .. ~or ~~(~ Z ~ Z .. .. Z .. ..
Z~ c'~i c$ mU U Z ~ t~c~ ~ M c~U U c~U V °° U U
~y ~~n N~ ~ ~.. .. U~~ _ ~ c Z ~ c Z ~ c ~UU Nca o UU ~oUU ~~ o Nas o Nra o _ ~ c UUu- Nti ~ Z ~ c UUu. UUts. UUti U U t° U U ti V U li ~n n. a~ ~.. r cmn c~ er n. M a r. oo sn N o co c» co a co o~ co o~ ~ r. o~ co o c~
V ~~, h~~- tf?r Inr efr CGMr tOr (pr r r r T r r r r r r r T r T r N ~ ~ N ~ T
MN ~~ MM M _._. _-M~~ M~ MM
1~ r T~ Ch P~ t'0 h. N 1~. M 1~ In C~ i~ C9 1~ CO
H rT r~ rr rr rr rrr rr rr c' O~ oo ~- 1~ tp I~ _t0 N
N N N N ~r O ~~ ~ , , O ~ ~ ~ oo~ o o N
~y r r- r N N N N r Z
iE tY. Qi Ow Pr' Qi ~.i C4' Pr' O
m_ I \ ~'' \ \ \ \ I \ \
/ I/ I/ I/ I/ I/ / I/
Z v Z vZ Z vZ Z Z ~ Z ~Z Z v °' Z, Z Z.Z Z.Z n Z Z, z Z.Z Z.ZZ Z_ ~Z
\ ( \ I ~~, I I \ I \ I \ I
O U
ap ti O 1i U Z Ue.~ Z
Z
S Z ~ ~ Z ~ Z Z
U U U U U U U U
\ \ '\ ~. \ \ \ \
I/ I/ I/ I/ I/ I/ I/ !/
C. 00 C: O ~-~ N M et' W
N N M M C'~ f0 c~ M
N N N N N N N N

Table 42 co co MM
~ci Sri m ~
c~~N ~N ~~ N~
f0 CC lI7 CO - - (n r p r f0 l69 le i~
!lJ Cl) Cl? Cn ~_P' V_' U7 U Cl) ~lJ tn N
47 OD O et Z Z M A N O
C9 M t~ M p ~p tO ~O CO GD Z Z
r r r r M r r r r r p p zZ OzZ MM ~ZZ OZZ ~ta~
CO tn N C~ N r r N CL1 0 N O ~h td M ~ Z in In ~ ~ ~ iW : x tn ~fl Z f' r N~ LL
= m m co ~. ~ yn ui °i~ oii N°~ i cn ~ rMM Uo~N ~o~o oeF~r °' n~ cNOv in d' ~ ua ~' o N
v= = O O CJ~ ~ Z
Zco o z~c.NO, Ooi. Zus°rW
NUU R;UU zcoac cNVUU n,UU
_~c =~c COvv =tic Sic ~i'on.
~o- ~ ao- ~ ~ in- ~ o_~- ~ co~j U
Nca Q Ncc Q UU N~s Q m Q
UUtL UUu. ~ti j UUti UUu.
UUti UUu°.
co o~ N o ec os ~c o~ c~ re ors o co so ~
N ~ 1~. O In r tt) r N CO h~ V
v ~r rr rr pr ~M ~O M laM
r rr r r rr > CC ~ O O Es N t0 ~ 09 Mr MN CO~ rM-et ~001~ ~C~ ~C~O strld9 ~M PAM 6nN AM 1'~el'r h~M h~r h.l~r r r r r r r r r r r r r r r r r r r v n N N p N O 4 O O
~ r N N N N N
~ $ ~ ~t N N r N N ~ N N
z 3t x x x ~ G; x x x O
I ~ I ~ ~ I ~' I ~ w i z' i I i i i z 'z ~~ z z 'z z. Z'z Z 'z Z 'z z 'z Z 'z z ' z.Z z ~ z.~ z. z.Z z.z n z z z-z i ~ ~ w I / ~ i i o W y ~. I ~ I ~ I
m ~I z m' N N
_ U U U U U U
N N
t'7 N
I ~ I / I r I r C~ U
\ / \
ss. co c~ oo a: o ,-, cu c~
c~c Z n' r= m c~ 'd° ~ ~ d' N N N N N
~7 Table 43 a a~°o ~i m M M CV CV r r r r r r r r f~ ~
fn fn fn !n ell Cl~ V? !O
0 0 ~ O 4 0h rr y~'-.r il~rl~7 N~
oZZ QZZ ~ZZ UZZ
ZOO =NO =OtD N~~tO
r O N ~" c~ r~ .- st ca = O os I i i ~'. ~r= In tt1 p 'cf' ~' r d' tt ~ V' ~
~' NSF N=r N=Z oZZ
't W r ~' f~~ I 1 ~ ~ N ~ ~ !~%.
O~I~CI~ Otlt Z .. Z .. Z .. Z ..
NUU n,UU ~N"UC) mUU
~fC p Nl0 Q NfC Q ~~ O
UUtL UUu. UUu. UUti m~
v r r r~ v-_ r_ r r r I I I
tD r O t0 C~1 tt9 OD in O OD h Q? f~. N ~D lh N r y~. 07 N
t0 r P r h. ~ 1~. '?' r ~D C9 H rr rr e~r rrr rr R
v $~Nr~NN
I I
V ~ ~ N ~ N N
t Z
Z iE fx C' t:,' W' p.' \ \ \ \ \
I/ I/ I/ Ir I/ I/ I/
\ Z
Z y ~ vZ Z y I Z vz Z
Z,ZZ Z.Z Z_Z Z_Z / Z.Z Z.ZZ
/ / ~ Z y.
I \ I \ I \ I z.= ~ I \ I \ I
_ rn rn tn z cn U Z Z Z = ~
N N
z = , , , U U g U U U U
N N
Co c~7 \ =Z SZ \ \ \
U U I/ - - I/ I/ I/
~e ~e a, ~r O cc c~ oo m o ~r rr ~r tr rr mn N N N N N N N N

Example 252 - 266 The compounds which were shown in Tables 44 to 45 were synthesized in a manner similar to those described in Example 15'7.

Table 44 =i BZSZ t=.'==__=NN_ G. C9 = IV t~7 ~ hl nj = ~ N t~'~ = ni N = '- N ~ _ __ O fh v tp O Z N V~ S ~ CO , ~ N S ~ ~Y Z N 60 ~ N S ~ ~ N N S = Q1 t0 = O rb = ~ ~ _ _ tD ~ ~ m = ~ ~ _ _ V' CD CD = = et et nj ~" ~ fC r tp r t0 In ... r tp r f0 h P7 ~ Q d _ il ~ Z 11 II ~ Z 11 II _ 11 O 11 N ~ I 11 II Z il r. r (p m ~ ~O t9 '~ '? ~O M -7 ~ O ~ ~ (p 7 ? ~C Ch 7 ~ ~ ~ ~! II 11 ~ ~ II li ~~~v ~7 '7-7 C~J
h- h. r m CD CC In N eh ~ N ~ LP7 ~ ~ O ~ ~ CAD n O C~ r I~ CO OD V' tC9 00 1~ O In CD O 07 CA N ~ 'C ~ 'C (p h~ N
OrN'~ OONCO OOC~ Or~"~ CCLV~ OONd' ~~~ p~p»
OON
N P) ~ ~
.a 0 0 O t0 0 0 O h t0 ~ C~
~nr cpr <nr Or Cco O~ Oret rN
rr rr rr Nr Nr Nr Nrr ~'r ~~Od' NN ~N O.-N O~-Lf7 Of~C9 O~GetN V~'ehr OODr Or0 Ortn IrNIO7~ OrM
~r CM~r C~~eN~- f~tCN C91~~- COhr ~D/~Wr NPr (hrr Orr ('err (Qrrr Orr O /1 ~ O N
r r ( N P7 ' r r _ "~..C O ~ O N st r r N C~7 r r aE (3.~' P.i' P'., I~.,' CL' ~' Rr' R.i' O
N
S
S~ * ~ c O o ~ O ~ O O
u' U O O U U U U U
U U
LC
N
Z Z U Z Z ~ U 2 A: U U ~ N U l.) ~ U
ti w \ w w p' ~ ~ p ' cn f~ ~~ I~ i i i °° z ~ z ~ z ~
O O O O z.Z'~ z.~z z.Zz w a z U U
_ U U U U U ~ U
N N N N N ~ N
N f~ M ~~'7 ~ N ~ M
U U U U U = I / U
U
a~
G. . N M Q' tf~ Cp Ice- 00 Q7 lf.' Lf~ LC~ LCD In In l.t~ LC~
yC ~r N N N N N N N N

Table 45 '-~_~'_ ==i r r r r ~ r ~~ N N N N
O, 0~~117 ~,~Otfl >a ~U r t~ '~ ~., v ~ tD Vi _~_'~,''~. °~°~r~fc I I I i I
tGN ~ N»7 !~ t~ S ~! th ~
N dy _ ~~
NQO tpE~D~t~O.
CO ~ ~ Z N lV ch V' v a-O et O Itf O
~~M
N r r I I ( I I
wr~ OODr O~Net Ortn OrOtn CwO1~hr ~lfh~!nr r r ~ r r r /S

N
OJ N
O O O V V O O
, , , , , , , N = N
°' U = U Z = U Zv I/ I/ U U I/ U
w ~ v ... O I i i ,~ I i i i U U U U
Z= ZS III III III III
\ UO UO U U U U
I / ~ w ~ w w ~ ~, ~ y i i U
U
_~
Z S = Z T S
, , , Z Z Z Z S
U U U U U U
U
~ N
U I \ I I I I I
-- .~ / / / s /
p. O ~ N M ~' tfJ CD
CO to Cp cp ca O O
k N N N N N C1'I N
~1 Example 267 The compounds which were shown in Tables 46 were synthesized in a manner similar to those described in Example 92.

Table 46 wo=
r 40 ~ N C9 tn =
r. N 'g [~ ~ 9 c~
=rnoi u~ _~''i o0 Gr' C~ c'~ Z M ~ = T~3 ~- r CO r CV
ef nj t'9 ~j ~f OD=r ~~CO
~~ N
td O O M ~ _ GO (G d' h. II i'7 (V '3 CO N ~ 07 O_ ~_ ... (Q~- Mr ~N ~N
~t ~r ~N
O l~ p N
MN Nc7 O
V r r CL--C # ~O ~ CAD
r N
C_0 O n.'rL
C ~ O
O
O U
U I
I
'-' U U
n~ m U U
I
N N
_ U v x Iw Iw c~ o M N N
W

Test examples on the compounds of the present invention are described below.
The test compounds are the ones described in the Examples and Tables.
Test example (1) Isolation and purification of MMP-9 (92 kDa, gelatinase B) Type IV collagenase (MMP-9) was purified according to the methods descrived in the following literature. Scott M. Wilhelm et al., J. Biol. Chem., 264, 17213-17221, {1989), SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV
Collagenase Which Is Identical to That Secreted by Normal Human Macrophages;
Yasunori Okada et al., J. Biol. Chem., 267, 21712-21719, (1992), Matrix Metalloproteinase 9 (92-kDa Gelatinase I Type IV Collagenase) from HT 1080 Human Fibrosarcoma Cells; Robin V. Ward et al., Biochem. J., (1991) 278, 1?9-187, The purification of tissue inhibitor of metalloproteinase-2 from its 72 kDa progelatinase complex.
MMP-9 is secreted from human fibrosarcoma cell line ATCC HT 1080, into its culture medium when it is stimulated with 12-tetradecanoylphorbol-13-acetate (TPA).
The production of MMP-9 in this culture was verified by the gelatin zymography as described in the following literature (Hidekazu Tanaka et al., (1993) Biochem.
Biophys.
Res. Commun., 190, ?32-740, Molecular cloning and manifestation of mouse 105-kDa gelatinase cDNA). The condition medium of the stimulated HT 1080 was concentrated and was purified with gelatin-Sepharose 4B, concanavalin A-sepharose, and Sephacryl S-200. The purified pro-MMP-9 (92 kDa, gelatinase B) thus obtained gave a single positive band in the gelatin zymography. Subsequently, activated MMP-9 was obtained by treating the pro-MMP-9 with trypsin.
(2) Assay methods of type IV collagenase inhibitors Collagenase assay was performed using the activated MMP-9 described above and the substrate supplied in the type IV collagenase activity kit (YAGAI, inc.), according to the manufacturer's protocol. The following 4 assays are performed per compound (inhibitor).

(A) substrate (type IV collagenase), enzyme (MMP-9), inhibitor (B) substrate (type IV collagenase), inhibitor (C) substrate (type IV collagenase), enzyme (MMP-9) (D) substrate (type IV collagenase) According to the manufacturer's protocol, fluorescent intensity was measured and percent inhibition was determined by the following equation.
Inhibition (%) _ {l - (A - B) l (C - D)} x 100 ICso is a concentration at which the percent inhibition reaches 50 %. The results are shown in Tables 47 to 54.

Table 4?
Exam le No. Com ound No. ICso C ) Com ound No. ICSO t ) 1 la-1-1 0 2 4 ib-1-1 0 . 0 3 0 .

2 la-i-2 2 6 lb-1-2 0 . 0 4 .

3 la-1-3 0 1 8 lb-1-3 0 . 0 0 5 .

4 la-1-4 2. 2 5 la-1-5 0 8 1 Ib-1-5 0. 0 4 1 .

6 la-1-6 0 6 8 lb-1-6 0. 0 3 4 7 . 1b-1-? 0. 0 2 8 8 la-I-8 0 lb-1-8 2 . 0 .

9 lb-1-9 0. 41 1 0 ib-1-10 2. 1 1 1 ib-1-11 1 . 7 1 2 lb-1-12 0. 0 8 5 1 3 lb-1-13 0. 3 8 1 4 la-1-14 3 7 lb-1-14 0 . 1 1 .

1 5 lb-1-15 0 . 0 2 7 1 6 la-1-16 0. 5 2 Ib-i-16 0. 0 1 0 1 7 la-1-I? 0. 2 0 Ib-1-1? 0. 0 2 0 1 8 la-1-18 0. 5 0 lb-1-18 0 . 0 2 8 2 0 lb-1-20 0 . 1 3 4 2 1 la-1-2I 4. 6 5 lb-1-21 0. 0 0 4 2 3 lb-I-23 0. 0 ? 3 2 4 lb-I-24 0 . 2 2 6 ib-1-2fi 1. 3 2 ? lb-1-27 3 . 0 3 0 la-1-30 1 1 6 1b-1-30 0. 2 1 3 3 1 . lb-1-31 0. 0 1 2 Table 48 Exam le No. Com ound ICso ( ) Compound ICso ( ) 3 3 No. 0 . 2 4 No. 0 . 0 0 5 la-1-33 lb-1-33 3 5 la-1-35 2. 6 lb-1-35 0 . 0 2 1 3 8 la-1-38 0. 0 1 8 4 0 la-1-40 0 . 0 ? 6 4 1 la-1-41 0 . 3 1 2 4 2 la-1-42 0. 0 1 2 4 3 la-1-43 0. 6 2 5 4 4 la-1-44 1 . 9 1 0 4 5 la-1-45 0 . 0 4 0 4 6 la-1-46 1 . 1 2 4 7 la-1-47 0 . 3 8 9 4 8 la-1-48 1 . 1 5 4 9 1a-1-49 0. 2 4 9 0 1a-1-50 0 . 5 5 3 5 1 1a-1.51 0 . 1 1 0 5 2 la-1-52 0. 3 2 9 5 3 la-1-53 1 . 8 5 4 1a-1-54 0. 0 ? 5 5 5 1a-1-55 0. 0 3 9 6 0 la-1-60 1 . 3 1 lb-1-60 0 . 0 0 1 6 1 la-1-61 0 . 2 4 7 lb-1-61 0. 2 4 ?

6 2 lb-1-62 3. 5 0 6 3 la-1-63 1. 0 5 lb-1-63 0. 0 0 0 3 6 4 la-1-64 1 . 9 0 lb-1-64 0. 0 0 3 7 6 5 la-1-65 0. 2 9 1 lb-1-65 0. 0 0 3 5 Table 49 Exam le No. Com ound ICSO (~.M) Com ound ICso ( ) 6 7 No. No. 0. 0 0 6 1 la-1-67 lb-1-67 6 8 la-1-68 0-. 2 3 1 8 0 la-1-80 1 . 9 1 8 3 la-1-83 1 . 7 7 8 5 la-1-85 1 . 2 lb-1-85 0. 0 1 3 8 6 la-1-86 0. 3 5 lb-1-86 0. 0 0 5 3 8 7 lb-1-8'7 0 . 9 4 0 9 3 la-2-2 0 . 2 3 7 9 4 la-2-3 0 . 0 1 0 9 5 la-2-4 0. 0 7 5 9 6 la-2-5 0 . 1 2 3 _ 9 7 la-2-6 0 . 0 8 8 98 la-2-'T 0. 0699 1 0 0 la-2-9 0 . 0 5 7 1 0 1 la-2-10 0 . 0 2 3 1 0 2 la-2-11 0 . 0 4 7 1 0 3 la-2-12 0. 0 9 8 1 0 4 la-2-13 3 . 2 8 1 0 5 la-2-14 2 . 9 8 1 0 6 la-2-15 0. 1 3 3 1 0 7 la-2-16 0. 3 2 5 1 0 9 la-2-18 1 . 1 9 1 1 0 la-2-19 0. 2 0 3 1 11 la-2-20 3. 41 1 1 2 la-2-21 3 . 7 4 1 1 4 la-2-23 0. 9 2 9 Table 50 Exam le No. Com ound ICso (N.M) No.

11 5 la-2-24 0. 16I
1 1 7 Ia-2-26 1. 1 9 i 1 8 la-2-2 7 0 . 0 8 $

1 1 9 la-2-28 1. 1 1 1 2 0 la-2-29 1. 5 3 1 2 1 la-2-30 0. 0 7 3 6 1 2 2 la-2-31 0 .. 2 2 4 1 2 3 Ia-2-32 0 . 0 2 3 1 2 4 la-2-33 0 . 0 2 1 1 2 5 la-2-34 0 . 0 I 4 1 2 6 la-2-35 0 . 1 5 6 1 2 7 la-2-36 0 . 0 2 4 1 2 8 la-2-37 0 . 0 9 2 1 2 9 la-2-38 0. 2 2 2 1 6 0 Ia-3-2 0 . 0 4 0 1 6 I la-3-3 0 . 0 1 0 1 6 2 la-3-4 0. 8 7 3 1 6 3 la-3-5 0. 0 1 2 6 1 6 4 1a-3-6 0 . 0 9 6 1 6 5 1a-3-7 0. 2 3 0 1 6 6 Ia-3-8 1 . 2 8 1 6 7 la-3-9 0. 0 1 4 1 6 8 la-3-10 0 . 0 0 8 1 6 9 la-3-11 0. 2 4 4 1 7 0 la-3-12 2. 0 3 1 7 1 la-3-13 0. 0 3 9 5 Table 51 Exam Ie No. Com ound ICso C ) No.

1 ? 7 la-4-2 0 . 6 8 4 178 la-4-3 0. 0252 1 7 9 la-4-4 2 . 3 6 1 8 0 la-4-5 0 . 0 4 5 1 s 1 la-4-s o . 0 5 3 1 8 2 la-4-'7 0 . 0 0 5 1 8 3 la-4-8 0 . 0 0 2 ?

1 8 4 la-4-9 0 . 0 0 3 185 la-4-10 0. 0422 186 la-4-11 0.0982 1 8 7 la-4-12 0. 1 7 7 1 8 8 la-4-13 0 . 8 4 3 189 la-4-14 0. 0375 1 9 0 la-4-15 0. 0 5 9 7 __ la-4-16 0 . 0 0 9 1 9 2 la-4-1? 0. 3 2 4 1 9 3 la-4-18 0. 7 2 2 1 9 5 1a-4-20 1 . 1 196 la-4-21 0.0573 1 9 7 la-4-22 0. 0 1 6 1 1 9 8 la-4-23 0 . 4 9 3 1 9 9 la-4-24 2 . 0 6 2 0 0 la-4-25 0 . 1 7 3 2 0 1 la-4-26 0 . 2 5 2 2 0 2 la-4-27 0 . 0 1 1 2 0 3 la-4-28 0 . 1 7 3 Table 52 Exam le No. Com ound ICSO ( ) Com ound No. IC3o ( ) No.

2 0 4 la-4-29 3 . 9 5 2 0 7 la-4-30 4 . 4 4 2 1 0 la-5-2 0 . 0 2 4 2 1 1 la-5-3 0 . 2 1 0 1 b - 2 1 1 0 . 0 0 5 fi 5 2 1 2 1a-5-4 0. 3 9 3 2 I 3 la-5-5 0. 1 2 8 2 1 4 la-5-6 0. 8 3 2 2 1 5 la-5- t 0 . 1 1 0 2 1 6 la-5-8 0. 1 0 7 2 1 8 1a-5-10 0 . 7 4 4 2 1 9 la-5-11 0 . 5 7 4 2 2 0 la-5-12 0 . 0 1 6 7 2 2 1 la-5-13 0 . 3 1 6 222 la-5-14 0. 078 2 2 3 la-5-15 0 . 3 4 9 2 2 4 la-1-16 0 . 0 1 0 1 2 2 5 la-5-17 0. 0 1 2 2 2 2 fi la-5-18 0. 1 fi 6 2 2 7 la-5-19 0. 0 1 9 8 2 2 8 la-5-20 0 . 1 0 fi 2 2 9 la-5-21 0 . 2 1 5 2 3 0 la-5-22 0 . 2 8 1 2 3 1 la-5-23 0. 1 9 7 2 3 2 la-5-24 0 . 1 4 4 233 la-5-25 0. 0864 2 3 4 la-5-26 0 . 1 5 3 Table 53 Exam le No. Com ound ICso ( ) Com~,ou_nd ICso ( ) No. No.

2 3 5 la-5-27 0. 2 6 5 2 3 6 la-5-28 0 . 3 0 4 2 3 7 la-5-29 1. 3 2 2 3 8 la-5-30 2 . 8 5 2 3 9 la-5-31 0 . 2 4 3 2 4 0 la-5-32 0 . 0 0 4 2 4 1 la-5-33 0 . 0 1 3 2 4 2 la-5-34 0 . 0 2 3 2 4 3 la-5-35 0 . 0 5 2 2 4 4 la-5-36 0 . 0 1 6 2 4 5 la-5-37 0 . 0 0 5 2 4 6 la-5-38 9 2 4 7 la-5-39 0 . 0 1 0 0 . 0 0 3 2 6 7 la-2-66 1 . 5 lb-2-66 0. 0 1 1 Table 54 Exam le No. Com ound ICso~) No.

2 5 2 1-252 0 . 2 4 253 1-253 0. 000039 254 1-254 Oo 00063 2 5 5 1-255 0 . 5 2 9 2 5 6 1-258 0 . 6 0 1 2 5 7 1-25'7 0 . 7 ? 6 2 5 8 1-258 0 . 9 0 8 2 5 9 1-259 0 . 1 3 0 2 6 0 1-260 0 . 1 5 9 2 6 1 I-2so o . 1 8 2 The compound of the present invention showed strong activity for inhibiting type IV collagenase.
Industrial Applicability It is considered that the compound of the present invention is useful to prevent or treat osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced: virus infection (e.g., HIV), arteriosclerosis obliterans, arterioselerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, and gastric ulcer, because the compound of the present invention has strong inhibitory activity against metalloproteinase, especially MMP.

Claims (19)

1. A composition for inhibiting metalloproteinase which contains a compound of the formula I:

wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R3 is optionally substituted arylene, or optionally substituted heteroarylene;
R4 is -(CH2)m-, -CO-, -CO-NH-, -N=N-, -N(R A)-, -NH-CO-NH-, -NH-CO-, -O-, -S-, -SO2NH-, -SO2-NH-N=CH-, or tetrazol-diyl;
R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
R A is hydrogen atom or lower alkyl;
Y is -NHOH or -OH; and m is 1 or 2;
provided R2 is hydrogen atom when Y is -NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof, together with a pharmaceutically acceptable carrier therefor.

2. A composition for inhibiting metalloproteinase which contains a compound of the formula I:

wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R3 is optionally substituted arylene, or optionally substituted heteroarylene;
R4 is -(CH2)m-, -CO-, -CO-NH-, -N=N-, -N(R A)-, -NH-CO-NH-, -NH-CO-, -O-, -S-, -SO2NH-, -SO2-NH-N=CH-, or tetrazol-diyl;
R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
R A is hydrogen atom or lower alkyl;
Y is -NHOH or -OH; and m is 1 or 2;
provided R2 is hydrogen atom when Y is -NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is -CO-NH- or -NH-CO-, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is tetrazol-diyl, and R4 is not -O- when R3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof, together with a pharmaceutically acceptable carrier therefor..

3. A composition for inhibiting metalloproteinase of claim 1 or 2, which is a composition for inhibiting type-IV collagenase.

4. A compound of the formula I:

wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R3 is optionally substituted arylene, or optionally substituted heteroarylene;
R4 is -(CH2)m-, -CO-, -CO-NH-, -N=N-, -N(R A)-, -NH-CO-NH-, -NH-CO-, -O-, -S-, -SO2NH-, -SO2-NH-N=CH-, or tetrazol-diyl;
R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
R A is hydrogen atom or lower alkyl;
Y is -NHOH or -OH; and m is 1 or 2;
provided R2 is hydrogen atom when Y is -NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is -CO-NH- or -NH-CO- (when R3 is phenylene and R4 is -CO-NH-, R1 is not methyl or phenyl and R5 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R5 is optionally substituted aryl, or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is tetrazol-diyl, R4 is not -O- when R3 is optionally substituted arylene or optionally substituted heteroarylene, R3 is not naphthalenediyl when R4 is -N=N-, R5 is not phenyl substituted with dimethylamino when R4 is -N=N-, R5 is not 1H-azepine when R3 is 1,2-phenylene and R4 is -CO-, R1 is not carboxyalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, or phenylaminocarbonylalkyl when R3 is phenylene and R4 is -CO-NH-, and R5 is not optionally substituted heteroaryl when R3 is phenylene and R4 is -CH2-, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

5. A compound of the formula II:

wherein R6 is -N=N-, -NH-CO-NH-, -S-, -SO2NH-, or -SO2-NH-N=CH-;
R7 is optionally substituted aryl or optionally substituted heteroaryl;
R8 and R9 are each independently hydrogen atom, lower alkoxy, or vitro;
R1, R2, and Y are as defined in claim 4, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

6. A compound of the formula III:

wherein R10 is -(CH2)m-, -CO-, -CO-NH-, -N(R A)-, -NHCO-, or tetrazol-diyl;
m is 1 or 2;
R1, R2, R A, and Y are as defined in claim 4, and R7, R8, and R9 are as defined in claim 5, provided R1 is not methyl or phenyl and R7 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when R10 is -NH-CO-, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

7. A compound of the formula I':
wherein R1' is benzyl, (indol-3-yl)methyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-fluoroindole-3-yl)methyl, (1-acetylindol-3-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, (1-alkoxycarbonyl-3-yl)methyl such as ethoxycarbonylmethyl, or i-propyl;
R2' is hydrogen atom, methyl, 4-aminobutyl, or benzyl;
R3' is 1,4-phenylene;
R4' is -O-;
R5' is phenyl or 4-hydroxyphenyl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

8. A compound of the formula VI:
wherein R2 is as defined in claim 4, and R8, and R9 are as defined in claim 5, R13 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R14 is optionally substituted aryl or optionally substituted heteroaryl;
provided R13 is not methyl or phenyl and R14 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

9. A compound of the formula VII:
wherein R1 and R2 are as defined in claim 4, and R7, R8, and R9 are as defined in claim 5, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

10. A compound of the formula IX:
wherein R1 and R2 are as defined in claim 4, and R7, R8, and R9 are as defined in claim 5, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

11. A compound of the formula XI:
wherein R1 is as defined in claim 4, R8 and R9 are as defined in claim 5, and R13 and R14 are as defined in claim 8, provided R13 is not methyl or phenyl and R14 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

12. A compound of the formula XII:
wherein R1 is as defined in claim 4, and R7, R8, and R9 are as defined in claim 5, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

13. A compound of the formula XIV:
wherein R1 is as defined in claim 4, and R7, R8, and R9 are as defined in claim 5, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

14. The compound of any one of claims 4 to 13, wherein R1, R1', and R13 are i-propyl, benzyl, or (indole-3-yl)methyl.

15. The compound of any one of claims 4 to 6 and 8 to 13, wherein R5, R7, and R14 are phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.

16. The compound of any one of claims 4 to 13, wherein the configuration of the asymmetric carbon atom bonding with R1, R1', and R18 has the R configuration.

17. A pharmaceutical composition containing a compound of any one of claims 4 to 13, together with a pharmaceutically acceptable carrier therefor..

18. A composition for inhibiting metalloproteinase containing a compound of any one of claims 4 to 13, together with a pharmaceutically acceptable carrier therefor..

19. A composition for inhibiting type IV collagenase containing a compound of any one of claims 4 to 13, together with a pharmaceutically acceptable carrier therefor.