AU738793B2 - Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION C. C

C

C

C.

C

C..

Name of Applicant: Actual Inventor: Address for Service: Shionogi Co., Ltd.

WATANABE Fumihiko TSUZUKI Hiroshige OHTANI Mitsuaki DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, Victoria 3000.

Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same"

C

C

Invention Title: The following statement is a full description of this invention, including the best method of performing it known to us: 1 Q:\OPER\MKR\GENERAL\13195-97-122.doc 1/5/00

DESCRIPTION

SULFONATED AMINO ACID DERIVATIVES AND METALLOPROTEINASE INHIBITORS CONTAINING THE SAME This application is a divisional of Australian patent application No. 13195/97 (715,764), the entire contents of which are incorporated herein by reference.

Technical Field This application relates to sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same.

:10 Background Art An extracellular matrix consists of collagen, proteoglycan, etc., 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 15 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 20 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 (W095/35276), 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 Nb P:\OPER\MKR'SPECR\13195-97.330 29111 /99 -2related 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 1:

R

1 R_ R3-SO 2 -N COY I

R

2 o 10 wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 3 is a bond, optionally substituted arylene, or 15 optionally substituted heteroarylene; R 4 is a bond, -(CH 2 -CH=CH-, CO-NH-, -NH-CO-NH-, -NH-CO-, -SO 2 NH-, -SO2-NH- N=CH-, or tetrazol-diyl; R 5 is optionally substituted lower alkyl, optionally substituted

C

3 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an i optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower 20 alkyl; Y is -NHOH or -OH; and m is 1 or 2; provided R 2 is hydrogen atom when Y is -NHOH, R 4 is not -CH 2 when R 3 is optionally substituted arylene, and R 5 is not alkyl substituted with heterocyclic ring when R 3 and R 4 are bond, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

Mentioned in more detail, the invention relates to the following and a) A composition for inhibiting metalloproteinase which contains a compound of the formula I: R1 R- R 4 -R3-SO 2 -N COY

I

wherein R is optionally substituted lower alkyl, optionally substituted aryl, optionally wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally P:\OPER\MKRXSPECI',13195-97.330 29111;99 -3substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R 4 is a bond, -(CH 2 -CH=CH-, -CO-, -CO-NH-, -NH-CO-NH-, -NH-CO-, -SO2NH-, -SO2-NH- N=CH-, or tetrazol-diyl; R 5 is optionally substituted lower alkyl, optionally substituted

C

3 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R A is hydrogen atom or lower 10 alkyl; Y is -NHOH or -OH; and m is 1 or 2; provided R 2 is hydrogen atom when Y is -NHOH, R 5 is optionally substituted aryl or optionally substituted heteroaryl when R 3 is optionally substituted arylene or optionally substituted heteroarylene and R 4 is -CO-NH- •or -NH-CO-, R 5 is optionally substituted aryl or optionally substituted heteroaryl when R 3 is optionally substituted arylene or optionally substituted heteroarylene and R 4 is tetrazol- 15 diyl, R' is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or heteroaryl substituted by lower alkyl or optionally substituted aryl when R 3 is optionally substituted arylene and R 4 is a bond, both of R 3 and R 4 are not a bond at the same time, and R 4 is not when R 3 is optionally substituted arylene or optionally substituted heteroarylene, R 4 is not -CH 2 when R 3 is optionally substituted arylene, and R s is not alkyl substituted with heterocyclic ring when R 3 and R 4 are bond, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

b) A composition for inhibiting metalloproteinase as mentioned above, which is a composition for inhibiting type-IV collagenase.

Preferred embodiments of the present invention are as follows.

1) A compound of the formula I:

R

1 R -R4-R3-S0 2 -N COY I

R

2 wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally P:\OPERMKR\SPECI\ 13195-97.330- 2911.99 -4substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R 4 is a bond, -CH=CH-, -CO-, -CO-NH-, -N(RA)--NH-CO-NH-, -NH-CO-, -SO2NH-, -SO2-NH- N=CH-, or tetrazol-diyl; R 5 is optionally substituted lower alkyl, optionally substituted

C

3 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R A is hydrogen atom or lower 10 alkyl; Y is -NHOH or -OH; and m is 1 or 2; provided R 2 is hydrogen atom when Y is o: -NHOH, R 5 is optionally substituted aryl or optionally substituted heteroaryl when R 3 is optionally substituted arylene or optionally substituted heteroarylene and R 4 is -CO-NHor -NH-CO- (when R 3 is phenylene and R 4 is -CO-NH-, R' is not methyl or phenyl and R is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R 5 is lower alkyl, 15 optionally substituted aryl, or optionally substituted heteroaryl when R 3 is optionally substituted arylene, or optionally substituted heteroarylene and R 4 is tetrazol-diyl, R 5 is aryl substituted with lower alkyl or optionally substituted aryl, or heteroaryl substituted with lower alkyl or optionally substituted aryl when R 3 is optionally substituted arylene and R 4 is a bond, both of R 3 and R 4 are not a bond at the same time, and R 4 is not -0- 20 when R 3 is optionally substituted arylene or optionally substituted heteroarylene, R 3 is not naphthalenediyl when R 4 is R 5 is not phenyl substituted with dimethylamino when

R

4 is -N R 3 is not 1,2-phenylene, R 5 is not phenyl when R 3 is 1,3-phenylene and R 4 is -SO2-, R' is not carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, or phenylaminocarbonylalkyl when R 3 is phenylene and R 4 is -CONH-, and R 5 is not optionally substituted heteroaryl when R 3 is phenylene and R 4 is

-CH

2 its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

2) A compound of the formula II: R8

R

R7-' SO-N COY H

R

2

R

9 W. P:\OPER\.MKR'SPECI,13195-97.330 29/11/99 wherein R 6 is -CH=CH-, -NH-CO-NH-, -SO 2 NH-, or -SO 2

-NH-

N=CH-; R 7 is optionally substituted aryl or optionally substituted heteroaryl; R 8 and R 9 are each independently hydrogen atom, lower alkoxy, or nitro; R 2 and Y are as defined above; provided R 7 is not phenyl substituted with dimethylamino when R 6 is its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

3) A compound of the formula III:

R

8

R

I

10 R S0 2 -N COY R2

R

9 S wherein R' 0 is -(CH 2 -CO-NH-, -NHCO-, or tetrazol-diyl; m is 1 or 2; R 2

R

7

R

8

R

9 RA, and Y are as defined above, provided R' is not methyl or phenyl and R 7 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when R 0 is -NH-CO-, R' is not carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, or phenylaminocarbonylalkyl when R 1 0 is -CONH-, and R 7 is not optionally substituted heteroaryl when R 1 0 is -CH 2 its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

20 4) A compound of the formula IV:

R

1 R'-R11 ^SO^2- N COY IY wherein R" is a bond, -CH=CH-, or X is oxygen atom or sulfur atom, R 2

R

7 and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

1. P:\OPER\MKR\SPECI\13195-97.277 30/9/99 A compound of the formula If: R 5

-R

4

-R

3 -S0 2 -N COY COY A2 wherein is benzyl, (indol-3-yl)methyl, (1 -methylindol-3-yl)methyl, (5-methylindol-3yl)methyl, (1 -acetylindol-3-yl)methyl, (1 -methylsulfonylindol-3-yl)methyl, (1alkoxycarbonyl-3-yl)methyl (for example ethoxycarbonylmethyl), or i-propyl; R 2 is 10hydrogen atom, methyl, 4-aminobutyl, or benzyl; R 3 is 1,4-phenylene; R 4 is R 5 is 10 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 I": R 5 4 R"-S0 2 -N lj"COY I" wherein RI" is 4-thiazolylmethyl, (indol- 3-yl)methyl, (5-methoxyindol-3-yl)methyl, 1naphthylmethyl, 2- naphthylmethyl, 4-biphenylylmethyl, 2,2,2-trifluoroethyl, 2p henylethyl, benzyl, i-propyl, 4- nitrobenzyl, 4-fluorobenzyl, cyclohexylmethyl, (1methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-fiuoroindol-3-yl)methyl, (pyridin-4-yl)methyl, (benzothiazol-2-yl)methyl, (p henyl)(hydroxy)methyl, phenyl, carboxymethyl, 2-carboxyethyl, hydroxymethyl, p henylmethoxymethyl, 4- 10 carboxybenzyl, (benzimidazol-2-yl)methyl, (1-methylsulfonylindol.3.yl)methyl, or (1ethoxycarbonylindol-3-yl)methyl;

R

2 is hydrogen atom; RV" is 1,4-phenylene; R 4 is a bond; R 5 is phenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tertbutylp henyl, 4-trifiuoromethylp henyl, 4-fluorophenyl, 4-methyithiophenyl, 4biphenylyl, 2-thienyl, benzoxazol-2-yl, benzothiazol-2-yl, or tetrazol-2-yl; and Y is as 15 defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

7) A compound of the formula V: R R R7- R12~ S02-N )"COOH V R

R

wherein R1 2 is -CH=CH- or -CM R 2

R

8 and R 9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

8) A compound of the formula VI: P:\OPER\MKR\SPECI.13195-9 7 .330 9:11 99 -7-

R

8

R

13 14- -N S0 2 -N COOH VI

R

9 wherein R 2

R

8 and R 9 are as defined above, R 13 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 R 1 3 is not methyl, phenyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, or 10 phenylaminocarbonylalkyl and R' 4 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

9) A compound of the formula VII:

R

8

R

1 R-N 'N S02-NO 2 COOH II R2

R

9 wherein R 2

R

7

R

8 and R 9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

10) A compound of the formula III: Ri

R

1 R7-R (SO 2 -N COOH MIII S

R

2 wherein R 2

R

7 and R" are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

11) A compound of the formula IX:

R

8

R

1 R 7-0

SO

2 -N COOH IX -1 2 I

R

R

9 P:\OPER'MKR SPEC' 13195-97.330 29 1199 -8wherein R 2

R

7

R

8 and R 9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

12) A compound of the formula X:

R

8 Ri

R

7 -R2 SO2-N COOH X -I

R

9 wherein R 1 2 is -CH=CH- or R 7

R

8 and R 9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

10 13) A compound of the formula XI: R8 R13 o o *R

R

R 4C-N- -SO -N COOH 2X

R

9

R

wherein R 8

R

9

R

1 3 and R 14 are as defined above, provided R 1 3 is not methyl, phenyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, or phenylaminocarbonylalkyl and is not 2chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

14) A compound of the formula XH:

R

8

R

i N=N I

R

7 N.N SO2-N COOH XII

R

9 wherein R 7

R

8 and R 9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

I.

P:\OPER\MKR\SPECI\13195-97.277 30/9199 -9- A compound of the formula XLII: R -7 1 0-N)ICOOH XIII H-c, wherein R 7 and R 1 are as defined above, its optically acceptable substance, their pharmaceutically acceptable salt, or hydrate thereof.

16) A compound of the formula XIV: -S0 2 -N COH V

H

:.wherein R 1

R

7 R' and R 9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

15 17) A compound of the formula XXVII: 7_0 _SO 2 -N CO O H XXVIIL

H

wherein R' and R 7 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 c any one of above 1) to 16), wherein and R 3 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 R 5

R

7 and R1 4 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 R 1 R and R 3 is R configuration.

P:\OPER\MKR\SPECI\13195-97.330 2911/99 -9A Further, this invention relates to a pharmaceutical composition, a composition for inhibiting metalloproteinase, and a composition for inhibiting type IV collagenase which contain the compound above 1) to 16) and A) to C).

The present invention also relates to use of a compound of the formula I:

R

1

R

5

-R

4

-R

3

-SO

2 -N COY I R 2 :i wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally 10 substituted aralkyl, optionally substituted heteroaryl, or optionally substituted S heteroarylalkyl; R 2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R 3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R 4 is a bond, -(CH 2 -CH=CH-, -CO-NH-, -NH-CO-NH-, -NH-CO-,

-SO

2 NH-, -S0 2 -NH-N or tetrazol-diyl; R 5 is optionally substituted lower alkyl, optionally substituted C 3 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 R 2 is hydrogen atom when Y is -NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof, in the preparation of a medicament for the inhibition of metalloproteinase.

In another aspect the present invention relates to use of a compound of the formula

I

R1 R1 4

-R

3

-SO

2 -N COY I

R

2 wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted t P:\OPER\MKR\SPECI\13195-97.330 29/1199 -9B heteroarylalkyl; R 2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R 4 is a bond, -(CH 2 -CH -CO-, -CO-NH-, -NH-CO-NH-, -NH-CO-, -SO 2 NH-, -SO 2

-NH-

N=CH-, or tetrazol-diyl; R 5 is optionally substituted lower alkyl, optionally substituted

C

3

-C

8 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 R 2 is hydrogen atom when Y is S10 -NHOH, R 5 is optionally substituted aryl or optionally substituted heteroaryl when R 3 is optionally substituted arylene or optionally substituted heteroarylene and R 4 is -CO-NHor -NH-CO-, R 5 is optionally substituted aryl or optionally substituted heteroaryl when R 3 is optionally substituted arylene or optionally substituted heteroarylene and R 4 is tetrazoldiyl, R 5 is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or 15 heteroaryl substituted by lower alkyl or optionally substituted aryl when R 3 is optionally substituted arylene and R 4 is a bond, both of R 3 and R 4 are not a bond at the same time, and R 4 is not when R 3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof, in the preparation of a medicament for the inhibition of metalloproteinase.

20 The invention also relates to a method for the inhibition of metalloproteinase including the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of the formula I:

R

1

R

5

R

4

R

3 SO0 2 -N COY I R2 wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R 4 is a bond, -CH=CH-, -CO-, P:\OPER\MKR\SPECI\13195-97.330 -30/11/99 -9C- -CO-NH-, -N(RA) -NH-CO-NH-, -NH-CO-, -SO2NH-, -SO2-NH- N=CH-, or tetrazol-diyl; R 5 is optionally substituted lower alkyl, optionally substituted

C

3

-C

8 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 R 2 is hydrogen atom when Y is -NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

This invention also relates to a method for the inhibition of metalloproteinase including the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of the formula I:

R'

I

R5-R 4

-R

3

-S

2 -N COY I

R

2 wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, R 3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R 4 is a bond, -(CH 2 -CH=CH-, -CO-, -CO-NH-, -NH-CO-NH-, -NH-CO-, -SO 2 NH-, -SO2-NH- N=CH-, or tetrazol-diyl; R 5 is optionally substituted lower alkyl, optionally substituted

C

3

-C

8 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 R 2 is hydrogen atom when Y is NHOH, R 5 is optionally substituted aryl or optionally substituted heteroaryl when R 3 is optionally substituted arylene or optionally substituted heteroarylene and R 4 is -CO-NHor -NH-CO-, R 5 is optionally substituted aryl or optionally substituted heteroaryl when R 3 is optionally substituted arylene or optionally substituted heteroarylene and R 4 is tetrazoldiyl, R 5 is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or heteroaryl substituted by lower alkyl or optionally substituted aryl when R 3 is optionally P: OPER'MKR'SPECI 3195 )-7-div docln M15/0 -9Dsubstituted arylene and R 4 is a bond, both of R 3 and R 4 are not a bond at the same time, and R 4 is not when R 3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

In a particularly preferred aspect of the present invention there is provided a compound of the formula IV:

R

1 R7R11--R L -SO 2 -N COY X 2

R

wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R

2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;

R

7 is optionally substituted aryl or optionally substituted heteroaryl; R" is X is oxygen atom or sulfur atom; and Y is -NHOH or -OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

All of compounds of above 1) to 16) and A) to C) have strong metalloproteinase inhibitory activity, and the following compo'md is more preferable: Ri

R

5 _R4 R 3

-SO

2 -N COY I

R

2 1) A compound wherein R' is i-propyl, benzyl, or (indol-3-yl) methyl, R 2 is hydrogen atom, R 3 is 1,4-phenylene, R 4 is and R 5 is optionally substituted phenyl.

PAkOPER\MKR\SPECrI3193-97dv.doc4OIAS/uo 9E 2) A compound wherein R' is i-propyl, benzyl, or (indol-3-yl) methyl, R 2 is hydrogen atom, R 3 is optionally substituted 2,5-thiophen-diyl, R' is and W 5 is optionally substituted phenyl.

3) A compound wherein R' is i-propyl, benzyl, or (indol-3-yl) methyl, R 2 is hydrogen atom, R 3 is 1,4-phenylene, R 4 is tetrazol-diyl, and R 5 is optionally substituted phenyl.

The term "alkyl" herein used means Ci-Cio straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, npentyl, i-pentyl, neo-pentyl, tert-pentyl, and the like.

The term "lower alkyl" herein used means C1-C6 straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tertbutyl, and the like.

The term "C3-Cs cycloalkyl" herein used is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

10 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 subL ituted by the above mentioned aryl at any possible position. Examples of the aralkyl are ~benzyl, phenethyl, phenylpropyl 3-phenylpropyl), naphthylmethyl (anaphthylmethyl), 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 6 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 1-pyrrolyl), indolyl 2-indolyl), carbazolyl 3carbazolyl), imidazolyl 4- imidazolyl), pyrazolyl 1-pyrazolyl), benzimidazolyl 2-benzimidazolyl), indazolyl 3-indazolyl), indolizinyl 6-indolizinyl), pyridyl 4-pyridyl), quinolyl 5-quinolyl), isoquinolyl 3-isoquinolyl), acridinyl 1-acridinyl), phenanthridinyl 2-phenanthridinyl), pyridazinyl 3-pyridazinyl), pyrimidinyl 4-pyrimidinyl), pyrazinyl 2-pyrazinyl), cinnolinyl 3-cinnolinyl), phthalazinyl 2-phthalazinyl), quinazolinyl 2quinazolinyl), isoxazolyl 3-isoxazolyl), benzisoxazolyl 3-benzisoxazolyl), oxazolyl 2-oxazolyl), benzoxazolyl 2-benzoxazolyl), benzoxadiazolyl 4benzoxadiazolyl), isothiazolyl 3-isothiazolyl), benzisothiazolyl 2benzisothiazolyl), thiazolyl 2-thiazolyl), benzothiazolyl 2-benzothiazolyl), furyl 3-furyl), benzofuryl 3-benzofuryl), thienyl 2-thienyl), benzothienyl 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 4-thiazolylmethyl), thiazolylethyl 5-thiazolyl-2-ethyl), indolylmethyl 2-indolylmethyl), imidazolylmethyl 4- 10 imidazolylmethyl), benzothiazolylmethyl 2-benzothiazolylmethyl), benzopyrazolylmethyl 1-benzopyrazolylmethyl), benzotriazolylmethyl 4- 99** benzotriazolylmethyl), benzoquinolylmethyl 2-benzoquinolylmethyl), benzimidazolylmethyl 2-benzimidazolylmethyl), pyridylmethyl 2- ~pyridylmethyl), and the like. The aryl part of the above heteroaryl is optionally substituted.

S. 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.

9 The term "heteroarylene" herein used is exemplified by thiophen-diyl, furandiyl, pyridin-diyl, and the like, in more detail, by 2,5-thiophen-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.

The term "lower alkoxy" herein used means alkoxy of which alkyl part is the above mentioned lower alkyl. Examples of the lower alkoxy are methoxy, ethoxy, npropoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-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 C3-Cs cycloalkyl", and "optionally substituted non-aromatic heterocyclic group" are hydroxy, 10 alkoxy methoxy and ethoxy), mercapto, alkylthio methylthio), cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen fluoro, chloro, 000* ~bromo, and iodo), carboxy, alkoxycarbonyl methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl trifluoromethyl), substituted or unsubstituted amino 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 0*0*00 heteroarylalkyl", "optionally substituted arylene", and "optionally substituted 0 heteroarylene" are, for example, hydroxy, alkoxy methoxy and ethoxy), mercapto, alkylthio methylthio), cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl), halogen fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl trifluoromethyl), aryloxy phenyloxy) substituted or unsubstituted amino methylamino, dimethylamino, diethylamino, and benzylidenamino), guanidino, alkyl methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neopentyl, and tert-pentyl), alkenyl vinyl and propenyl), alkynyl ethynyl and phenylethynyl), alkanoyl formyl, acetyl, and propionyl), acyloxy acetyloxy), acylamino, alkylsulfonyl methylsulfonyl), phenyl, benzyl, an azo group phenylazo), optionally substituted heteroaryl 3-pyridyl), optionally substituted ureido 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 10 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 S 15 formula I.

Method B: A synthetic method of the compound wherein and R 3 is optionally substituted arylene or optionally substituted heteroarylene, R 4 is and R 5 is optionally substituted aryl or optionally substituted heteroaryl.

Method C: A synthetic method of the compound wherein R 3 is optionally substituted arylene or optionally substituted heteroarylene, R 4 is a bond, and R 5 is optionally substituted aryl or optionally substituted heteroaryl.

Method D: A synthetic method of the compound wherein R 3 is optionally substituted arylene or optionally substituted heteroarylene, R 4 is -CO-NH-, and R 5 is optionally substituted aryl or optionally substituted heteroaryl.

Method E: A synthetic method of the compound wherein R 3 is optionally substituted arylene or optionally substituted heteroarylene, R 4 is tetrazol-diyl, and R is optionally substituted aryl or optionally substituted heteroaryl.

Method F: A synthetic method of the compound wherein R 3 is optionally substituted arylene or optionally substituted heteroarylene, R 4 is -CH=CH-, and R 5 is optionally substituted aryl or optionally substituted heteroaryl.

Details of these methods are explained as follows.

(Method A)

R

1 R 1 Process 1

H

2 N COOR 1 5 Pro s RS-R 4

-R

3 -S0 2 -N COOH

R

5

-R

4

-R

3 -S0 2 -Hal R2 XV Ia-1

R

i Process 2 P J Ia-I R R4-R -SO 2 -N CONHOH

.R

Ib-1

R

1

XVI

protective group, R16 iS a hydroxy protective group, and Hal is halogen.

igo Conversion of compound (XV) to compound is sulfonation of an amino group of the compound (process If necessary, after this reaction, N-alkylation, deprotection of a c a r b oxyl protective group, etc. are carried out. Conversion of Conversion of compound (XV) to compound (Ia-1) is sulfonation of an amino group of the compound (XV) (process 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 To obtain compound (Ib-1) from compound compound (Ia-1) may also be reacted with hydroxylamine having a hydroxyl protective group or its acidic salts to give compound (XVI) (process followed by and deprotection (process 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 (XV) is reacted with a sulfonating agent such as sulfonyl halide represented by RR 4

-R

3 -SO2Hal (R 3

R

4 and R 5 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 (XV) or its acidic salts 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, 1689-1700, 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, 1787, 1978, Synthesis 852-854, 1986, etc.

A carboxyl protective group is exemplified by esters methyl ester, tert-butyl ester 10 and benzyl ester). Deprotection of this protective group may be carried out by hydrolysis with acid hydrochloride and trifluoroacetic acid) or base sodium hydroxide) depending on the type of the group, or by catalytic reduction, under palladium-carbon catalyst condition. To obtain a compound the esters may directly be converted to hydroxamic acid by the method of process 2. When a compound (XV) is an amino acid wherein R' 5 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 R 15 is a protective group such as an ester, a solvent for S S this sulfonylation is exemplified by the above solvents and mixed solvents of waterinsoluble solvents 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 R 3

R

4

R

5 or R 15 of compound (la-1) contains a functional group(s) possibly interfering this sulfonylation 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 R 2 is not hydrogen atom, compound (Ia-1) wherein R 2 is hydrogen atom is further reacted with haloalkyl methyl iodide, and ethyl iodide) or haloaralkyl benzyl chloride, and benzyl bromide) in dimethylformamide, 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-R 2 derivative.

(Process 2) A hydroxylamine is reacted with compound (la-1) or its reactive derivatives to give hydroxamic acid derivatives A hydroxylamine is usually used as its acidic salts hydrochloride, and phosphate, sulfate: commercially available) in the S. presence of a base. A base to be used in this reaction is exemplified by organic bases 10 such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc.

When compound (la-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 dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'carbonyldiimidazole, or a mixture of one of the above agents with 1hydroxybenzotriazole, N-hydroxy sucinicimide, etc.). A solvent for this reaction may be dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, and mixed solvent thereof. This reaction is carried out at -20 C to 40 °C, 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 (Ia-1) with acid halide derivatives ethyl chlorocarbonate) in the presence of a base triethylamine), and acid halide derivatives can be produced by a reaction of compound (Ia-1) with a halogenation agent oxalylchloride, and thionylchloride). Ester derivatives may be inactive or active. Sulfonyl derivatives converted from a compound (XV) wherein R 15 is a carboxyl protective groups methyl, tert-butyl, and benzyl) at process 1 can be used as inactive esters without deprotection. Active 16 esters can be produced by a reaction of compound carbodiimide reagents dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and hydroxy derivatives corresponding to the active ester residue such as 1hydroxybenzotriazole, 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) 10 A protected hydroxylamine to be used in this reaction includes Obenzylhydroxylamine, O-(p-methoxybenzyl)hydroxylamine, O-(tertbutyl)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 cone. hydrochloric acid, or treatment with trifluoroacetic acid to give the desired compound The compounds of this invention (Ia-1) and (Ib-1) can be isolated and purified by usual separation methods and purification methods chromatography, crystallization, etc.).

(Method B)

R'

RIProcess 1 1 Process 2 H C(Hal-)R"-SO2-N

COOR

15

H

2 N COOR

H

XV

XVII

R

1 R'

COOR'

5 Process 3

R

7

-CC-R'

7

-SO

2 -N COOR15 Pros R -CEC- 17SO 2 -N COOH H R2 xvII Ia-2

R

1 Process 4 R -C C-R"-S 2 -N CONHOH 112 2 Ib-2 wherein R 2

R

7

R

15 and Hal are as defined above, R 17 is optionally substit ted aryl or optionally substituted heteroaryl.

Conversion of compound (XV) to compound (XVII) is performed by sulfonation S 5 of an amino group of compound (XV) (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 Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 4467(1975) etc.) wherein halogen of R 17 is utilized to insert a triple bond (process Conversion of compound (XVIII) to compound (Ia-2) is N-alkylation, deprotection of a carboxyl protective group, etc. (process which can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-2) to t compound (Ib-2) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 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 Pd(Ph3P) 2 C12), a divalent copper reagent Cul), and an organic base 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, 10 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

S

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

1

R

1 (Hal-)R7-SO,-N COOR 15 Process 1 R 7 -R-SO2-N COOR 1 H H XVI XIX

R

1

R

1 Process 2 Process 3

R

7 Proe R R 1 7 -S0 2 -N COOH Procs R'-R 1 -S0 2 -N CONHOH

R

2

R

2 Ia-3 Ib-3 wherein RI, R 2

R

T

R

1 5

R

17 and Hal are as defined above.

Conversion of compound (XVII) to compound (XIX) is performed by Suzuki reaction J. Sharp and V. Shieckus, Tetrahedron Lett., 26, 5997 (1985) etc.) wherein halogen of R 1 is utilized to introduce aryl or heteroaryl (process 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 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.

S. (process 1) 10 Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having a B(OH)2 (otherwise B(Et)2) group such as phenylboronic acid in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst Pd(Ph3P)4) and a base potassium carbonate, calcium carbonate, triethylamine, sodium methoxide S 15 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

1 Process 1 2N)R7_ 2 COOR 15 Process 2

R

1

R

1 Process 3 11 H

(H

2

N-)R

7 -S0 2 -N COOR 5

R

7

-C-N-R-SO

2 -N COOR 1 H

H

XXI

XXII

R

Process 4 9 H Process

R--C-N-R

7

-SO

2 -N COOH Ia-4 R1 R R7-SO-N CONHOH

.R

2 Ib-4 wherein R 2

R

7

R

15

R

17 and Hal are as defined above.

Conversion of compound (XV) to compound (XX) is sulfonation of an amino group of the compound (XV) (process 1) and this process may be carried out in the same 5 manner as that described in process 1 of method A. Conversion of compound (XX) to compound (XXI) is reduction of a nitro group of R 17 to an amino group (process 2) and this process can be carried out by catalytic reduction or other reduction using i 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 R" is utilized (process 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 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 (XX) is treated with hydrogen in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, etc. in the presence of a catalyst Pd-C, PtO 2 Raney Ni etc.) under a no-pressure or pressured condition to give the desired 10 compound (XXI). This reaction is carried out at a temperature under ice-cooling to 80 preferably room temperature to 50 C, and is completed for 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 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 t, preferably room temperature to 60 and is completed for 3 to 30 hours, preferably 10 to 25 hours.

I

(Process 4) This process may be carried out in the same manner as that described in process 1 of method A.

(Process This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

(Method E)

R'R'

R Process 1 Process 2 HC 1 5

(CH

2 =CH-)R -SO 2 -N COOR 15

H

2 N COOR

H

xv xxm

R

1

R

1 17_C R 15 Process 3 0 2 H H 17 15 (OHC-)R-S0 2 -N COOR R-S-N-N=C-R -S0 2 -N COOR i s H H xxrv xxv XXIV XXV

R

1 Process 4 N=N Process SR 7 N/ R SO2-N COOR 1 5 N

H

R R 1 N=N Process 6 N=N

R

7 SO0-N COOH Pr o ce R7N R-SO 2 -N CONHOH N R 2 N 2 Ia-5 wherein R 1

R

2

R

7

R

15

R

17 and Hal are as defined above.

Conversion of compound (XV) to compound (XXIII) is performed by sulfonating an amino group of the compound (XV) (process 1) in the same manner as 5 that described in process 1 of method A. Conversion of compound (XXIII) to compound (XXIV) is done by the reduction wherein an ethenyl group ofR 17 is converted into an aldehyde group (process Conversion of compound (XXIV) to compound (XXVI) 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 (XXVI) (process 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 hydroxamic acid derivatives (process 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 (XXIV) The reduction can also be carried out by catalytic hydrogenation. This reaction is carried out at -100 °C to room temperature, preferably -78 'C to a temperature under icecooling, and is completed for 0.5 to 10 hours, preferably 1 to 3 hours.

(Process 3) 10 A compound (XXIV) 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 (XXV). This reaction is carried out at a temperature under ice-cooling to 80 preferably room temperature to 50 and is completed for 3 to 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 ethanol) and water. To this mixture cone. hydrochloric acid and a diazotizing agent such as a sodium nitrite aqueous solution are added at -20 'C to 10 preferably 0 "C to 5 C, 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 (XXV) and allowed react for 1 to 10 hr, preferably 2 to 5 hr, at -30 'C to 50 C, preferably -15 'C to room temperature to giv the desired compound (XXVI). 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 This process may be carried out in the same manner as that described in process 1 of method A.

(Process 6) This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

(Method F)

R

1

R

1 S Process 1 H H

(OHC-)R-S

2 -N COOR 5 R -C=C-R -SO-N COOR H H XXIV XXVII

RC

Process 2 H H 1 Process 3 R7C= -R7-SO2- N

COOH

2

R

2 S* Ia-6

R

1 7 H 17 R -C=C-R -S0 2 -N CONHOH '2 R 2 Ib-6 wherein R 1

R

2

R

7

R

15

R

17 and Hal are as defined above.

Conversion of compound (XXIV) to compound (XXVII) is performed by Wittig reaction Wittig et al., Chem. Berr. 87, 1318 (1954)) wherein an aldehyde group of

R"

7 is utilized to introduce aryl or heteroaryl through a double bond (process 1).

Conversion of compound (XXVII) to compound (Ia-6) is N-alkylation, deprotection, etc.

of compound (XXVII) (process and this process can be carried out the same similar as described in process 1 of method A. Conversior' of compound (Ia-6) to compound (Ib-6) 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 (XXIV) is reacted with ylide derivatives of optionally substituted aryl or optionally substituted heteroaryl such as Ph 3 P=CHPh, etc., which is produced by an usual method, in a solvent such as toluene, xylene, tetrahydrofuran, ether, dimethylformamide, etc. at -100 C to room temperature, preferably -78 "C to icecooling for 1 to 20 hours, preferably 1 to 5 hours, to give the desired compound (XXVII).

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 10 process 1 of method A.

(Process 3) This process may be carried out in the same manner as those describe 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 lithium, sodium, and potassium), alkaline earth metals magnesium and calcium), ammonium, organic bases, amino acids, mineral acids hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids 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 metalloproteinase, 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 HIV), 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.

10 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 parenteral administration such as injections, suppository, percutaneous formulations, insufflation, 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 mg/kg/day, preferably 1 20 mg/kg/day. In the case of parenteral administration, the daily dosage can generally be between 0.01 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) S Process 1

H

2 N COOH

S

0 2 -N C OO H XV-1 Ia-1-1 Process 2*

'S

To a suspension of (R)-(+)-phenylalanine (compound XV-1, 1.65g (10 mmol)) in 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 4biphenylsulfonyl chloride in 10 ml of dimethylformamide was added dropwise to the 10 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-dimethylaminopropyl)carbodiimide hydrochloride, 3.47 g (50 mmol) of hydroxylamine hydrochloride, and 7 ml (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 HC1, 5% NaHCO3, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl3 MeOH 40/1 to 20/1 were collected to yield 1.70 g of compound (Ib-1-1) as a foam.

Yield 43%. mp. 169-170'C.

Elemental analysis C2 1 H2oN204S Calcd. C; 63.62, H; 5.08, N; 7.07, 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, 1674, 1320, 1159.

NMR (6 ppm) d 6 -DMSO: 2.61 (dd, J=8.6, 13.4Hz, 1H), 2.80 (dd, J=6.0, 13.6Hz, 1H), 3.80 1H).

+18.5± 1.2 (c=0.503 25C, DMSO) Example 1' Another synthetic method of compound (Ib-1-1) p-TsH Process 1 p-TsOH SO N" "COOCH

H

2 N COOCH 2 Ph SO 2 -N COOCH 2 Ph -a-1-1' Process 2 S N, COOH Process 3

H

a-1-1 I Process 4 -Process j- SO2-N CONHOCH 2 Ph XVI-1 Process 1 To a solution of (R)-phenylalanine benzyl ester tosylate (compound XV-1', g (5.85 mmol)) in 60 ml of dichloromethane was added triethylamine (1.8 ml, 12.87 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 HC1, 5% NaHCO3 and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCla MeOH 40/1 to 20/1 were collected and crystallized from dichloromethane hexane to give 2.32 g of compound Yield 84.1%. mp. 130-131C.

Elemental analysis C 28 H2 5 N04S Calcd. C; 71.32, 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 (Nujol): 3352, 1732, 1341, 1190, 1163.

NMR (6 ppm) (CDC3): 3.06 J=5.8Hz, 2H), 4.30 (dt, J=6.0, 9.0Hz, 1H), 4.89 2H), 5.12 J=9.0Hz, 1H), 6.98-7.81 14H).

-16.4±1.1(c=0.506 25'C, MeOH) Process 2 10 A solution of compound (2.28 g) which was obtained process 1 in 50 ml of mixed solvents of methanol ethyl acetate 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 Yield 99.1 mp. 146-147C.

15 Elemental analysis C 2 1H19NO4S Calcd.: C; 66.12, H; 5.02, N; 3.67, S; 8.41 Found: C;65.97, H; 5.06, N; 3.61, S; 8.48 IR v max (cm- 1 (Nujol) 3408, 3305, 1751, 1325, 1161, 1134.

NMR (6 ppm) (CDCl1): 2.97 (dd, J=7.0, 13.8Hz, 1H), 3.14 (dd, J=5.2, 14.0Hz,lH), 4.13 1H), 7.03-7.78 14H).

-4.0±0.4(c=1.000 25'C, MeOH) Process 3 To a solution of compound 1.0 g (2.62 mmol)) which wPs 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 NaHCO3 1.54 g (18.34 mmol) in 10ml of tetrahydrofuran and of water was stirred for 5 min under ice-cooling. To the mixture was added the above solution of acid chloride in tetrahydrofuran and the resulting mixture was stirred for 30 min. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with 5% NaHCO3, and water, and concentrated in vacuo to give compound (Ia-1) (969 mg). Yield 93.3 Process 4 To a solution of compound 2.0 g, 5.24 mmol) which was obtained process 2 in dimethylformamide (20 ml) was added 1-hydroxybenzotriazole hydrate (0.7 g, 5.24 mmol), N-methylmorpholine (2.9 ml, 26.2 mmol), 1-ethyl-3-(3diisopropylamino) carbodiimide hydrochloride (8 mmol), and O-benzylhydroxylamine 10 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 HC1, 5% NaHC03, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CH2Cl2 hexane 1/1 were collected 15 and recrystallized from dichloromethane hexane to give 2.04 g of compound (XVI-1).

Yield 80 mp. 171-173C.

Elemental analysis C28H26N204S Calcd.: C; 69.12, H; 5.39, N; 5.76, S; 6.59 Found 68.85, H; 5.46, N; 5.76, S; 6.78 20 IR v max (Nujol) 3248, 1661, 1594, 1333, 1163.

NMR (8 ppm) (CDC13): 2.85-3.60 2H), 3.86 1H), 4.77 (ABq-Apart, J=11.4Hz, 1H), 4.82 (ABq-Bpart, J=11.4Hz, 1H), 5.00 1H), 6.95-7.70 19H).

[a -40.2 ±1.6 (c=0.505 25C, DMSO) Process A solution of compound (XVI-1) (1.97 g) which was obtained process 4 in a ml of mixed solvents of methanol ethyl acetate =1/1 was hydrogenated using 10 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 Yield 84.4 Example 2 91 The compounds which were shown in Tables 1 to 22 were synthesized in a manner similar to those described in Example 1' .e .e a a a a a a a a

R'

8

'SO

2 NH CONHOH (1b) Example R R mp (decomp.) IR (v cnv') IH-NMR(O ppm) No. (IKBr) d6-DMSO 2.87(dd,J=5.6,14.2Hz,1 2.98(dd, s R 73> 3258,1650,1377, J=8.4,14.2Hz,1 H),4.02(dd,J=2.2, 2 S'HN 13 1348,1163 (Nujol) 8.6Hz,1 7.24(d,J=2.0Hz, 1H), 8.83(d,J=2.2Hz,1 H)

H

3 N R 20-0 3403,3386,3265,1673 2.72(dd,J=7.2,1 3.8Hz, 1H), 2.97(dd,

OH

2 0i2-0i- R 0-0 1320,1162 (Nujol) 7.0,14.8Hz, 1H),3.81 1H), H E N-I 277,669,397, 3.12(dd,J=1O.3,14.3Hz,1H), 3.89(dd, RS 12412 1327,1669,137 J=3.3, 13.5Hz, 1 H),4.20(m, 1 5.90 1322,159,(brs, 1 H)

CH

2 6 H 19-41 3262,1663,1322, 2.67(dd,J=9.2,1 3.1 Hz, 1 2.84(dd, 6 O H 2- R 1911 1157, J=5.3,13.5Hz, 1 H),3.82(m, 1 H) 7 F3H2 R 16-19 3265,1676,1642, 2.2-2.7(m,2H),3.99(t,J=7.OHz, 1 H) ur~ 3 u~12-R 16-169 1337,1161 (Nujol) 8EHC2 S 1713 3403,3261,1669, 1 .68(m,2H), 2.37(m,2H), 3.64(t, ~jCHCH2 17173 1321,1160 J=6.9Hz,1 H) 3700-200br3264, 2.61 (dd,J=9.4,13.8Hz, IH),2.78(dd, 9 CH 2 BrR 144-146 1,34-20b,164, J=-6.0,13.8Hz,1 H),3.78(m,1 H),7.43 1635,342,164, (d,J=8.2Hz,2H),7.60(d,J=8.2Hz,2H), 0 6 Ob) Rl&S0 2 NH *CONHOH r-r r I Example No.

mp (decomp.) Oc) IR (v cm-1) (KBr) IH-NMR(d ppm) d6-DMSO I t O CH 2

F

3 C 116-118 3600-2400br,3257, 1743,1721,1323,1132, 2.60-2.82(m,2H),3.84(m,1 H),7.00- 7.1 8(m,5H),7.62-7.80(m,4H), 1 1-4 I t O- CH 2 (0H 3 2

CH-

(C H 3 2

N~

91-92 3700-2 1 Obr,31 76, 1664,1320,1143, 2.70-2.93(m,2H),2.82(s,6H), 3.75(m, 1 H), I 4-4 I i i

H

3

CO-

178-179 3268,1632,1598, 1336,1162 0.71 (d,J=6.8Hz,3H),0.74(d,J=5.4Hz,3H),1.

73(m,1 H),1 .73(m, 1 H).3.22(m,1 H),3.82(s,3 H) ,7.05(d,J=9.OHz,2H),7.69(d,J=9.OHz,2H) 4 02NG CH2- GHa 184-185 3257,1662,1516, 1344,1322,1160, 2.80(ddJ=1 0.0 1 3.8Hz,1 H),2.92(dd, J=5.O,12.8Hz,1 H),3.90(dd,J=5.4, 9.6Hz, 1 H), 4-1 4 1

FOG~CH

2 0-0- 128-130 3258,1669,1509, 1322,1157 2.62(dd,J=9.9,13.5Hz,1 H),2.78(dd, J=5.8,1 3.OHz,l H),3.77(t,J=6.2Hz, 1 H), C-R 16-6 3278,2920,1632, 0. 50-1 .62 1 3H), 3.56(t,J= 5 0\>-H2 0(x-0 6-6 1337,1161' 7.4Hz, 1H)

CH

3 172-173 3272,1631,1332, 1161 2.71 (dd,J=7.9, 14.2Hz, 1 H),2.94(dd, J=6.9,1 4.2Hz,1 H),3.57(s,3H),3.83 (dd,J=7.0,7.4Hz,1 H) I I I .L 4.

H

0-0- 144-146 3404,1670,1320, 1159 2.25(s,3H),2.67(dd,J=7.5, 14.2Hz, 1 H),2.95(dd,J=7.7,14.6Hz,1 H), 3.81 (dd,J=6.2,14.2Hz, 1H) r"3%.1 I I 9.* S

S

S S S S S S S S S S S S S S *5 555 Rl&SO 2 NH CONHOH (1b) Example R mp (decomp.) IR cm-1) 'H-NMR( 6 ppm) No. Xt) (KBr) do-DMSO 1 S3420,1670,1592, 2.72(dd,J=8.0, 14.0Hz, 1 H),2.90(dd, 18~j\~j' ~1321,1159 J=6.2,14.2Hz, 1H),3.82(m, 1H) 1 9 1OiIP11I1LCH 2

RS~

NS 118 3186,1593,1480, 2.68(dd,J=9.8, 13.7Hz,l1H),2.79(dd, N /jCH2. S 15- 1379 J=5.6,12.8Hz,1 H),3.85(t,J=7.0Hz,1 H), 3700240br,352, 3.22-3.38(m,2H),4.1 7-4.24(m,2H), 2 1 RS 111-115 1668,126,10b322 7.80(d,J=8.OHz,2H),7.96(d,J=6.4 166813261160Hz,2H) H_ 3455,3362,1672, 3.86(d,J=3.6Hz, 1 H).4.91 22 O S -1398,1162 (d,J=3.6Hz,1H) 2 R 19-17 3404.3315,1669, 4.88(d,J=9.4Hz,1 H),8.74(d,J=9.4Hz,1 H), 23 R 1961971594,1316,1162 8.98(s,1 H),10.92(s,1 H) 37002400br),473, 2.69(dd,J=7.6,13.5Hz, 1 H),2.93(dd, 24C2 OR 197-199 37020(r J=7.6, 13.5Hz, 1 H) ,3.77(t,J=7.6Hz, 1675,1310,1152 1H),(CD 3

OD)

2.74(dd,J=8.3, 13.5Hz, 1 H),2.95(dd, 2 5 F C2 O R 201 -202 3700-2200(br),3278, J=6.5,1 3.5Hz, 1 H),3.87(dd,J=6.5, \-jCH O -aj- 1706,1645,1322,1162 18.3Hz,1H),(CD 3

OD)

B C C Rl&-SO 2 NH CONHOH (lb) Example R mp (decomp.) IR cm'1) 'H-NMiR( 6 ppm) No. (KBr) dj6.DMSO 2 6 F J-CH 2 F- ji R 63-65 3700-2200(br),3362, 1670, 2.60(dd,J=9.0, 13.8Hz, 1 H) ,2.79(dd, 1590,1336,1152 J=9.3,1 3.8Hz,!H),3.76(m,1IH) 2.66(dd,J=9.5,13.6Hz,1I H),2.79(ddJ=5.

2 H- 0NR 70-71 3700-2200br,3372, 1674, 4,13.6Hz,l1H),3.84(m,l1H),7.73(A2

B

2 qJ= 27 ,rCH 2 0 2 1531,1348,1310,1161 8.9Hz,2H),8.20(A 2

B

2 q,J=8.9Hz,2H),8.7 2(d,J=9.OHz, IH),8.86(s. 1H), 10.7(s, 1H) 2 8 HOOC-CH 2

R-

2 9 HOOC-0H 2

-CH

2 0 R 3.29(dd,J=5.7,10.7Hz,1 H),3.43(ddJ= 30HOH2 R 19-13 3700-2400(br) .3392, 8.4.10.7Hz, 1 H),3.62(m,1 H),7.85(A 2

B

3 0HOC 2 R 92- 1667,1320,1161 2 q,J=8.7Hz,2H),7.88(A 2

B

2 q,J=8.7Hz, 2H),7.98(d.J=7.8Hz,1 H),1 0.61 1 H) -\--H20C132911632.69(dd,J=7.6, 13.5Hz, H)2.93(dd, 3 2 R 69-70 3700-2200(br),1 671, J=7.6,1I3.5Hz,1 H),3.77(t,J=7.6Hz, 2 0 H- CjFxjY12916 1H),(CD 3

OD)

3 2 HOOC-r-J CH 2 K-D R 33NR 160-162 3401,3260,1673, 2.66(dd,J=7.5, 13.4Hz,1 H),2.96(dd, ~1 t.4J C H 2 1316,1165 J=7.6,14.2Hz, 1H),3.81 (m,1IH) 9 a 9 9 9 Rl&'SO 2 NH CONHOH (lb) Example No.

34

H

N

N

H

mp (decomp.) (c) IR (v cm-') (KBr) IH-NMR(O ppm) d6-DMSO Br-~7) I

X

0r-0- 141-145 3700-2400(br), 1672, 1443,1327,1094 2.84-3.21 (m,2H),4.29(m, 1H) I I

R'

8 S0 2 NH COOH (1a) Example R' R* mp (decomp.) IR cm-) IH-NMR( 6 ppm) No. (KBr) d6-DMSO 2.95(dd,J=9.0,1 4.OHz,1 H),3.1 2(dd, s N RS 159-161 3276,2503br,1 897br, J=5.4,1 4.OHz,1 H),4.1 3(m,1 H),7.29 2 H-1724,1344,11 70(NujoI) (d,J=2.OHz,1 H),8.34(d,J=8.6Hz,1 1

-CH

2 -),8.88(d,J=2.OHz, 1 H),1 2.79(br, 1 H) H -2.88(dd,J=8.0,1 4.OHz,1 H),3.09(dd, 3N R 227-229 3386,3305,1747,1363, =.,4Oz1H)39(m1H,82 4 S 8-19 2400-3700(br),1 734, 2.75-3.06(m,2H),3.69(s,3H),3.90 O H 2 RS 1189 1484,1327,1160 1H) 3 CO C 3446306,154,197, 3.1 7(dd,J=7.4,1 3.8Hz,1 H),3.57(dd, 5K 3446,00 30654,1594137 J-5.5,13.9Hz, 1 H),3.80(t,J=5.6Hz, 1 H),8.1 1 (d,J=7.4Hz,1 H) 3184,723,337, 2.77(dd,J=9.7,13.7Hz, 1 H),3.03(dd, 6 OH 2 R 213-215 13184,171337 J=4.9, 13.3 Hz, 1 3.93 1 8.38 1317,1156 (d,J=8.8Hz,1H) R3276,1706,1344. 2.40-2.90(m,2H),4.05(m, 1 H),8.51 7CF 3

CH

2 176-1 77 1260,1165 J 0Hz, 1 13.2 (b r, 1 H) RS 153-156 3289,1739,1326 1 .83(m,2H),2.52(m,2H),3.70(m, 8 Gj-CH2CH2- -1159,1089 1 H),8.32 (d,J=9.OHz, 1H) 4k.2.86(m, 1H),2.87(s,6H),2.98(dd,J= R1 115 2200-3700br,3439,3288, 5.1,13.8Hz, 1 15(m, 1 H),5.54 1 H- (CH 3 2 N{ 10-0 1725,1329,1143 1H) S S

S

S

S S S

S

S S S S S S S S S S S S *5 S *S* R S 2 N COOH (1a) Example No.

1 3 mp (decomp.)

(C)

IR (v cm-1) (KBr) IH-NMR( 6 ppm) do-DMSO 1 16 0 2 N GJ0H 2 Q- CH 2

OH

3

N

H-

H

3 C C2

N-CH

2 OL-0CH2-

C

C

C

3113,724,520,2.86(dd,J=10.2,13.2Hz,1

H),

RS 212-213 313,171520 3.1 4(dd,J=4.5,1 3.7Hz,1 H), 1345,11584.02(m, 1H),8.42(d,J=8.4Hz,1

H)

3426,114,715, 2.71 (dd,J=9.9,1 3.7Hz,1 H),2.96(dd, RS 164-165 1429,1224,17159 J=5.3,13.5Hz,1 H),3.89(m,1 H), 1509122411598.34(d,J=9.0Hz,1

H)

R 8-72919,1688,1448, 0.52-1 .72(m,13H),3.68(m,1 jr-xjm R 8-871335,1326,1169 8.20(br.s,1H) RS 1913 3432.3294.1713, 2.80-3.12(m,2H),3.61 (s,3H), RS 17-183 1482,1341,1159' 3.94(m, 1H),8.30(d,J=8.6Hz,1

H)

RS 11-10 3419,3397,3291,1736, 2.28(s,3H),2.78-3. 1 O(m,2H),3.91 RS 11-10 1482,1336,1321,1165 1H),8.29(d,J=8.3Hz,1

H)

0 208-211 3407,3285,1751,1735, 1703,1486,1321,1162 8.29(d,J=8.2Hz,1 H) jRS 197-205 1 13 b,1635,19 4, 2.60-3.04 (m,2H),3.98 1 H) 196-199 2200-3700br,1 71 3br, 1345,1125 3.24-3.56(m,2H),4,34(m, 1 H) I_ I t R3 18 S0 2 NH COOH (1a) Example No.

R'

nip (decomp.) IR (v cm-1) (KBr) IH-NMR(6 ppm) d6-DMSO II-I4 2 2 2 3 2 8 2 9 3 1 32

H

0-

HOOC-CH

2

HOOC-CH

2

-CH

HOCH

2

HOOC(

0-0- 141-143 3335,3246,1732, 13 15,1152 4.10(d.J=3.2Hz,1 H),5.13(d,J= 3.2H1z, 1 H) R 2124 3316,1734,1325, 4.94(d,J=9.4Hz, 1 H),8.80(d,J= 0 -21-21 11 59(Nujol) 9.411z, 1H), 13.O(br.s,l1H) 171173 3353,1752,1326, 2.45(dd,J=6.2,1 6.4Hz,1 H)2.63(dd, R 1113 1155,1096 J=6.6,16.4Hz,1H), 1 z1 H)18(d 2- H2- 0-0o-c#

R

R

185-187 3270.1709,1336.

1 159,1093 J=6.O, 13.4H1z,1I H),2.22(t,J=7.2Hz, 2H),3.80(m,1 H), 277-279 2200-3700br,3430, 3292,1728,1324,1162 3.51 (dd,J=6.0,12.9Hz,1 H),3.55(dd, J=5.4,1 2.9Hz,1I H),3.80(m, 1 H), 8.06(d,J=8.7Hz,1 H)

I

I-I I 1- 0-0- 0-0- 89-91 2200-3700br.3432, 3289,1733,1330,1165 3.54(dd,J=4.8,9.9Hz,1I H),3.60(dd, J=5.7,9.9Hz, 1 H),4.04(m, 1 H), 4.39 (s,2H),8.34(d,J=8. 1 Hz, 1H) I IIi- ,H2- >270 3319,3052,1701,1317, 1284,1162 2.81 (dd,J=9.7,13.7Hz, 1H),3-05 (dd, J=4.8,13.4Hz,1I H),3.96(m, 1 H), 8.40(d,J=9.OHz,1I H),1I 2.88(br.s, 1 H)

L-

I a a..

a. a a a a. a a a a a. a. a. a a a a a a C a a

R'B

8 S0 2 NH COOH (1a) Example No.

mp (decomp.) IR (v cm-1) (KBr) 'H-NMR(e5 ppm) d6-DMSO I I-I 1-

H

'17z C N CH2- IAN -CH2-

H

N~

S43 243-246 3420,1588,1402, 1324,1151 3.06(dd,J=5.414.4Hz, 1 H),3.14(dd, J=5.1 ,14.4Hz,1 H),3.65(t,J=5.4Hz, 1 H),6.92(m,M ),10.72(s,1 I I 0-0- 151-156 2200-3700br, 1734, 1334,1161 3.17-3.50(m,2H),4.51 1H)

J

S

S

S

*5 .5

S.

S

*r S

S

S*

S S

SOS

*5* *5S S S 0@ S S *SS S S. S. S S S**

R

18 S0 2 NH COOH (1a) Example R R 1 mp (decomp.) IR (v cm') Elemental analysis No. (t (KBr) S0 2

CH

3 6 N RS >145 1726,1354 1326,1161 N7 -2 1732,1594 1404,1155 H C 24

H

22

N

2 0 5 S.0.5H 2 0 N R 1 9 1607,1594 Calc. C:62.73 H:5.04 N:6.10 S:6.98 38 H 3 co R 188-190 1294,1153 Foun.C:62.75 H:5.08 N:6.31 S:7.05 0111a, H2- H H 3 CO C 2 4

H

2 2

N

2 0 5 S*0.8H 2 0 39 N03 1724,1594 Calc. 0:62.00 H:5.12 N:6.03 S:6.90 CH 1326,1159 Foun.C:62.03 H:5.06 N:6.08 S:6.82

H

14152 1685,1349 4 0 ,H 3 C- j-Qj0 R 149-1 1166

H

N 1725,1599 4 1 iCH 2 F0 /R 104-107 1372,1173

H

N 1745,1653 42 iiCH H3CS- R 167-169 1391,1147

C

17

H

9

NO

4 S.0. 1 CF 3

COOH

332 R1714,1594 Calc. 0:59.99 H:5.58 N:4.06 S:9.30 1334.1166 Foun.C:60.37 H:5.74 N:4.13 S:9.76 a. (Ia)

R

1 -S0 2 NH COOH Elemental analysis

C

21

H

27 N0 4 S*O.3H 2 0 CaIc. C:63.87 H:7.04 N:3.55 S:8.12 Foun.C:63.84 H:6.86 N:3.42 S:8.01

C

23

H

23 N0 4 S-0.3H 2 0 CaIc. 0:66.58 H:5.73 N:3.38 S:7.73 Foun.C:66.45 H:5.52 N:3.24 S:7.56

C

17

H

18 FN0 4

S

CaIc. 0:58.11 H:5.16 F:5.41 N:3.99 S:9.12 Foun.C:58.11 H:5.17 F:5.86 N:3.92 S:9.69

C

27

H

23 N0 4 S'0.7H 2 0 CaIc. 0:68.98 H:5.23 N:2.98 S:6.82 Foun.C:69.08 H:5.09 N:2.91 S:6.73 t. a a a Ri

R

18 S0 2 NH *COOH (1a) Example R 1 mp (decomp.) IR (v cm') Elemental analysis No. X) (KBr) 52 CH 2

H

3 C R 157-160 1685,166 1691,1567 53 a ~-CH2- R 111-112 1391159 1390,1159 1749,1592 54 -CH2 HCS R 194-195 1323,1564 2- 1323,1164

C,

8

H

21 N0 4

S

2 -0.2H 2 0 R 197-199 1746,1337 Calc. C:56.43 H:5.63 N:3.66 S:16.74 5 (CH 3 2 CH- 3 S I 9-9 1164 Foun.C:56.74 H:5.67 N:3.86 S:16.35

H

6 N HOOC R 108-110 1649,1337 56 1165 011 1i: C H 2

H

7 5 N

(H

3

C)

2 N R 187-190 1588,1308 LI'I QILCH 2 1141

COOC

2

H

5 0211H 18

N

2 0 4

S

2 .0.3H 2 0 58 239-243 1744,1592 Calc. 0:58.40 H:4.34 N:6.45 S:14.85 1323,1160 Foun.C:58.40 H:4.44 N:6.58 S:14.57 H 02N 1751,1734 C 17

H

14

CN

3 0 6 S.0.3H 2 0 9 N R 222-224 1537,1347 Calc. C:47.48 H:3.44 CI:8.39 N:9.65 S:7.52 'CH- C \/1172 Foun.C:47.57 H:3.43 01:8.26 N:9.79 S:7.47 Rl&SO 2 NH CONHOH (lb) Example No.

mp (decomp.) IR (v cm-') (KBr) IH-NMR(O ppm) d6-DMSO I I-I I t O- H 2 foam 3700-2400br,3277, 1669,1325,1152 2.60(dd,J=8.7,1 3.7Hz,1 2.79(dd, J=6.O,13.7Hz,1 H),3.75(ddd,J=6.O, 8.7,9.0,1 H),6.94(d,J=8.9Hz.2H) L I-I I t

H

NfJiLCH, 0 115-118 3302,1667,1324, 1 153(NuJoI) 2.71 (dd,J=7.O,14.4Hz, 1H), 2.96(dd, J=7.0,14.2Hz,1I H),3.78(t,J=7.6Hz, 1 H) C al I i

H

0 3406,1670,1582, 1325,1153 2.71 (dd,J=7.9,1 4.4Hz,1 H),2.96(dd, J=7.6,1 4.4Hz,1 H),3.78(dd,J=7.2, 7.3Hz, 1 H) 4 4-4

(CH

3 2

CH-

0 149-151 3268,1634,1584, 1336,1157 0.76(d,J=6.6Hz,6H), 1 .77(m,1 H), 3.26(m, 1 H) 4i

OH

3 3314,1669,1582, 1420,1328,1154 2.71 (dd,J=7.9,1 4.2Hz,1 H),2.93(dd, J=6.5,1 4.3Hz,1 H),3.65(s,3H),3.78 (dd,J=7.1 ,7.2Hz,1 H) I.-II4 66 67

NH

H

3

C

F COCH 3 I{1a

OH

2 3405,1671,1582, 1487,1324,1154' 2.34(s,3H),2.65(dd,J=7.8,14.1 Hz, 1 H),2.93(dd,J=7.6,1 4.4Hz,1 H), 3.75 (dd,J=6.8,7.7Hz, 1 H) 4- C 0 3317,1670,1582, 1488,1323,1153 2.71 (dd,J=8.9,1 4.4Hz,1 H),2.89(dd, J=6.6,1 4.4Hz,1 H),3.75(dd,J=6.5, 6.8Hz, 1 H) I +i 0

G

3421,1702,1676,1582, 1354,1328,1153 2.54(s,3H),2.69-2.89(m,2H),3.87 1H) C

R

18

'SO

2 NH COOH (1a) Example No.

mp (decomp.) IR (v cur') (KBr) 1 H-NMR(6 ppm) d6-DMSO I I C

H

2 a0a 108-109 2400-3600br,3345,321 3, 1735,1700,1346,1163 2.72(dd,J=8.7,1 3.6Hz, 1H),2.94(dd, J=5.6,1 3.6Hz, 1 H),3.84(ddd,J=5.6, 8.7,8.7Hz, 1 H),8.23(d,J=8.7Hz, 1 H) H4037,7418 2.88(dd,J=7.4, 15.2Hz, 1 H),3.07(dd, N R 82-87 310,3276,1415 82jOI J=6.2,14.4Hz, 1H),3.83(m, 1H),8.08 CHT18,311 2~jl 1 H),1I0.80(s, 1 H),1I 2.70(br, 1 H)

H

0 om 3412,1724,1582,1488, 2.81-3.1 2(m,2H),3.88(m, 1H),8.1 9 I S2oa 1332,1152 (d,J=8.4Hz, 1 H)

(CH

3 2

CH-

OH

3 Ol T-

H

2 ao-a 137-1 38 3154,1720,1688,1583, 1488,1251 0.89(d,J=7.OHz,3H),0.98(d.J=6.8 Hz,3H),2.1 2(m,2H),3.80(dd,J=4.7 ,9.7Hz,l H),5.1 7(d,J=9.6Hz,1 H) I I. I 3273,1724,1582,1487.

133 1,1198,1153 2.78-3.1 0(m,2H),3.67(s,3H), 3.86(m,1 H) I 4-I I H0 H

F

COCH

3 ayI1CH2 3409,3281,1725,1582, 1331,1197,1153 2.34(s,3H),2.75-3.08(m,2H),3.86(m,1 H), 8.19(d,J=8.4Hz,1 H) I-I I 3415,1725,1582,1488, 1329,1196,1174,1152 2.78-3.08(m,2H),3.85(m, 1 18 (d,J=8.6Hz,1 H) I .l I4 FVO-a 236-237 3296,1742,1647,1604, 1581,1342,1334,1152 2.55(s,3H),2.79-3.1 1 (m,2H),3.98 1H) i S S S S S S S S S S S

S

R'

8 S0 2 NH COOH (1a) Example R' R 8*mp (decomp.) IR (v cm-) Elemental analysis No. (IC) (KBr) H16819 68 NHOa 0D R >240 1607,1590 a ICH2-1157

'SO

2

CH

3 13,53 C 24

H

22

N

2 0 7

S

2 6 S 1352,1583 CaIc. C:56.02 H:4.31 N:5.44 S: 12.46 6 9 J CHT 3217 Foun.C:55.75 H:4.4 N:5.41 SA 1.21

COOC

2

H

N 1733,1583 70H2 O\ RS 1150

S

S S.

S..

.6. S S S S S S S S S S S S S S S t S S S..

R'8-SO 2 NH CONHOH (Ib) Example R' R 1 mp (decomp.) IR (v cm'1) 'H-NMR( 6 ppm) No. XC) (KBr) d6-DMSO 0.90(t,J=6.8Hz,3H),1 .22-1 .40(m,4H),1 .52-1.6 7 1CH2 C3(C2)4R 29-31 3700-2400br,3247, 7(m,2H),2.62(t,J=7.7Hz,2H),2.86(ddJ=8.4, 13 7 1 j-CH- C~(CH)4-'jr- 129131 1636,1337,1160 .7Hz,1 H),3.02(dd,J=5.7,1 3.7Hz, 1H) (ODGI 3) 3700240br,163, 0.87(t,J=6.3Hz,3H),2.50(t,J=7.4Hz,2H), 7 2CH- C3(H27- ol 320 1 663,m 2.76(dd,J=9.6,1 4.OHz,1 H),2.87(dd,J=5.

2 \jr-rl2 CH(CH) 7 R ol 120,145(fim) 8,14.OHz,1IH),3.84(dd,J=5.8,9.6HZ, 1H), 3600-2400br,3262, 1673, 0.79(t,J=7.OHz,3H) ,2.32-2.56(m,2H), 7 3 GjCH2- CH 3

(CH

2 3 R oil 1321,1142 (CHCb) 2.92(m,1H),3.26(m,1 H), H ci ~CH 3 74IiC R 2.80(m,1 H),2.96(m,l1H),3.94(s.2H),3.86( 7 C2-R 5-6 3700-2200(br) ,3262, m,l1H) ,6.80-7.52(m,1 OH) ,7.08(A 2

B

2 qj=7.

7 5 H 2 58 1639,1332,1156 5Hz,2H) ,7.42(A 2

B

2 q,J=7.5Hz,2H) (CDC 3

H

7 6 c c 0 1 H- CN- R-

S

S S S S S S S S S S S S S S S S *5 S

RISO

2 NH CONHOH (lb) Example RR 1 g mp (decomp.) IR (v cm-1) IH-NMIR( 6 ppm) No. do.DMSO -7020(r,32 2.79(dd,J=8.5, 13.4Hz, 1 H),2.89(dd, 77 CH-R 13-3 1,3729(,344 J=6.0,13.4Hz, 1H),3.81 \K I 3-3 62,3914 8.5Hz, 1 H),6.55(d,J=1I5.5Hz 1 H) O- OH 2 aH 2 69-70 3700-2200(br),1 670, 131 8,1152 2.78(dd,J=8.6,1 3.4Hz,1 H),2.91 (dd,J=6 .0,1 3.4Hz,1 H),3.92(ABq,j=1 3.5Hz, 1 H) ,3.90(m,1 H),9.01 (s,1 H),1 0.78(s,1 H) I 4-1 4

H

M NiLC

&-H

II H _1 VO. *9

R

18

'S

2 NH COOH (1a) Example R'Rmp (decomp.) IR (v cm-1) 'H-NMR( 6 ppm) No. (KBr) d6-DMSO 2300-3700br,3426,331 8, 0.89(t,J=6.7Hz,3H),2.62(t,J=7.6Hz,2H),2.96(d 7 H- CH 3

(CH

2 4 R~j 121-122 1713,133,159 d,J=7.0, 13.9Hz, 1 1 O(dd,J=5.4, 13.9Hz, 1 H) R 1 33,1 4.1 9(dt,J=6.9,8.2Hz, I H),5.30(d,J=8.2Hz, I H), 2400-3600br,3340, 1736, 0.88(t,J=6.9Hz,3H),2.55-2.73(m,2H),2.9 7 H- CH 3

(CH

2 7 R oil 1334,1142(CHCb) 7(dd,J=8.4,13.8Hz,1IH),3.24(dd,J=4.8,13.

\~j/~"28Hz,1H),4.35(m.1H),4.98(m,1H) (CDCb) 0.84(t,J=7.1 Hz,3H),2.57-2.70(m,2H),2.97(d 7 H- CH 3

(CH

2 3 R 89-90 2300-3700br,3240, d.J=8.4,1 3.9Hz,1 H-),3.25(dd,J=4.8, 13.9Hz. I 73 1725,1341,1144 H),4.35(m,1 H),4.96(d,J=9.6Hz,1 H) (00013) H fN ci OH3 3421,1580,1333, 2.41 (S,3H),3.01 (dd,J=6.0,14.4Hz,1 H),3.

41 R >250 1421,1153 1 2(dd,J=4.5,1 4.4Hz,1I H),3.67(t,J=5.4Hz, I1-S 1 H),6.79(m, 1 H),6.89(m, 1 1 0.59(s, 1 H) H 3.03 (dd,J=6.5,15.l Hz, 1 H),3.15 INY 3413,1594,1456, 7 6 0 N N- R foam 1416,1157 (dd,J=4.7, 14.1 Hz, 1 H),3.64(t,

CH

2 J=5.1 Hz, 1 H),1I0.68(s,1I H) N.2400-3700br,3252, 1765, 2.81 (dd,J=9.2, 13.7Hz,1I H),3.03(dd,J=5.4, 13.7H 7 7(!]-CH 2 /R 1725,1301,1140 Z, 1 H),3.94(dt,J=5.4,9.2Hz, 1 H),6.66(d,J= 1 5.2H z,I1H),7.16(d,J= I5.2Hz,1IH),8.01 (d,J=9.2Hz, 1H) 2200-3700br,3268,1 726, 2.81 (dd,J=9.2, 13.7Hz,1 7 8F9-CH 2 ~CH2- R 1321,1152(film) =5.6,1 3.7Hz,1 H),4.01 (ABq,J=1 3.7Hz 2H),4.01(m,lH),7.65(d,J=8.3Hz,lH) H 0.90-1.68(m,9H),1.78(m,1H),2.74 NH- R 3413,2931,1720,1585, 377, -NH- H ~~~1455,1421,1313.1144 (n H,.032(,H,.7m C112-___ H)6.45(br.s, 1H),6.77(br.s, 1H) a a a a a a a a a a a S a *aa

RA

R

18 S0 2 NH COOH (1a) r-r r r Example No.

mp (decomp.) (r) IR (v cm-1) (K~r) Elemental analysis I I--I I- G-CH2t Bu 153-155 1704,1596 1349,1164 4- I-f I

H

N

H

N

n-C 8 H1 17 >130 1576,1356 1139 I I t

N

0) 128-130 1732,1342 1167

C

24

H

19

N

3 0 5 S-1.3H 2 0 Calc. C:59.45 H:4.49 N:8.67 S:6.61 Foun.C:59.43 H1:4.45 N:8.59 S:6.58 I i

H

3

N

H

4 NIi 12 C 2 0: 210-214 1745,1590 1316,1157 I 4-F t I 198-200 1594,1456 1200,1188 J 9* Rl&-SO 2 NH CONHOH (lb) Example R*R mp (decomp.) IR (v 'H-NMR( 6 ppm) No. (IKBr) dci-DMSO 8 5 H2- 15-160 3700240br,373, 2.65(dd,J=8.9,13.6Hz, 1 2.82(dd, 157-160 6,1380-40b,166 J=6.6,1 3.6Hz,1 H),3.86(m,l1H),7.75 ~x~rH2~ 633,338,166(d,J=7.8Hz,2H),7.87(d,J=8.7Hz,2H) 86 M2N :N 700-400r,221, 262(dd,J=8.6, 13.5Hz, 1 H),2.81 (dd,J=6.

CH-R 138-142 1721314,165, 5,113.6Hz,1 H),3.09(S,6H),3.83(m,1 H),6

OH

2 162,114,165, .86(d,J=9.OHZ,2H),7.83(d,J=8.8Hz,2H) 8 7F\\OH2 1 3700-2400(br) .3357,1686, 2.7d,=.313.6Hz,1 H),2.79(ddJ=6.O, 13.6Hz, I 8l 7 ,-H 2 S 206-207 H),3.76(m.1 H),8.02(d,J=8.7Hz1 H),8.80(s,1 H),8.8 H H 1641,1314,1155 5(d.J=1.7.lH-),9.06(sIH),10.59(d,J=1 .7Hz.1H) 6 6* 6 6* 6 6* 6*

R

18

'SO

2 NH COOH (1a) mp (decomp.) IR (v cm- 1 'H-NMiR( 6 ppm) X) (JKBr) dfi-DMSO 240-360br342,326, 2.75(dd,J=9.1 ,l3.7Hz,1 H),2.98(dd, .1 172-174 1698,1350b,1639 J-5.5,13.7Hz, 1 H),3.96(ddd,J=5.5, 1698,130,11679.1 ,9.lHz,1H),8.51 (d,J+9.1 Hz,1H) 2200370br,331, 2.74(dd,J=9.1 ,13.6Hz, 1 H),2.96(dd,J R 93-94 1735,13910b,143 =5.7,13.6Hz, 1H),3.09(s,6H),3.93(dt, 1735,1391 1154J=5.7,9.l1Hz,1 H),8.39(d,J=9. 1Hz,l1H) 2300-3700br,3358, 2.71 (dd,J=9. 1,1 3.7Hz,1 H),2.93(ddJ=5.6 3 203-204 3262,1718,1686, ,13.7Hz,l H),3.84(dt,J=5.6,9.l Hz,I1H),8.

1660,1313,1159 11 (d,J=9.1 Hz,1 H),8.78(s,1 H),9.06(s,1 H) 4 4 4 4 44 .4 4* 4444 4444 4 4 4 4 4 444444444 4 4 4 4* 44 4 4. 4 *44 *44 **4

R

18 S0 2 NH *COOH (1a) Example R' mp (decomp.) IR (v cm') Elemental analysis No. (KBr)

H

8 8 5 N N-C- R 103-106 1719,1390 HO 1229 1734,1461

C

1 7

H

2 0

N

2 0 6

S

2 OO.M9hylether

(CH

3 2 CH- Q R 96-99 1734,1461 Calc. C:51.63 H:6.10 N:5.85 S:13.38 802H 1327,1158 Foun.C:51.23 H:6.17 N:5.87 S:13.11 1724,1325

~C

1 8

H

2 1

N

3 0 6

S

2 0.8Ehylether -N-NZC R 110-112 1724,1325 Cal. 0:51.05 H:5.86 N:8.42 S:12.86 \/0 2 H H 1168 Foun.C:50.75 H:5.89 N:8.15 S:12.47 O-CH2- Br -OS- h 98-101 1735,1598 1327,1185 C21 H 19 BrN 2 06S 2 0.5CF 3 C00H CaIc. C:44.30 H:3.30 Br:13.40 N:4.70 S:10.75 Foun.C:44.62 H:3.52 Br:13.07 N:4.64 S:10.85 Example 92 (Method B) i il-Process 2- HCl Process 1 B 3 0-

H

2 N ~'COOMe CS H XV-2 XVII-1 MeO S0- Coome Process 3 S H xvIll-1 :MeO I IS0 2 -N COOH ES H .Ia-2-1 0 Process 1 To a solution of D-valine methylester hydrochloride (XV-2) (755 mg, 4.5 mmol) 5 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 icecooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HC1, 5% NaHCO3, and water. The organic layer was concentrated in vacuo, and dried over Na2SO4. The residue was subjected to silica gel column 10 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'C.

Elemental analysis CioH1 4 BrNO4S2 Calcd. 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 [ar D: -34.5 ±0.7(c=1.012 CHC13 IR(CHC1 3 V max cm'1)1737,1356, 1164,1138 NMR (CDCl3, 8 ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz, 3H), 2.00 (in, 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 under an argon atmosphere. Then 39 mg (0.05 x 1.12 mmol) of bis(triphenylphosphine)paladium dichloride (II) and 0.47 ml (3 x 1.12 mmol) of triethylamine were added to the reaction mixture. The resulting mixture was degassed and stirred overnight under an argon atmosphere at 50 1C.

The reaction mixture was diluted with ethyl acetate. The organic later was washed with 1N HC1, 5 NaHCO3, and water, dried over Na2S04, and concentrated in vacuo.

The resulting residue was column chromatographed on silica gel. The fractions Seluting with n-hexane ethyl acetate 2/1 were collected and recrystallized from ethyl acetate n-hexane to give 392 mg of the desired compound (XVIII-1). Yield 86 mp.

S131-132C.

15 Elemental analysis C19H21N05S 2 -0.2 Calcd. C; 55.51 H; 5.25 N; 3.41 S; 15.60 Found C; 55.80 H; 5.19 N; 3.38 S; 15.36 IR(KBr, v max cm-) 3268,2203,1736,1604,1524,1348,1164.

NMR(CDCl3, 8 ppm) 0.90(d, J=6.6 Hz, 3H), 1.00(d, J=7.0 Hz, 3H), 2.00(m, 1H), 3.60(s, 20 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, °0o 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 C. 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 Na2SO4, and concentrated in vacuo to give 373 mg of compound Yield 100%. mp. 147- 148'C.

IR (KBr, v max cm-) 1710,1604,1351,1216.

Elemental analysis C18Hi9N05S2 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 S; 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.

57 00 0 0 :0* R1 8 -S0 2 NH *COOH (1a) Elemental analysis

C

26

H

22

N

2 0 5

S

Ca~c. 0:65.81 H:4.67 N:5.90 S:6.76 Foun.C:65.34 11:4.90 N:5.56 S:6.40

C

26 H1 20

N

2 0 6 S-0.4H1 2 0 Calc. 0:63.00 11:4.23 N:5.65 S:6.47 Foun.C:62.99 H1:4.32 N:5.82 S:6.76

C

25 11 21

N

3 0 4 S.0.8H1 2 0 Calc. 0:63.36 11:4.81 N:8.87 S:6.77 Foun.C:63.45 11:4.92 N:8.77 S:6.57 6

RM

8

SO

2 NH COOH (1a) Elemental analysis

C

26

H

22

N

2 0 4 S-O.2H 2 0 CaIc. 0:67.57 H:4.89 N:6.06 S:6.94 Foun.C:67.66 H:4.77 N:6.09 S:6.71 Cj 9

H

1 8

N

2 0 6 S0-1 H 2 0 Caic. C:56.46 H:4.54 N:6.93 S:7.93 Foun.C:56.30 H:4.37 N:7.14 S:7.85 S S S S S S S S* S S S S S S S S S S S S S S S S S S. S 555 SSS

RI

R'

8 S0 2 NH COOH Elemental analysis 021 H 23 N0 5 S.1 .3H 2 0 Catc. C:59.36 H:6.07 N:3.30 S:7.55 Foun.C:59.36 H:6.06 N:3.50 S:7.44

C

23

H

1 8

FNO

4 S*O.3H 2 0 Caic. C:64.41 H:4.37 F:4.43 N:3.27 S:7.48 Foun.C:64.37 H:4.38 F:4.96 N:3.31 S:7.24

R

18

S

S*

S

*55 S S S S S S SS S

*C*

Ri

R'

8 S0 2 NH *COOH (1a) Example R1R mp (decomp.) IR (v cm1) Elemental analysis No. (KBr) (CH 1712,1350 C 18

H

19

N

4

S

2 '0.2H 2 0 1253)2CH- H1 3 C-n--CEC4 R 157-158 1712,1350 Calc. 0:56.73 H:5.13 N:3.68 S:16.83 32 _S 1 Foun.C:57.03 H:5.30 N:3.89 S: 16.56 1710,1499 1 2 6 (CH 3 2 CH- F- H R 154-156 1710,1499 s 1356,1165 1275.1334 C/C 22

H

9 N0 5

S

2 '0.2H 2 0 2- H 3 R 149-150 1695,1334 Calc. C:59.36 H:4.39 N:3.15 S:14.41 a 1184 Foun.C:59.43 H:4.61 N:3.25 S:14.02 R 161164 1710,1329 128 csj-C 2 HN S- 1180 1734,169 C21 H 1 6 FN0 4

S

2 1 2 9 CH2- F 1734,1699 Cac. C:58.73 H:3.75 F:4.42 N:3.26 S:14.93 29 F1324,1105 Foun.C:58.66 H:3.93 F:4.52 N:3.33 S:14.41

OCH

3 130 Ki/-CH 2 0

R

OCH

3

H

3

CO

1 31 K1-H2- H 3 CO R 1 3 2 Q?-CH 2 0 z0 R

NO

2

S**

S S S

S

S S S S S S S S S S S. S*S 555 *SS R1 8 -S0 2 NH COOH (1a) Example R*R1 mp (decomp.) IR (vL cm'1) Elemental analysis No. (I)(KBr) 1 33 0-H 2 Qc=c R 1 34 O /CH 2

CH

3

(CH

2 5 -C=C R 1 35 /CH 2 HCO- j~-CCGJ R 1 36 j-CH2- H1 3 CO R 1 37 (~CH 2 F R 138 -C1 2 Br 'R- 140 O-CH 2 11-a =C R a. a a

R

18 -S0 2 NH COOH (a a a a a a a a a a a a a a a a.

a a a a a. a a. .aa R'1 8

'SO

2 NH COOH (1a) Example R* mp (decomp.) IR (v cm-1) Elemental analysis No. ()(KBr) 1 49 C H 2 H2O R=C R 1 50 /CH 2 OHC-#a-C=C-- R 1 51 K-CH 2 0 2 N R R 152 CH- H 2 N C= 1 53 c CH 2 Me2 R E 1 54 (j&CH 2 MeO 2 S -a cR 1 55 G-CH 2 HS- -EC3

R

156 (3 CH 2 NC- R Example 157, 158 Process 1 MeO S0 2 -N COOMe rocess 1 S H XVIII-2

-X

MeO- S0 2 -N COOH S R2 Ia-2-66, Ia-2-67 Process 1 (R 2 CH3) 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 Na2SO4, and concentrated in vacuo to give 373 mg of N-methyl derivative as an oil. Yield 91%.

Elemental analysis C 24 H2 3 N05S2 Calcd. C; 61.39 H; 4.94 N; 2.98 S; 13.66 Found C; 61.22 H; 5.18 N; 2.93 S; 13.27 Further, a solution of 140 mg of the above oily compound which was ob'ained the above process in 2 ml of methanol was added 0.6 ml of IN NaOH, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was acidified with 2N HC1 and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, and concentrated in vacuo to give 105 mg of compound (Ia-2-66) Me). Yield 77 mp. 185 1861C.

Elemental analysis C 23

H

21 NOsS Calcd. 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- 3600-2300br, 3426, 2203, 1710, 1604, 1503, 1344, 115 1.

NMR (dG-DMSO, 5 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(s, 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), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).

The compound (Ia-2-67) (R 2 CH2Ph) was synthesized in the same manner as those described in Example 157,.

IR(KBr, v max cm- 1 2200,1722,1340,115 1.

NMR (d6-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.) a* Example 159 (Method C) 9, 4 0, iri Process 1 Br--N COOMe MeO C\~ 0rA)-S0 2 N 7iZiLO 1 COe S ~HH ge*: meMeO S0- H OO 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 mng (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 (trip he nylp hosp hine)p alladiu m. The resulting mixture was stirred under argon atmosphere for 48 h at 75tC. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1N HCl, NaHCO3 aq., and water, dried over Na2SO4, and concentrated in vacuo. The residue was column chromatographed on silica gel. The fractions eluting with n-hexane ethyl acetate 3/1 were collected and recrystallized from n-hexane to give 447 mg of the desired compound (XIX-1). Yield 83 mp. 122-123C.

Elemental analysis C 1 7H21N05S2 Calcd. C; 53.25 H; 5.52 N; 3.65 S; 16.72 Found C; 53.26 H; 5.50 N; 3.69 S; 16.63 [a]D -21.7±0.6 (c=1.000 DMSO IR (KBr, v max cm 1 1735,1605,1505,1350,1167,1136 NMR (CDCl, 6 ppm) 0.90(d, J=7.0 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 2.10(m, 1H), 3.54(s, 10 3H), 3.85(s, 3H), 3.87(dd, J=5.0, 10.2 Hz, 1H), 5.20(d, J=10.2 Hz, 1H), 6.94(d, J=9.0 Hz, 2H), 7.52(d, J=9.0 Hz, 2H), 7.11(d, J=4.0 Hz, 1H), 7.49(d, J=4.0 Hz, 1H).

Process 2 .0 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 15 mixture was stirred at 60C 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 Na2SO4, and concentrated in vacuo to give 373 mg of compound Yield 100%. mp. 174 20 176CC IR(KBr, v max cm') 1735, 1503, 1343, 1163.

Example 160 175 The compounds which were shown in Tables 31 to 32 were synthesized in a manner similar to those described in Example 159,.

*1

C

R

1

BSO

2 NH COOH Elemental analysis

C

22

H

20

N

2 0 4

S

3 *O.4H 2 0 Caic. C:55.07 H:4.37 N:5.84 S:20.05 Foun.C:55.35 H:4.43 N:6.04 S:19.65

C

15 Hl 6 FN0 4

S

2 0.1 H 2 0 CaIc. C:50.15 H:4.55 F:5.29 N:3.90 S: 17.85 Foun.C:49.99 H:4.58 F:5.22 N:4.05 S: 17.77

C

16 HjqN0 4

S

3 Ca~c. C:49.85 H:4.97 N:3.63 S:24.95 Foun.C:49.70 H:5.00 N:3.93 S:24.96 No R' X. a ra..

a. a

C

20

H

19 N04S 2 R 16\6 1713,169 Ca~c. C:57.54 H:4.59 N:3.35 S: 15.97 1 68 9 xjCH2- H 3 C00 s R 6116 1374,1163 Foun.C:59762H:4.862N:3.61 S: 15.86

CH

1 N0 4

S

2 1 70 CH- F R 174-175 1721,1654 Calc. 0:56.28 H:3.98 F:4.09 N:3.45 S: 15.82 1365,1148 Foun.C:56.33 H:4.09 F:4.65 N:3.65 S: 15.84 \1750,1730

C

20

H

19 N0 4

S

3 *0.2H 2 0 17 H-H 3 SR 203-205 1428,1325 Calc. 0:54.95 H:4.47 N:3.20 S:22.00 1 1 a C2-HC S 1155 Foun.C:55.05 H:452 N:3.34 S:22.04 Example 176 (Method D) HCl Process 1 Process 2

H

2 N CO Bu 0NS2N COB XV-3 xx-1

H

2

N--SO

2 N~CO t~u Process 3

H

XXI-1 Process 4 MeS NSO, "N COO'Bu x: H XxllI-1 0 MeSN {~SO,-N'C0H

H

Ia-4-1 Process 1 To a solution of 10 g (47.68 mmol) of D-valine tert-butyl ester hydrochloride (XV-3) in 100 ml of dichloromethane was added 15.7 ml (3 x 47.68 mmol) of Nmethylmorpholine 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 HG1, 5% NaHCO3, water. The organic layer was dried over Na2SO4 and concentrated in vacuo, and the resulting residue was recrystallized from dichloromethane n-b xane to give 13.3g of the desired compound (XX- Yield 77.8%. mp. 89-90tC.

Elemental analysis C 1 5H22N206S Calcd. 50.27 H; 6.19 N; 7.82 S; 8.95 Found: C; 50.04 H; 6. 10 N; 7.89 S; 8.84 [cr]D -2.9±0.8(c=0.512 DMSO 23cC) 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 (Ig) 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. 164-166tC Elemental analysisClsH24N204S Calcd. C; 54.86 H; 7.37 N; 8.53 S; 9.76 Found C; 54.84 H; 7.33 N; 8 63 S; 9.50 10 [a]D +10.3±1.0(c=0.515DMSO23C) IR(KBr, v max cm- 1 3461, 3375, 1716, 1638, 1598, 1344, 1313.

NMR(d-DMSO, 8 ppm) 0.80(d, J=6.8 Hz, 3H), 0.82(d, J=6.6 Hz, 3H), 1.23(s, 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) 15 Process 3 a To a solution of 328 mg (Immol) of compound (XXI-1) in 10 ml of dichloromethane was added 0.33 ml (3 x 1 mmol) of N-methylmorpholine and 280 mg 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 20 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. 235-238C.

Elemental anal-sisC23H3oN205S2 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]D +5.7±0.9(c=0.512 DMSO IR(KBr, v max 3366, 3284, 1713, 1667, 1592, 1514, 1498, 1341, 1317.

NMR(d6-DMSO, 6 ppm) 0.82(d, J=6.6 Hz, 3H), 0.84(d, J=6.8 Hz, 3H), 1.22(s, 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 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 Yield 94.7 mp. 231-234C IR(KBr, v max cm 1 1748, 1655, 1592, 1323, 1161.

Elemental analysis C 1 9H22N205S2 0.1CF 3

COOH

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 176.

S. 5

RI

S02NH COOH (1a) Example RR18mp (decomp.) IR(v cm-1)Eeena nayi No. 1 77 c i CN R 215-217 17264 C-L H 2- 0 H 1341,1163 H 12,65C25H23N306S'0.9H20 I 1P 8H3CO CN R 23-234 alc. C:58.91 HA490 N:8.24 S:6.29 *1 HC H 1323,1177 Foun.C:58.97 H:5.07 N:7.95 S:6.10 N H -C-NC- R 216-218 17363 1 92N-( 1361,1149 CLH 2- 4H C24H2ON407S-. 1

R

18

O

2 N COH I 18 N I02N G R 211-213 alc. C:54.56 HAN N:10.60 S:6.07 ,I 134 .0,1156 Foun.C:54.51 HA432 N:10.83 S:6.15 H

C

2 6H 2 6N 4 0 5 S0.9H 2 0 181 5;1 N (H3C)N R 236-234 172,165 Cac. C:59.73 H:5.36 N:10.72 S:6.13 1 H& 0 H 1399,1199 Foun.C:59.58 H:5.23 N:10.85 S:6.47 Of IICH2

H

N

C

2 5H 2 3N305S'.H 2 0 CR 211-213 119,1327 Calc. C:60.82 H:5.06 N:8.51 S:6.49 1180 O 2 0 H 1160 Foun.C:60.83 H:5.19 N:8.66 S:6.66 N

C

2 4H 2 BrN30 5 S.0.6H 2 0 1H8C) 2 N Br C R 236-238 1732,16 Calc.0C:52.11 H:3.86 Br:14 N:7.60 S:5.80 I CH -a O QH 1154 Foun.C:52.13 1:4.04 Br:14.57 N:7.43 S:5.70 N 1731,1656 C 25

H

23

N

3 0 5 S2'0.9H 2 0 1 8 2 H 3 R 240-244 1593,1323 Calc. C:57.50 H:4.71 N:8.05 S:12.28 C 0 1159 Foun.C:57.63 H:4.79 N:8.00 S:12.08

YL-LCH

2 onC5.3 :.4B:45 :.3S57 S S S S S

S

S

S *S*

R'

8 -S0 2 NH *COOH (1a) Example R R mp (decomp.) IR (v Elemental analysis No. (KBr) H 1730,1651 C 24

H

20

FN

3 5 S'0.6H 2

O

185 N C-N-a R 170-175 1603,1333 Calc. C:58.55 H:4.34 F:3.86 N:8.54 S:6.51

H

2 1 0 H 1161 Foun.C:58.67 H:4.51 F:3.77 N:8.42 S:6.47 IICH2- 1~ 1723,1651 023H 22

N

2 0 6

S

186 C OH 2

H

3 CO C-N R 237-239 1591,1322 Calc. C:60.78H:4.88N:6.16 S:7.05 0 H 1161 Foun.C:60.50 H:4.99 N:6.14 S:7.31 1 23523 1719,1672

C

22

H

19

N

3 0 7

S

R 235-239 1593,1327 Calc. 0:56.29 H:4.08 N:8.95 S:6.83

CH

2 1159 Foun.C:56.01 H:4.09 N:8.93 S:6.75 1748,1658 C 22

H

2 0

N

2 0 5 S-0.5CF 3

COOH

1 88 CH 2 N- R 114-115 1592,1325 Calc. C:57.37 H:4.29 N:5.82 S:6.66 0 H-0 1159 Foun.C:57.53 H:4.45 N:5.75 S:7.11 1743,1670 C 22

H

19 BrN 2

O

5

S*CF

3

COOH

1 8 9 2 Br- C-N R 242-243 1591,1335 Calc. 0:46.69 H:3.27 Br:12.94 N:4.54 S:5.19 0 H 1167 Foun.C:46.79 H:3.41 Br:12.86 N:4.57 S:5.37 1 1752,1726 C 2 3

H

2 2

N

2 0 5

S

1 90 (,CH 2 H1 3 Cr C-N R 242-244 1656,1591 Calc. C:63.00 H:5.06 N:6.39 S:7.31 0 H 1324,1160 Foun.C:62.70 H:5.13 N:6.36 S:7.36 1742,1667 C 23

H

22

N

2 0 5

S

2 .0.8CF 3 000H 1 9 1 C11OH 2

H

3 CS- R 232-235 1591,1334 Calc. 0:52.59 H:4.09 N:4.99 S:1 1.42 \a H 1161 Foun.C:52.77 H:4.24 N:5.12 S:11.58 1737,1651 C 22

H

19

FN

2 0 5

S

1 9 2 /-H 2 F C-N R 218-220 1598,1324 Calc. 0:59.72 H:4.33 F:4.29 N:6.33 S:7.25 1a a11160 Foun.C:59.59 H:4.42 F:4.30 N:6.37 S:7.24

U

U S U S U a U a U U U U U

U

S. 9 *Ua

RI

R'

8 S0 2 NH *COOH (1a) Example No.

193 194 195 196 197 198 199 200 mp (decomp.) c) IR (v cm-') (KBr) Elemental analysis I I I+ ICH2aCH2-

(CH

3 2

CH-

(CH

3 2 0H-

(CH

3 2

CH-

(CH

3 2

CH-

(CH

3 2

CH-

(CH

3 2

CH-

11 Cl e N 0

H

201-203 1724,1673 1592,1326 1156 021H 18 C1N 3 0 5

S

Catc. 0:54.84 H:3.94 CI:7.71 N:9.14 S:6.97 Foun.0:54.39 H:4.06 CI:7.42 N:8.98 S:6.99 I I i i

H

3 0 C-N -a N 0 H 206-208 1725,1682 1592,1332 1160

C

22

H

20

CN

3 0 5 S'O 1 CF 3

COOH

Catc. 0:55.15 H:4.19 C1:7.33 N:8.69 S:6.63 Foun.C:55.25 H:4.28 CI:7.10 N:8.80 S:6.80 1748,1659

C

24

H

24

N

2 0 5 S0.5H 2 0 c-N R 254-256 1590,1324 Calc. C:62.46 H:5.46 N:6.07 S:6.95 1161 Foun.C:62.42 H:5.54 N:6.26 S:6.97 1749,1658 C 19

H

22

N

2 0 5 S0.2H 2 0 C-N- R 227-229 1592,1323 CaIc. C:57.91 H:5.73 N:7.11 S:8.14 H3C a OH 1161 Foun.C:57.94 H:5.69 N:7.03 S:8.14 1748,1655 0 19

H

22

N

2 0 5

S

2 *01 CF 3

COOH

H

3 CS- 'C-N R 231-234 1592,1323 Calc. C:53.14 H:5.13 N:6.46 S:14.78 JoHaI I 1161 Foun.C:53.48 H:5.31 N:6.57 S:15.06 FaO N- 235-236 1749,1726 1668,1597 1322,1160 C18Hl9FN205S'1 CF3COOH Calc. 0:53.86 H:4.74 F:6.09 N:6.90 S:7.90 Foun.C:53.82 H:4.85 F:5.60 N:6.93 S:7.78 1728,1661 C1 8

H

20

N

2 0 5 S.0 1 H 2 0 R 226-227 1591,1317 Calc. 0:57.16 H:5.38 N:7.41 S:8.48 1159 Foun.C:57.01 H:5.46 N:7.57 S:8.57 H3CO-F\V-N 220-221 1696,1654 1591,1317 1255 Cl9H22N206S'.2H20 Calc. 0:55.65 H:5.51 N:6.83 S:7.82 Foun.C:55.63 H:5.48 N:7.03 S:7.75

I

I L I 4 *4 4

C

S 4 4 .4 4 C S 4 4 4 S 4

R.

R

18

-SO

2 NH COOH (1a) mp (decomp.) IR(v cm-') (KBr) Elemental analysis 0 2 N C-N-- 0 H

-N

H

3 0 N Br N--Na

-HH

H

2 1726,1688

C

18 Hl 9

N

3 0 7 S30.4H 2 0 R 240-242 1591,1347 Ca~c. 0:50.44 H:4.66 N:9.80 3:7.48 1166 Foun.C:50.40 H:4.55 N:9.90 S:7.44 1726,1663 Cj 8

H

1 9 BrN 2

O

5 S.0.2Ethylether R 229-230 1592,1318 CaIc. :48.03 H:4.50 Br: 17.00 N:5.96 S:6.82 1159 Foun.C:48.04 H:4.61 Br: 16.83 N:5.96 3:6.86 1659,1591 1316,1159 214-216 Caic. C:56.17 H:5.84 N:6.55 S:7.50 Foun.C:56.21 H:6.02 N:6.50 S:7.33 I I

R

R

236-237 1723, 679 1590,1337 1162 021 H~oN 4

O

5 S.0.25CF 3

COOH

Ca~c. C:55.06 H:4.35 NA1 1.95 S:6.84 Foun.C:54.80 H:4.90 N: 12.16 S:7. I1.

272-275 1719,1672 1594,1339 1165 ~1 021 Hj 9

N

3 0 5

S

Ca~c. C:59.28 H:4.50 N:9.88 S:7.54 Foun.C:58.84 H:4.56 N:9.71 S:7.36

I-

214-215 1733,1685 1594,1319 1154 0 20

H

19

N

3 0 6

S

CaIc. 0:55.94 HA4.46 N:9.78 S:7.47 Foun.C:55.50 H:4.47 N:9.74 S:7.31 4.

1732,1679 1592,1312 1155 217-220 I_ I I I I Example 209 (Method E) HCI Process 1 Process 2

H

2 N COOtBu S0 2 -N COOtBu

H

XV-3 XXIII-1 Process 3 OHC SO2-N COOtBu Process 3 XXIV-1 H 02 H H t Process 4 SS-N-N=C S02-N COO Bu MeS

SO

2 -N COOBu N H

XXVI-

a

N=N

MeS N v- SO 2 -N__COOHBu N =NH 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 Nmethylmorpholine and 20.27 g (99.8 mmr.i) of p-styrenesulfonyl chloride under icecooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HC1, 5% NaHCOa, water. The organic layer was dried over Na2SO4 and concentrated in vacuo, and the resulting residue was column chromatographed on silica gel. The fractions eluting with ethyl acetate n-hexane 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. 118-120C.

If I, IR(KBr, v max cm- 1 3419, 3283, 1716, 1348, 1168.

NMR(CDC13, 6 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 bubbled through a solution of 5.09 g (15 mmol) of compound (XXIII-1) in 300 ml of dichloromethane for 15 h at -78r. To this solution was added 22 ml (20 x 15 mmol) of methylsulfide, and the reaction mixture was allowed to warm 10 to room temperature gradually over 80 min and concentrated in vacuo to give 6.03g aldehyde derivative (XXIV-1).

IR(CHCl3, v max 3322, 1710, 1351, 1170.

NMR(CDCl3, 6 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).

15 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 20 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%. mp. 163-164r.

Elemental analysis C 22 H29N306S2 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]D -11.6±1.0(c=0.509 DMSO 23.5cC) IR(KBr, v max 3430, 3274, 1711, 1364, 1343, 1172.

NMR(CDCl3 6 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),

II

7.78-7.84(m, 2H), 7.96-8.02(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 cone. 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 -251C. This reaction mixture was stirred for additional 4 h at -15'C to rt, poured into water, and extracted 10 with ethyl acetate. The organic layer was washed with 2N HC1, 5% NaHCO3, and water, dried over Na2SO4, and concentrated in vacuo. The residue was column chromatographed on silica gel and the fractions eluting with chloroform ethyl acetate 1/9 were collected to give 374 mg of the desired compound (XXVI-1). Yield 74%.

Elemental analysis C23H29N 5 0 4 S2 0.3H20 15 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- 1 3422, 3310, 1705, 1345, 1171.

NMR(d6-DMSO, 6 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, 20 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 A solution of 353 mg of compound (XXVI-1) in 2.5 ml of dichloromethane and 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 Yield 98%. mp. 194 195'C.

IR(KBr, v max cm- 1 1720, 1343, 1166.

Elemental analysis C 1 9H2 1

N

5 0 4

S

2 1.1H20 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 37 to 43 were synthesized in a manner similar to those described in Example 209.

a.

a.

a. a.

a.

a.

a a a a a a a a

C

81 Rio .0N-CNO SS* *S Rl&S 2 NH* COHOH (Ib) 8* mp (decomp.) IR (v IH-NMR( 0 ppm) (KBr) d6-DMSO ~Q R- 2.65(dd,J=9.3,13.1 Hz, 1 H),2.82(dd, 37002200br),278, J=5.8, 13.1 Hz, 1 H),3.86(dt,J=5.8,9.3 R 194-195 37020(r 37, Hz, 1 H) ,7.72(A 2

B

2 q,J=8. 1 Hz,2H), 1634,1337,1160 8.1 9(A 2

B

2 q,J=8.l1Hz,2H),8.49(d,J= 9.3Hz,l1H),8.88(s,l1H),1 0.69(s,1 H) S S S S S S S. S S S S S S S S S S S S S. S 555 S..

R'

8 S0 2 NH COOH 00 r Example No.

2 1 0

H

alOH 2 a-

OH

2 mp (decomp.) IR (v cm-') (KBr) 4-

N-N

a N- -a

R

IH-NMR(6 ppm) dG-DMSO 2 11 a -NN. N- L -L 215-216 2400-3700br,3422,3337, 1733,1698,1347,1170 2.75(dd,J=9.3,13.7Hz, 1 H),2.99( dd,J=5.3,13.7Hz,1 H),3.96(dt,J= 5.3,9.3Hz, 1 H),8.53(d,J=9.3Hz, 1 H) I .7 0 0 00 C S 0 0 0 0 *00 000 000 o 0 00 0 *0 S 000 000 *0 0 000 0 S S SB S* 05 *.s 0 0@ 5 5 0 000 0 0 5 55.0 p 55 9 005 505 505

R

18

-SO

2 NH COOH (la) Elemental analysis

C

25

H

22

N

6 0 4 Ca~c. C:60.10 H:5.04 N:15.57 S:5.94 Foun.C:60.41 H:4.69 N: 15.52 S:5.57

C

24

H

19

FN

6 0 4 S.0.4Ethylether Ca~c .0:57.35 H:4.32 F:3.54 N: 15.67 S:5.98 Foun.C:56.74 H:4.37 F:3.47 N:15.17 S:568

C

19

H

21

N

5 0 4

S

CaIc. 0:54.93 H:5.09 N: 16.86 S:7.72 Foun.C:54.75 H:5.1 4 NA1 6.81 S:7.55

CIB

8

H

19

N

5 0 4

S

Ca~c. 0:53.38 H:4.83 N: 17.29 S:7.92 Foun.C:53.38 H:4.80 N: 17.05 S:7.67

C

2 8

H

2 3

N

5 0 4 S-0.6H 2 0 Catc. 0:62.70 H:4.55 N:13.06 S:5.98 Foun.C:62.61 H:4.50 N: 13.29 S:5.87 0 26

H

21

N

5 0 4 S*0.2H 2 0 CaIc. 0:62.07 H:4.29 N:13.92 S:6.37 Foun.C:61 .93 H:4.30 N: 14.01 S:6.43

C

25

H

20

N

6 0 5

S.H

2 0 CaIc. 0:56.17 H:4.15 N:15.72 S:6.00 Foun.C:56.20 H:4.18 N:15.68 S:6.10

R

18 S0 2 NH COOH (1a) Example RR np (decomp.) IR (v cm-1) Elemental analysis No. (KBr) H

C

25

H

22

N

6 0 5

S

N N 0 R 195-196 1749,1719 Calc. 0:57.91 H:4.28 N: 16.21 S:6.18 -N 1331,1165 Foun.C:57.77 H4.29N:16.01 S:6.37 N=N C 19

H

2 1

N

5 0 4

S

221 CH 3

CH

2

(CH

3 )CH- R 205-207 1730,1693 Calc. C:54.93 H:5.09 N:16.86 S:7.72 1349,1173 Foun.C:54.71 H:5.09 N:16.70 S:7.56 N 1791 20

H

23

N

5 0 5 S.0.4H 2 0 a204-207 1729,1693 Calc. 0:53.06 H:5.30 N:15.47 S:7.08 22 HH H H 3 CON Foun.C:53.13 H:5.13 N:15.12 S:7.14 N-N R 190 1718,1601

(CH

3 2 CH- decomp. 1385,1162 N C 20

H

2 3

N

5 0 5 S.0.4H 2 0 224 (CH 3 2 CH- HCO R 195-197 179,1304 Calc. C:53.06 H:5.30 N:15.47 S:7.08 Foun.C:53.13 H:5.13 N:15.12 S:7.14 CN 1H 18 BrN 5

O

4 S*0.8H 2 0 2 25' (CH 3 2 CH- Br R 227-228 1696,1348 Calc. C:43.70 H:3.99 Br:16.15 N:14.16 S:6.48 N 11Foun.C:43.93 H:3.85 Br:15.92 N:13.87 S:6.47 N-N R 204207 1698,1344 2 2 6 (CH 3 )3C- H 3 CO- J-N. j 1168 H

N-N

N R 203-205 1757,1738 H-7 CH F- 1331,1163

R

18 S0 2 NH COOH (1a) Example R R mp (decomp.) IR (v cm') Elemental analysis No. (KBr) N=N 1744,1325 2 2 8 G CH 2 Br R 197-199 1154 N-N C 23

H

1 8

F

3

N

5 0 4

S

22 9 CH2- F3C CaR 197-198 1738,1707 Calc. 0:53.38 H:3.51 F:11.01 N:13.53 S:6.20 N 1328,1169 Foun.C:53.11 H:3.55 F:10.89 N:13.66 S:6.31 N-N C 22

H

18

N

6 0 6 S*0.4H 2 0 0R 190-191 1730,1597 Calc. 0:52.67 H:3.78 N:16.73 S:6.39 .iN 1345,1161 Foun.C:52.73 H:3.92 N:16.53 S:6.55 NN 170C 22

H

18

FN

5 0 4 S*0.2H 2 0 231 CR 205-207 1730,1509 Catc. C:56.09 H:3.94 F:4.03 N:14.87 S:6.81 N1236,1165 Foun.C:56.10 H:4.09 F:4.12 N:14.84 S:7.08 N-N C 22

H

1 8

CN

5 0 4 S*0.6H 2 0 232 C0 0-R 204-206 1730,1493 Calc. C:53.41 H:3.91 CI:7.17 N:14.16 S:6.48 N' 1346,1164 Foun.C:53.33 H:3.90 C:7.22 N:14.19 S:6.68 -N 1732,1697 C 2 3

H

21

N

5 0 4 S*1.2H 2 0 2 3 3 CH 2

H

3 0 R 226-227 1509,1373 Calc. C:56.94 H:4.86 N:14.44 S:6.61 1345,1170 Foun.C:56.88 H:4.49 N:14.31 S:6.72 N-N C 23

H

21

N

5 0 5 S'1.7H 2 0 234 CH2- H3C- R 214-216 1732,1697 Calc. C:54.15 H:4.82 N:13.73 S:6.29 234 .21421 1345,1168 Foun.C:54.05 H:4.35 N:13.60 S:6.77 N-N 1 23

H

18

N

6 0 4 S-0.8H 2 0 2/3 5 CH2- NC R 190-192 1731,1605 Cal. :56.50 H:4.04 N:17.19 S:6.56 N1336,1160 Foun.C:56.52 H:4.16 N: 17.00 S:6.52

R'

R

18 80 2 NH COOH (1a) R mp (decomp.) IR (v cm') Elemental analysis VC) (KBr) N=N C 26

H

27

N

5 0 4

S

'rN R -224-226 1738,1328 CaIc. C:61.77 H:5.38 N:13.85 S:6.34 1 Foun.C:61.59 H:5.45 N:13.89 8:6.27 N-N 17911 C28H29N04S'03H20 NN R 225-227 1329,1178 Calc. C:62.62 H:5.56 N:13.04 S:5.97 N- 317Foun.C:62.46 H:5.52 N:13.43 S:6.28 N-N 1587,1506 R 182-184 1242,1159 N R 21713,1514 R 226-228 1341,1159 N=N 1744,1716 C 24

H

19 BrN 6

O

4 S.1.7H 2 0 R 205-207 1490,1327 Calc. C:48.20 H:3.78 Br:13.36 N:14.05 S:5.36 1159 Foun.C:48.27 H:3.75 Br:13.16 N:14.11 8:5.38 N=N C 25

H

22

N

6 0 4 S'0.6H 2 0 R 199-201 1718,1685 CaIc. 0:58.49 H:4.56 N:16.37 S:6.25 N1 Foun.C:58.52 H:4.69 N:16.71 S:5.90 N=N 1 1C 19

H

2 1

N

5 0 4 S.0.8H 2 0 R 206-207 176,1346 Cabc. 0:53.09 H:5.30 N:16.29 S:7.46 N Foun.C:53.20 H:5.14 N:16.06 S:7.70 N=N 1746,1726 C 18

H

1 8

FN

5 0 4 S*0.2H 2 0 R 208-209 1715,1334 CaIc. C:51.11 H:4.38 F:4.49 N:16.55 S:7.58 1159 Foun.C:50.90 H:4.37 F:4.89 N:16.28 S:7.46 S S S *5 S *SS **S

R

18 S0 2 NH COOH (1a) Elemental analysis

C

19

H

2 1

N

5 0 4

S

2 *1 .1 H 2 0 Caic. C:48.83 H:5.00 N: 14.99 S: 13.72 Foun.C:49.1 3 H:5.25 N: 14.55 S: 13.34

C

23

H

21

N

5 0 4

S

2 .O.2H 2 0 Caic. C:55.34 H:4.32 N: 14.03 S: 12.85 Foun.C:55.37 H:4.35 N: 14.00 S: 12.86

C

25

H

22

N

6 0 4

S

2 .1 .1 H 2 0 Caic. C:54.16 H:4.40 N:15.16 SA1 1.57 Foun.C:54.20 H:4.66 N: 15.09 S: 1.62

C

1 8

H

1 6

N

6 0 4 S'0.4H 2 0 Caic. C:51 .52 H:4.04 N:20.03 S:7.64 Foun.C:51.34 H:3.96 N: 19.76 S:8.02 Example 252 266 The compounds which were shown in Tables 44 to 45 were synthesized in a manner similar to those described in Example 157.

«8 o *89 9 *9 9..

9 9 9* 9 9 9 99 99* 999 R 18

SQ

4 r 2 0~

A

(I)

Example R' R 1 8 R 1 9

R

20 mp (decomp.) IR cm-1) 'H-NMR( 6 ppm) No. KBr) dfi-DMSO 0.96(d,J=6.6Hz,3H) 252 (CH )CH- 0 -CH3 COOH R -1715,1583 1.01 (d,6.8Hz,3H) 3) 1340,1151 2.87(s,3H) 4.1 7(d,J=1 0.4Hz,1 H) 1~~I\0.71 (d,J=6.6Hz,3H) 2 5 3 (CH 3 2 CH-

-CH

3 -CONHOH R 110-111 3323,1678 0.88(d,6.4Hz,3H) 1328,1150 2.88(s,3H) 3.48(d,J=1O.8Hz,1 H) 3344,168 0.55(d,J=6.8Hz,3H) 254 (CH 3 2 CH- a CH -CONHOH R 148-150 133,11849 0.82(d,6.6Hz,3H) 13231149 3.74(s,3H) 2 55 (H C- -(H2)NH -COH -3700-2200br 0.91 (d,J=5.6Hz,6H) 2 C 3 2 C- /-H)NH -OH R- 1681,1319 1.52-1.69(m,4H) 1212 3.84(d,J=10.4Hz,1 H) 0.95(d,J=6.6Hz,3H)

(C

32 C- C 3 COH R 20-0 3300-2400br O.97(d,6.8Hz,3H) 2 5 (H32C- -C3 COH 26-07 118533 2.89 (s,3H) 1185___ 4.20(d,J=10.6Hz,1 H) 0.92(d,J=6.6Hz,3H)

(C

32

CC

2

/-C

3 -CONR 12-3. 3300-2400br 0.97(d,6.6Hz,3H) (CH)2CHH2-4 C3 CO R 12-3. 1719,1340 2.84(s,3H) N1153 4.73(t,J=7.4Hz,1 H) 3640-2400br 2.78(d.d,J=13.8,7.2Hz,1 H) 2 58CH- N NCH2- -COOH R 1736,1717 3.14(d.d,J=14.8,7.4Hz,1 H) 5' 8A~~2 1694,1346 4.43(d,J=16.4Hz,1H) 1162 4.68(d,J=16.4Hz,1H) \3284br,1 745 0.96(d,J=6.4Hz,3H) 2 5 9 (CH 3 2 CH- H 3 CS s-OH 3 -COOH R 141-144 1714,1323 0.97(d,J=6.4Hz,3H) 11131 2.52(s,3H),2.93(s,3H)

S

S* S S S S S S S S S. S **S

R'

8 S0 2 l R2 r 9

(I)

Example R R1 R' R 2 0 np (decomp.) IR (v IH-NMiR( 6 ppm) No. dr.-DMSO 0.72(d,J=6.4Hz,3H)0.85(d,J

(CH)

2 C- HCS -COH -3600-2400br =6.4Hz,3H)2.47(s,3),4.1 118134 J=1O.2Hz,1H)4.51(d,J=15.5 S 151Hz,l H)4.73(d,J=l 5.5Hz,1 H) 3600-2400br 2.54(s,3H),2.78(s,3H) 2 H-HC -CH3 COOH R -1719,1655 2.85(d.d,J=1 4.O,9.4Hz,1 H) CH- aC-& 0-C H 1592,1320 3.16(d.d,J=14.0,6.OHz,1H) 4.76(d.d,J=10.O,5.8Hz,1H) 2 62 ~DCH2- H 3 S -NC QCH 2 -COOH R 2 6 3 GJCH 2

H

3 CO-aj-CECJs -(CH 2 4

NH

2 -COOH R- 2 64 &~CH 2 HCO-Fj\cCCK3

-OH

3 -COQH R- 2 65 (j&CH 2

H

3 CO -Cjh &~CH 2 -COOH R- 2 6 6 &~CH 2

H

3 CO-F -c~c -KD -(CH 2 4

NH

2 *COOH R- Example 267 The compounds which were shown in Tables 46 were synthesized in a manner similar to those described in Example 92.

l e R1 8 -S0 2 HN R2 a a a *o a a. a a. a .*a IR cm-1) 'H-NMR( 6 ppm) (KBr) dr.-DMSO 3700-400br3267, 2.62(dd,J=8.4,13.5Hz, 1 2.80(dd, 227,16710b,32161 J=6.O ,13.5Hz,1H),3.82(ddd,J=6.O, 2217167113211161 8.4,8.7Hz,1 H),8.38(d,J=8.7Hz,1 H) 2200370br,430 2.73(dd,J=9.3,13.6Hz,1 H),2.96(dd, 22,1-728,3243,6 J=5.4,1 3.5Hz,1 H),3.92(dtJ=5.4, 3292172813241162 9.3Hz, 1 H),8.42(d,J=9.3Hz, 1 H) 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 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 Type IV Collagenase) from HT 1080 Human Fibrosarcoma Cells; Robin V. Ward et al., Biochem. (1991) 278, 179-187, The a 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, 732-740, Molecular cloning and manifestation of mouse 105-kDa 20 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.

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).

substrate (type IV collagenase), enzyme (MMP-9), inhibitor substrate (type IV collagenase), inhibitor substrate (type IV collagenase), enzyme (MMP-9) substrate (type IV collagenase) According to the manufacturer's protocol, fluorescent intensity was measured and percent inhibition was determined by the following equation.

Inhibition {1 B) (C x 100 ICso is a concentration at which the percent inhibition reaches 50 The results are shown in Tables 47 to 54.

Table 47 a. a a a Example No. Compound No. IC50 (PiM) Compound No. IC50 (ILM) 1 ia-i-i 0. 24 lb-i-i 0. 0 2 la-i1-2 2. 6 Ib-i1-2 0. 0 4 3 la-i1-3 0. 1 8 lb-i1-3 0. 00 4 la-l1-4 2. 2 5 ia-i1-5 0. 8 1 lb-i-5 0. 04 1 6 la-i1-6 0. 6 8 lb-i1-6 0. 034 7 b-i1-7 0. 02 8 8 la-i1-8 2. 0 lb-i1-8 2. 0 9 b-i-9 0. 4 1 1 0 lb-i-10 2. 1 1 1 lb-i-il 1. 7 1 2 b-1-12 0. 08 1 3 b-1- 13 0. 3 8 1 4 la-1- 14 3. 7 lb-1- 14 0. 1 1 1 5 lb-i-iS 0. 02 7 1 6 ia-i-16 0. 5 20 ib-1-16 0. 0 108 1 7 la-1- 17 0. 20 5 Ib-1- 17 0. 0 20 3 1 8 la-1- 18 0. 5 00 ib-1-18 0. 0 28 2 2 0 b-i-20 0. 134 2 1 la-i1-21 4. 6 5 lb-i1-21 0. 004 1 2 3 lb-i1-23 0. 07 3 2 4 b-1-24 0. 2 2 6 b-i1-26 1 3 2 7 b-i1-27 3. 0 3 0 ia-i-30 1 1. 1 6 1 ib-1-30 0. 21 3 3 1 ib-i-31 0. 012 Table 48

C

C.

Example No. Comp ound No. 1C.5 (PM Comnpound No. 3 3 la-1-33 0. 2 4 lb-1-33 0. 00 3 5 la- 1-35 2. 6 lb- 1-35 0. 0 216 3 8 la- 1-38 0. 0 18 4 0 la- 1-40 0. 0 7 6 4 1 la- 1-41 0. 3 12 4 2 la- 1-42 0. 0 1 23 4 3 la- 1-43 0. 6 25 44 la- 1-44 1 9 1 0 4 5 la- 1-45 0. 040 46 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 la- 1-49 0. 24 9 0 la-1-50 0.5 53 1 la- 1-51 0. 1 1 0 5 2 la- 1-52 0. 3 2 9 3 la- 1-53 1 8 54 la-1-54 0. 0 7 5 5 la-1-55 0. 0 3 9 8 6 0 la- 1-60 1. 3 1 lb- 1-60 0. 0 012 6 1 la- 1-61 0. 2 47 lb-1-61 0. 24 7 6 2 lb- 1-62 3. 5 0 6 3 la- 1-63 1 0 5 lb- 1-63 0. 00 03 9 6 4 1-64 1 1. 9 0 1 lb-1-64 0. 0 03 7 6 5 la-1-65 1 0. 29 11 lb- 1-65 0. 0 03 C Table 49 Example No. Compound No. IC50 (JIM) Compound No. IC50 (PAM) 6 7 la-1-67 lb- 1-67 0. 006 1 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 13 8 6 la-1-86 0. 3 5 lb- 1-86 0. 00 53_ 8 7 lb-1-87 0. 940 9 3 la-2-2 2 3 7 9 4 la-2-3 0. 0 10 9 5 la-2-4 0. 0 7 5 9 9 6 la-2-5 0. 12 3 9 7 la-2-6 0. 0 8 8 9 8 la-2..7 0. 0 6 9 9 1 00 1a*2-9 0. 0 5 7 7 1 01 1a-2-10 0. 02 3 1 02 la-2-11 0. 047 5 1 03 la-2-12 0. 0 9 8 1 1 04 la.2-13 3. 2 8 1 05 la.2-14 2. 9 8 1 06 la-2-15 0. 1 3 3 1 07 la-2-16 0. 3 2 5 1 09 la-2-18 1 1 9 1 10 la-2-19 0. 2 0 3 1 1 1 la-2-20 3. 4 1 12 la.2-21 3. 74 1 14 la-2-23 0. 9 2 9 Table Example No. Compound No. 1C50 1

IM)

11 5 la-2-24 0. 16 1 117 la-2-26 1 1 9 118 la-2-27 0. 08 8 1 19 la-2-28 1 1 1 1 20 la-2-29 1 5 3 1 21 la-2.30 0. 0 7 36 1 22 la-2-31 0. 2 24 1 23 la-2-32 0 234 1 24 la-2-33 0. 0 21 8 1 25 la-2-34 0. 0 144 1 26 la-2-35 0. 15 6 1 27 la-2-36 0. 0 24 3 1 28 la-2-37 0. 0 92 2 1 29 la-2-38 0. 22 2 1 60 la-3-2 0. 040 1 61 la-3-3 0. 0 1 08 1 62 la-3-4 0. 87 3 1 63 la-3-5 0. 0 12 6 1 64 la-3-6 0. 0 96 1 65 la-3-7 0. 23 0 1 66 la-3-8 1. 2 8 1 67 la-3-9 0. 0 14 1 68 la-3- 10 0. 0 08 3 1 69 la-3-11 0. 2 44 1 70 1 la-3-12 2. 0 3 17 11 la-3-13 0. 0 3 Table 51

S.

S

S

S S

S

S

Example No. Comnpound No. IC50jjtLN1 1 77 la-4-2 0. 6 84 1 78 -la-4-3 0. 0 25 2 1 79 la-4-4 2. 3 6 1 80 la-4-5 0. 04 1 81 la-4-6 0. 0 53 9 1 82 la-4-7 0. 005 9 1 83 la-4-8 0. 0 02 7 1 84 la-4-9 0. 0 032 1 85 la-4- 10 0. 042 2 1 86 la-4- 11 0. 0 98 2 1 87 la-4-12 0 17 7 1 88 la-4-13 0. 84 3 1 89 la-4-14 0 37 1 90 la-4-15 0. 0 59 7 1 91 la-4-16 0. 0 09 1 92 la-4-17 0. 32 4 1 93 la-4-18 0. 72 2 1 95 la-4-20 1. 1 1 96 la-4-21 0. 0 5 73 1 97 la-4-22 0. 0 1 61 1 98 la-4-23 0. 49 3 1 99 la-4-24 2. 0 6 2 00 la-4-25 0. 17 3 2 01 la-4-26 0. 2 52 2 02 la-4-27 0. 0 114 2 03 la-4-28 0. 17 3 Table 52 Example No. Comnpound No. J~IC0[IM) Cornpound No. jj504LM 2 04 la-4-29 3. 9 5 2 07 la-4-30 4. 44 2 10 la-5-2 0. 0 24 2 11 la-5-3 0. 2 10 1 b-211 0. 00 5 2 12 la-5-4 0. 3 93 2 13 la-5-5 0. 1 2 8 2 14 la-5-6 0. 8 3 2 2 15 la-5-7 0. 1 1 0 2 16 la-5-8 0. 1 0 7 2 18 la-5- 10 0. 7 44 2 19 la-5-li 0. 5 74 2 20 la-5-12 0. 0 1 6 7 2 21 la-5-13 0. 3 16 2 22 la-5-14 0. 0 78 2 23 la-5-iS 0. 349 2 24 la-l-16 0. 0 1 0 1 2 25 la-5-17 0. 0 1 2 2 2 26 la-5-18 0. 16 6 2 27 la-5-19 0. 0 1 98 2 28 la-5-20 0. 1 0 6 2 29 la-5-21 0. 2 15 2 30 la-5-22 0. 28 1 2 31 la-5-23 0. 1 9 7 2 32 la-5-24 0. 144 2 33 la-5-25 0. 0 864 2 34 la-5-26 0. 1 53 Table 53 Example No. Compound No. IC5o (tiM) Compound No. IC50 ([LM) 2 35 la-5-27 0. 2 6 5 2 36 la.5-28 0. 3 04 2 37 la-5-29 1. 3 2 2 38 la.5-30 2. 8 5 2 39 la-5-31 0. 2 43 2 40 la-5-32 0. 0 04 1 2 41 la-5-33 0. 0 13 1 2 42 la-5-34 0. 0 2 3 9 2 43 la-5-35 0. 0 5 2 9 2 44 la-5-36 0. 0 16 5 2 45 la-5-37 0. 0 05 9 2 46 la-5-38 0. 0 1 0 8 2 47 la-5-39 0. 0 0 3 5 2 67 la-2-66 1 5 lb..2.66 0. 01 1 9 9 9 Table 54 Example No. Compound No. IC50 (IL) 2 52 1-252 0. 24 2 53 1-253 0. 000039_ 2 54 1-254 0. 0 006 3 2 55 1-255 0. 52 9 2 56 1-256 0. 60 1 2 57 1-257 0. 7 76 2 58 1-258 0. 90 8 2 59 1-259 0. 13 0 260 1-260 0. 15 9 26 1 1-260 0. 18 2 0 0 0* 0 00 00 00 0 00 00 0000 0000 00 00 0 0 0 0 0 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 HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, 10 sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple Ssclerosis, 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, 15 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.

I

Claims (1)

105- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A compound of the formula IV: R 1 R-Ri1 S02-N- COY 1V X I wherein R' is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted 10 heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 7 is optionally substituted aryl or optionally substituted heteroaryl; R' is X is oxygen atom or sulfur atom; and Y is -NHOH or -OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof. *•ooo 2. The compound of claim 1, wherein X is sulfur atom and Y is -OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof. 3. The compound of claim 1, wherein R 2 is hydrogen atom, X is sulfur atom, and Y is -OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof. 4. A pharmaceutical composition containing a compound of any one of claims 1 to 3. A composition for inhibiting metalloproteinase containing a compound of any one of claims 1 to 3. P:\OPER\MKR\SPECI\13195-97-div.doc-01/5AMX -106- 6. A composition for inhibiting type IV collagenase containing a compound of any one of claims 1 to 3. 7. Use of a compound of any one of claims 1 to 3, in the preparation of a medicament for the inhibition of metalloproteinase. 8. A method for the inhibition of metalloproteinase including the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of any one of claims 1 to 3. DATED this 1st day of May, 2000 Shionogi Co., Ltd. 15 By DAVIES COLLISON CAVE Patent Attorneys for the Applicant