Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

TECHNICAL FIELD

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

BACKGROUND ART

An extracellular matrix consists of collagen, proteoglycan, 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 degradation of an extracellular matrix, and these enzymes work for growth, tissue remodeling, etc. under physiological conditions. Therefore, it is considered that these enzymes participate in progression of various kind of diseases involving breakdown and fibrosis of tissues, such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (for example, HIV infection). At the present time, it is not clear which enzyme participates in the above diseases seriously, but it is considered that these enzymes at least participate in tissue breakdown. As metalloproteinase inhibitors of amino acid derivatives, for example hydroxamic acid derivatives of amino acids (JP-A-6-2562939), carboxylic acid derivatives of amino acid and/or their hydroxamic acid derivatives (WO95/35276), 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 related to its activity. Therefore, development of MMP inhibitors has long been desired.

In the above situation, the inventors of the present invention found that a kind of sulfonamide derivatives have strong activity to inhibit MMP.

The present invention relates to a composition for inhibiting metalloproteinase which contains a compound of the formula I:

wherein R

1

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

)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(R

A

)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —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 —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-diyl, 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 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 —O— when R

3

is optionally substituted arylene or optionally substituted heteroarylene, 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 embodiment of the present invention are as follows.

1) A compound of the formula I:

wherein R

1

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

)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(R

A

)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —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 —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— (when R

3

is phenylene and R

4

is —CO—NH—, R

1

is not methyl or phenyl and R

5

is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R

5

is lower alkyl, 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 lower alkyl, 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 —O— when R

3

is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

2) A compound of the formula II:

wherein R

6

is —CH═CH—, —C≡C—, —N═N—, —NH—CO—NH—, —S—, —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

1

, R

2

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

3) A compound of the formula III:

wherein R

10

is —(CH

2

)m—, —CO—, —CO—NH—, —N(R

A

)—, —NHCO—, or tetrazol-diyl; m is 1 or 2; R

1

, R

2

, R

7

, R

8

, R

9

, R

A

, and Y are as defined above, provided R

1

is not methyl or phenyl and R

7

is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when R

10

is —NH—CO—, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

4) A compound of the formula IV:

wherein R

11

is a bond, —CH═CH—, or —C≡C—; X is oxygen atom or sulfur atom, R

1

, R

2

, R

7

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

5) A compound of the formula I′:

wherein R

1

′ is benzyl, (indol-3-yl)methyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (1-acetylindol-3-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, (1-alkoxycarbonyl-3-yl)methyl (for example ethoxycarbonylmethyl), or i-propyl; R

2

′ is hydrogen atom, methyl, 4-aminobutyl, or benzyl; R

3

′ is 1,4-phenylene; R

4

′ is —O—; R

5

′ is phenyl or 4-hydroxy-phenyl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

6) A compound of the formula I″:

wherein R

1

″ is 4-thiazolylmethyl, (indol-3-yl)methyl, (5-methoxyindol-3-yl)methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-biphenylylmethyl, 2,2,2-trifluoroethyl, 2-phenylethyl, benzyl, i-propyl, 4-nitrobenzyl, 4-fluorobenzyl, cyclohexylmethyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-fluoroindol-3-yl)methyl, (pyridin-4-yl)methyl, (benzothiazol-2-yl)methyl, (phenyl)(hydroxy)methyl, phenyl, carboxymethyl, 2-carboxyethyl, hydroxymethyl, phenylmethoxymethyl, 4-carboxybenzyl, (benzimidazol-2-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, or (1-ethoxycarbonylindol-3-yl)methyl; R

2

″ is hydrogen atom; R

3

″ is 1,4-phenylene; R

4

″ is a bond; R

5

″ is phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methylthiophenyl, 4-biphenylyl, 2-thienyl, benzoxazol-2-yl, benzothiazol-2-yl, or tetrazol-2-yl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

7) A compound of the formula V:

wherein R

12

is —CH═CH— or —C≡C—; R

1

, R

2

, R

7

, 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:

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 R

14

is optionally substituted aryl, or optionally substituted heteroaryl; provided R

13

is not methyl or phenyl and R

14

is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

9) A compound of the formula VII:

wherein R

1

, 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 VIII:

wherein R

1

, R

2

, R

7

, and R

11

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

11) A compound of the formula VIII:

wherein R

1

, 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:

wherein R

12

is —CH═CH— or —C≡C—; R

1

, R

7

, R

8

, and R

9

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

13) A compound of the formula XI:

wherein R

8

, R

9

, R

13

, and R

14

are as defined above, provided R

13

is not methyl or phenyl and R

14

is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

14) A compound of the formula XII:

wherein R

1

, R

7

, R

8

, and R

9

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

15) A compound of the formula XIII:

wherein R

1

, R

7

, and R

11

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

16) A compound of the formula XIV:

wherein R

1

, R

7

, R

8

, and R

9

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

A compound of the invention is more specifically illustrated below:

A) The compound of any one of above 1) to 16), wherein R

1

, R

1

′, R

1

″, and R

13

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 R

14

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

1

′, R

1

″, and R

13

is R configuration.

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)

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

1) A compound wherein R

1

is i-propyl, benzyl, or (indol-3-yl)methyl, R

2

is hydrogen atom, R

3

is 1,4-phenylene, R

4

is —C≡C—, and R

5

is optionally substituted phenyl.

2) A compound wherein R

1

is i-propyl, benzyl, or (indol-3-yl)methyl, R

2

is hydrogen atom, R

3

is optionally substituted 2,5-thiophen-diyl, R

4

is —C≡C—, and R

5

is optionally substituted phenyl.

3) A compound wherein R

1

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 C

1

-C

10

straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, and the like.

The term “lower alkyl” herein used means C

1

-C

6

straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, and the like.

The term “C

3

-C

8

cycloalkyl” herein used is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term “aryl” herein used means monocyclic or condensed ring aromatic hydrocarbons. Examples of the aryl are phenyl, naphthyl, and the like.

The term “aralkyl” herein used means the above mentioned alkyl substituted by the above mentioned aryl at any possible position. Examples of the aralkyl are benzyl, phenethyl, phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (α-naphthylmethyl), anthrylmethyl (9-anthrylmethyl), and the like. Benzyl is preferred. The aryl part may optionally be substituted.

The term “heteroaryl” herein used means a 5 to 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 (e.g., 1-pyrrolyl), indolyl (e.g., 2-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. The aryl part of the above heteroaryl is optionally substituted.

The term “heteroarylalkyl” herein used means the above mentioned alkyl substituted with the above mentioned heteroaryl at any possible position. Examples of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g., 5-thiazolyl-2-ethyl), indolylmethyl (e.g., 2-indolylmethyl), imidazolylmethyl (e.g., 4-imidazolylmethyl), benzothiazolylmethyl (e.g., 2-benzothiazolylmethyl), benzopyrazolylmethyl (e.g., 1-benzopyrazolylmethyl), benzotriazolylmethyl (e.g., 4-benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 2-pyridylmethyl), and the like. The aryl part of the above heteroaryl is optionally substituted.

The term “arylene” herein used is exemplified by phenylene, naphthylene, and the like. Mentioned in more detail, it is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, and the like.

The term “heteroarylene” herein used is exemplified by thiophen-diyl, furan-diyl, pyridin-diyl, and the like, in more detail, by 2,5-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, n-propoxy, 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 C

3

-C

8

cycloalkyl”, and “optionally substituted non-aromatic heterocyclic group” are hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl, benzyloxy, and the like. These substituents are able to bind them at one or more of any possible positions.

Substituents for the aromatic ring of “optionally substituted aryl”, “optionally substituted aralkyl”, “optionally substituted heteroaryl”, “optionally substituted heteroarylalkyl”, “optionally substituted arylene”, and “optionally substituted heteroarylene” are, for example, hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy) substituted or unsubstituted amino (e.g., methylamino, dimethylamino, diethylamino, and benzylidenamino), guanidino, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, and tert-pentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), alkanoyl (e.g., formyl, acetyl, and propionyl), acyloxy (e.g., acetyloxy), acylamino, alkylsulfonyl (e.g., methylsulfonyl), phenyl, benzyl, an azo group (e.g., phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally substituted ureido (e.g., ureido and phenylureido), and the like. These substituents are able to bind to it at one or more of any possible position.

Best Mode for Carrying Out the Invention

Compounds (Ia) and (Ib) of the invention are able to be synthesized from the corresponding α-amino acids represented by the formula (XV) by means of the following 6 synthetic methods. Generally, it is possible to produce the compounds of the invention by means of the method A. Each classified type of the compounds is possible to be produced by means of methods the B to F. However, these methods are only examples to produce the compounds represented by the formula I. A compound represented by the formula I produced by any other method is included in this invention.

Method A: A general synthetic method of the compound represented by the formula I.

Method B: A synthetic method of the compound wherein and R

3

is optionally substituted arylene or optionally substituted heteroarylene, R

4

is —C≡C—, 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

5

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.

wherein R

1

, R

2

, R

3

, R

4

, and R

5

are as defined above, R

15

is hydrogen atom or a carboxy protective group, R

16

is a hydroxy protective group, and Hal is halogen.

Conversion of compound (XV) to compound (Ia-1) is sulfonation of an amino group of the compound (XV) (process 1). If necessary, after this reaction, N-alkylation, deprotection of a carboxyl protective group, etc. are carried out. Conversion of compound (Ia-1) to compound (Ib-1) is to obtain hydroxamic acid derivatives from carboxylic acid derivatives (process 2). To obtain compound (Ib-1) from compound (Ia-1), compound (Ia-1) may also be reacted with hydroxylamine having a hydroxyl protective group or its acidic salts to give compound (XVI) (process 3), followed by and deprotection (process 4). Conversion to sulfonyl derivatives and hydroxamic acid derivatives are able to be carried out according to an usual method. For example, an amino acid represented by the formula (XV) is reacted with a sulfonating agent such as sulfonyl halide represented by R

5

—R

4

—R

3

—SO

2

Hal (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 (e.g., hydrochloride, p-toluenesulfonate, and trifluoroacetate) which are starting materials are commercially available. The other are able to be synthesized in accordance with a method described in Zikkenkagakukoza, vol. 22, IV (nihonkagakukai), J. Med. Chem. 38, 1689-1700, 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 (e.g., methyl ester, tert-butyl ester and benzyl ester). Deprotection of this protective group may be carried out by hydrolysis with acid (e.g., hydrochloride and trifluoroacetic acid) or base (e.g., sodium hydroxide) depending on the type of the group, or by catalytic reduction, e.g., under 10% palladium-carbon catalyst condition. To obtain a compound (Ib-1), the esters may directly be converted to hydroxamic acid by the method of process 2. When a compound (XV) is an amino acid wherein R

15

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 this sulfonylation is exemplified by the above solvents and mixed solvents of water-insoluble solvents (e.g., benzene and dichloromethane) and the above solvents. A base to be used in this sulfonylation is exemplified by organic bases such as triethylamine, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and the like. Usually this reaction can be carried out at ice-cooling to room temperature. When R

1

, R

3

, R

4

, R

5

, or R

15

of compound (Ia-1) contains a functional group(s) possibly interfering this sulfonylation (e.g., hydroxy, mercapto, amino, and guanidino), it can previously be protected in accordance with a method described in “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)) and then deprotected at an appropriate process. When R

2

is not hydrogen atom, compound (Ia-1) wherein R

2

is hydrogen atom is further reacted with haloalkyl (e.g., methyl iodide, and ethyl iodide) or haloaralkyl (e.g., benzyl chloride, and benzyl bromide) in dimethylformamide, tetrahydrofuran, dioxane, and the like at a temperature range of ice-cooling to 80° C., preferably ice-cooling to room temperature, or 3-10 hours, preferably 10-20 hours to give the desired N—R

2

derivative.

(Process 2)

A hydroxylamine is reacted with compound (Ia-1) or its reactive derivatives to give hydroxamic acid derivatives (Ib-1). A hydroxylamine is usually used as its acidic salts (e.g., hydrochloride, and phosphate, sulfate: commercially available) in the presence of a base. A base to be used in this reaction is exemplified by organic bases such as triethylamine, N,N-dimethylaniline, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. When compound (Ia-1) is used as a starting material of conversion to hydroxamic acid, this reaction is carried out in the presence of a peptide condensing agent (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-carbonyldiimidazole, or a mixture of one of the above agents with 1-hydroxybenzotriazole, N-hydroxy sucinicimide, etc.). A 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 (e.g., ethyl chlorocarbonate) in the presence of a base (e.g., triethylamine), and acid halide derivatives can be produced by a reaction of compound (Ia-1) with a halogenation agent (e.g., oxalylchloride, and thionylchloride). Ester derivatives may be inactive or active. Sulfonyl derivatives converted from a compound (XV) wherein R

15

is a carboxyl protective groups (e.g., methyl, tert-butyl, and benzyl) at process 1 can be used as inactive esters without deprotection. Active esters can be produced by a reaction of compound (Ia-1), carbodiimide reagents (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and hydroxy derivatives corresponding to the active ester residue such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, or the like. A reaction condition of conversion of the reactive derivatives of compound (Ia-1) to hydroxamic acid may be the same as that of conversion of compound (Ia-1) itself to hydroxamic acid. The reactions of processes 1 and 2 are able to continuously be carried out in one-pot reaction.

(Process 3)

A protected hydroxylamine to be used in this reaction includes O-benzylhydroxylamine, O-(p-methoxybenzyl)hydroxylamine, O-(tert-butyl)hydroxylamine, or the like. This reaction condition may be in the same manner as that of process 2.

(Process 4)

This process for deprotection is carried out by catalytic reduction, treatment with conc. hydrochloric acid, or treatment with trifluoroacetic acid to give the desired compound (Ib-1). The compounds of this invention (Ia-1) and (Ib-1) can be isolated and purified by usual separation methods and purification methods (e.g., chromatography, crystallization, etc.).

wherein R

1

, R

2

, R

7

, R

15

, and Hal are as defined above, R

17

is optionally substituted aryl or optionally substituted heteroaryl.

Conversion of compound (XV) to compound (XVII) is performed by sulfonation 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 (K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 4467(1975) etc.) wherein halogen of R

17

is utilized to insert a triple bond (process 2). Conversion of compound (XVIII) to compound (Ia-2) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 3), which can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-2) to compound (Ib-2) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 4), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(Process 1)

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

(Process 2)

Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an ethynyl group such as ethynylbenzene in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(Ph

3

P)

2

Cl

2

), a divalent copper reagent (e.g., CuI), and an organic base (e.g., triethylamine, and diisopropylethylamine) to give a desired compound (XVIII) (Heck reaction). This reaction is carried out at room temperature to 100° C., preferably room temperature to 80° C. This reaction is completed for 3 to 30 hours, preferably 10 to 20 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)), and then deprotected at an appropriate step.

(Process 3)

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

(Process 4)

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

wherein R

1

, R

2

, R

7

, R

15

, R

17

, and Hal are as defined above.

Conversion of compound (XVII) to compound (XIX) is performed by Suzuki reaction (M. J. Sharp and V. Shieckus, Tetrahedron Lett., 26, 5997 (1985) etc.) wherein halogen of R

17

is utilized to introduce aryl or heteroaryl (process 1). Conversion of compound (XIX) to compound (Ia-3) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 2) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-3) to compound (Ib-3) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 3), and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(Process 1)

Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having a B(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 (e.g., Pd(Ph

3

P)

4

) and a base (e.g., potassium carbonate, calcium carbonate, triethylamine, sodium methoxide etc.) to give the desired compound (XIX) (Suzuki reaction). This reaction is carried out at room temperature to 100° C., preferably room temperature to 80° C. 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.

wherein R

1

, 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 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 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

17

is utilized (process 3). Conversion of compound (XXII) to compound (Ia-4) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 4) of compound (XXII) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-4) to compound (Ib-4) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 5) and this process can be carried out in the same manner as those described 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 (e.g., Pd—C, PtO

2

, Raney Ni etc.), under a no-pressure or pressured condition to give the desired compound (XXI). This reaction is carried out at a temperature under ice-cooling to 80° C., 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 (e.g., triethylamine, N-methylmorpholine, potassium carbonate etc.) to give the desired compound (XXII). This reaction is carried out at a temperature under ice-cooling to 100° C., preferably room temperature to 60° C., and is completed for 3 to 30 hours, preferably 10 to 25 hours.

(Process 4)

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

(Process 5)

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

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 that described in process 1 of method A. Conversion of compound (XXIII) to compound (XXIV) is done by the reduction wherein an ethenyl group of R

17

is converted into an aldehyde group (process 2). 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 5), and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-5) to compound (Ib-5) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 6), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(Process 1)

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

(Process 2)

A compound (XXIII) is treated with ozone in a solvent such as dichloromethane, ethyl acetate, methanol, etc. to form an ozonide, and then a reagent such as zinc-acetic acid, triethylphosphate, dimethylsulfide, etc. is added to this reaction mixture for reduction to give the desired aldehyde derivatives (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 ice-cooling, and is completed for 0.5 to 10 hours, preferably 1 to 3 hours.

(Process 3)

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° C., preferably room temperature to 50° C., and is completed for 3 to 30 hours, preferably 10 to 20 hours.

(Process 4)

Optionally substituted aryl or optionally substituted heteroaryl having amino group such as aniline is dissolved in a mixed solvent such as alcohol (e.g., ethanol) and water. To this mixture conc. hydrochloric acid and a diazotizing agent such as a sodium nitrite aqueous solution are added at −20° C. to 10° C., 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 give 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 5)

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.

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 (G. Wittig et al., Chem. Berr. 87, 1318 (1954)) wherein an aldehyde group of R

17

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 2), and this process can be carried out the same similar as described in process 1 of method A. Conversion 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 ice-cooling 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 process 1 of method A.

(Process 3)

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

The term “compound of the present invention” herein used includes pharmaceutically acceptable salt or hydrate of the compound. The salt is exemplified by a salt with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, mallein acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid). These salts can be formed by the usual method.

The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.

The compound of the present invention has an excellent activity for inhibiting 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-α converting enzyme, etc.

Definitely, the compounds of the present invention are useful in the prevention or treatment of diseases such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., 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.

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 0.01-10 mg/kg/day, preferably 0.1-1 mg/kg/day. The daily dosage can be administrated in one to several divisions.

The following examples are provided to further illustrate the present invention and are not to be constructed as limiting the scope thereof.

Abbreviations described below are used in the following examples.

p-TsOH: p-toluenesulfonic acid

DMSO: dimethylsulfoxide

Me: methyl

t

Bu: tert-butyl

EXAMPLE 1

(Method A)

To a suspension of (R)-(+)-phenylalanine (compound XV-1, 1.65 g (10 mmol)) in 50 ml of dimethylformamide and 35 ml of water was stirred and treated with 2.78 ml (20 mmol) of triethylamine under ice-cooling. Then, 2.52 g (10 mmol) of 4-biphenylsulfonyl chloride in 10 ml of dimethylformamide was added dropwise to the mixture over 5 min. After the reaction mixture was stirred for 2 h at the same temperature, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 2.1 g (11 mmol) of 1-ethyl-3-(3-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 HCl, 5% NaHCO

3

, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl

3

/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 (%) C

21

H

20

N

2

O

4

S

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 ν max (cm

−1

) (Nujol): 3365, 3295, 3266, 1674, 1320, 1159.

NMR (δ ppm) d

6

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

[α]

D

: +18.5±1.2 (c=0.503%, 25° C., DMSO)

EXAMPLE 1′

Another synthetic method of compound (Ib-1-1)

Process 1

To a solution of (R)-phenylalanine benzyl ester tosylate (compound XV-1′, 2.5 g (5.85 mmol)) in 60 ml of dichloromethane was added triethylamine (1.8 ml, 12.87 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 HCl, 5% NaHCO

3

and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl

3

/MeOH=40/1 to 20/1 were collected and crystallized from dichloromethane/hexane to give 2.32 g of compound (Ia-1-1′). Yield 84.1%. mp. 130-131° C.

Elemental analysis (%) C

28

H

25

NO

4

S

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 ν max (cm

−1

) (Nujol): 3352, 1732, 1341, 1190, 1163.

NMR (δ ppm) (CDCl

3

): 3.06 (d, J=5.8 Hz, 2H), 4.30 (dt, J=6.0, 9.0 Hz, 1H), 4.89 (s, 2H), 5.12 (d, J=9.0 Hz, 1H), 6.98-7.81 (m, 14H).

[α]

D

: −16.4±1.1(c=0.506%, 25° C., MeOH)

Process 2

A solution of compound (Ia-1-1′) (2.28 g) which was obtained process 1 in 50 ml of mixed solvents of methanol/ethyl acetate=1/1, was hydrogenated using 10% Pd/C (200 mg) for 25 min. The reaction mixture was filtered off, and the filtrate was concentrated in vacuo. The residue was recrystallized from dichloromethane/hexane to give 1.83 g of compound (Ia-1-1″). Yield 99.1%. mp. 146-147° C.

Elemental analysis (%) C

21

H

19

NO

4

S

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 ν max (cm

−1

) (Nujol): 3408, 3305, 1751, 1325, 1161, 1134.

NMR (δ ppm) (CDCl

3

): 2.97 (dd, J=7.0, 13.8 Hz, 1H), 3.14 (dd, J=5.2, 14.0 Hz, 1H), 4.13 (m, 1H), 7.03-7.78 (m, 14H).

[α]

D

: −4.0±0.4(c=1.000%, 25° C., MeOH)

Process 3

To a solution of compound (Ia-1-1″, 1.0 g (2.62 mmol)) which was obtained process 2 in dichloromethane (20 ml) was added 0.33 ml (3.93 mmol) of oxalyl chloride and one drop of dimethylformamide. After being stirred for stirred for 1 h at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 10 ml of tetrahydrofuran. A solution of hydroxylamine hydrochloride (911 mg (13.1 mmol)) and NaHCO

3

1.54 g (18.34 mmol) in 10 ml of tetrahydrofuran and 10 ml 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% NaHCO

3

, and water, and concentrated in vacuo to give compound (Ia-1) (969 mg). Yield 93.3%.

Process 4

To a solution of compound (Ia-1-1″, 2.0 g, 5.24 mmol) which was obtained process 2 in dimethylformamide (20 ml) was added 1-hydroxybenzotriazole hydrate (0.7 g, 5.24 mmol), N-methylmorpholine (2.9 ml, 26.2 mmol), 1-ethyl-3-(3-diisopropylamino) carbodiimide hydrochloride (8 mmol), and O-benzylhydroxylamine hydrochloride (1.67 g, 10.48 mmol), and the resulting mixture was stirred for 6 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCO

3

, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CH

2

Cl

2

/hexane=1/1 were collected and recrystallized from dichloromethane/hexane to give 2.04 g of compound (XVI-1).

Yield 80%. mp. 171-173° C.

Elemental analysis (%) C

28

H

26

N

2

O

4

S

Calcd.: C; 69.12, H; 5.39, N; 5.76, S; 6.59.

Found: C; 68.85, H; 5.46, N; 5.76, S; 6.78.

IR ν max (cm

−1

) (Nujol): 3248, 1661, 1594, 1333, 1163.

NMR (δ ppm) (CDCl

3

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

[α]

D

: −40.2±1.6 (c=0.505%, 25° C., DMSO)

Process 5

A solution of compound (XVI-1) (1.97 g) which was obtained process 4 in a 60 ml of mixed solvents of methanol/ethyl acetate=1/1 was hydrogenated using 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 (Ib-1-1). 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′

TABLE 1

(Ib)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

2

RS

173>

3258, 1650, 1377, 1348, 1163 (Nujol)

2.87(dd, J=5.6, 14.2Hz, 1H), 2.98(dd, J=8.4, 14.2Hz, 1H), 4.02(dd, J=2.2, 8.6Hz, 1H), 7.24(d, J=2.0Hz, 1H), 8.83(d, J=2.2Hz, 1H)

3

R

203- 206

3403, 3386, 3265, 1673, 1320, 1162 (Nujol)

2.72(dd, J=7.2, 13.8Hz,1H), 2.97(dd, 7.0, 14.8Hz,1H), 3.81(m, 1H),

4

RS

—

—

—

5

RS

124- 126

3277, 1669, 1397, 1322, 1159,

3.12(dd, J=10.3, 14.3Hz, 1H), 3.89(dd, J=3.3, 13.5Hz, 1H), 4.20(m, 1H), 5.90 (brs, 1H)

6

R

139- 141

3262, 1663, 1322, 1157,

2.67(dd, J=9.2, 13.1Hz, 1H), 2.84(dd, J=5.3, 13.5Hz, 1H), 3.82(m, 1H)

7

CF

3

CH

2

—

R

167- 169

3265, 1676, 1642, 1337, 1161 (Nujol)

2.2-2.7(m, 2H),3.99(t, J=7.0Hz,1H)

8

RS

172- 173

3403, 3261, 1669, 1321, 1160

1.68(m, 2H), 2.37(m, 2H), 3.64(t, J=6.9Hz, 1H)

9

R

144- 146

3700-2200br, 3264, 1635, 1342, 1164,

2.61(dd, J=9.4, 13.8Hz, 1H), 2.78(dd, J=6.0, 13.8Hz, 1H), 3.78(m, 1H), 7.43 (d, J=8.2Hz, 2H), 7.60(d, J=8.2Hz, 2H),

TABLE 2

(Ib)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

10

R

116- 118

3600- 2400br, 3257, 1743 1721, 1323, 1132,

2.60-2.82(m, 2H), 3.84(m, 1H), 7.00-7.18(m, 5H), 7.62-7.80(m, 4H),

11

R

91- 92

3700- 2100br, 3176, 1664, 1320, 1143,

2.70-2.93(m, 2H), 2.82 (s, 6H),3.75(m, 1H),

12

(CH

3

)

2

CH—

R

178- 179

3268, 1632, 1598, 1336, 1162

0.71(d, J=6.8Hz, 3H), 0.74(d, J=5.4Hz, 3H), 1.73(m, 1H), 1.73(m, 1H), 3.22(m, 1H), 3.82(s, 3H), 7.05(d, J=9.0Hz, 2H), 7.69(d, J=9.0Hz, 2H)

13

RS

184- 185

3257, 1662, 1516, 1344 1322, 1160,

2.80(dd, J=10.0, 13.8Hz, 1H), 2.92(dd, J=5.0, 12.8Hz, 1H), 3.80(dd, J=5.4, 9.6Hz, 1H),

14

RS

128- 130

3258, 1669, 1509, 1322, 1157

2.62(dd, J=9.9, 13.5Hz, 1H), 2.78(dd, J=5.8, 13.0Hz, 1H), 3.77(t, J=6.2Hz, 1H),

15

R

165- 166

3278, 2920, 1632, 1337, 1161

0.50-1.62(m, 13H), 3.56 (t, J=7.4Hz, 1H)

16

RS

172- 173

3272, 1631, 1332, 1161

2.71(dd, J=7.9, 14.2Hz, 1H), 2.94(dd, J=6.9 14.2Hz, 1H), 3.57(s, 3H), 3.83 (dd, J=7.0, 7.4Hz, 1H)

17

RS

144- 146

3403, 1670, 1320, 1159

2.25(s, 3H), 2.67(dd, J=7.5, 14.2Hz, 1H), 2.95(dd, J=7.7, 14.6Hz, 1H), 3.81(dd, J=6.2, 14.2Hz, 1H)

TABLE 3

(Ib)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

18

RS

—

3420, 1670, 1592, 1321, 1159

2.72(dd, J=8.0, 14.0Hz, 1H), 2.90(dd, J=6.2, 14.2Hz, 1H), 3.82(m, 1H)

19

RS

—

—

—

20

RS

154- 158

3186, 1593, 1480, 1379

2.68(dd, J=9.8, 13.7Hz, 1H), 2.79(dd, J=5.6, 12.8Hz, 1H), 3.85(t, J=7.0Hz, 1H),

21

RS

111- 115

3700- 2400br, 3252, 1668, 1326, 1160

3.22-3.38(m, 2H), 4.17-4.24(m, 2H), 7.80(d, J=8.0Hz, 2H) 7.96(d, J=6.4Hz, 2H)

22

RS

—

3455, 3362, 1672, 1398, 1162

3.86(d, J=3.6Hz, 1H), 4.91(d, J=3.6Hz, 1H)

23

R

196- 197

3403, 3315, 1669, 1594 1316, 1162

4.88(d, J=9.4Hz, 1H), 8.74(d, J=9.4Hz, 1H), 8.98(s, 1H), 10.92(s, 1H)

24

R

197- 199

3700- 2400(br), 3473, 1675, 1310, 1152

2.69(dd, J=7.6, 13.5Hz, 1H), 2.93(dd, J=7.6, 13.5Hz, 1H), 3.77(t, J=7.6Hz, 1H), (CD

3

OD)

25

R

201- 202

3700- 2200(br), 3278, 1706, 1645, 1322, 1162

2.74(dd, J=8.3, 13.5Hz, 1H), 2.95(dd, J=6.5, 13.5Hz, 1H), 3.87(dd, J=6.5, 8.3Hz, 1H), (CD

3

OD)

TABLE 4

(Ib)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

26

R

63- 65

3700- 2200(br), 3362, 1670, 1590, 1336, 1152

2.60(dd, J=9.0, 13.8Hz, 1H), 2.79(dd, J=9.3, 13.8Hz, 1H), 3.76(m, 1H)

27

R

70- 71

3700- 2200br, 3372, 1674, 1531, 1348, 1310, 1161

2.66(dd, J=9.5, 13.6Hz, 1H), 2.79(dd, J=5.4, 13.6Hz, 1H), 3.84(m, 1H), 7.73 (A

2

B

2

qJ=8.9Hz, 2H), 8.20(A

2

B

2

q, J=8.9Hz, 2H), 8.72(d, J=9.0Hz, 1H), 8.86(s, 1H) 10.7(s, 1H)

28

HOOC—CH

2

—

R

—

—

—

29

HOOC—CH

2

—CH

2

—

R

—

—

—

30

HOCH

2

—

R

192- 193

3700- 2400(br), 3392, 1667, 1320, 1161

3.29(dd, J=5.7, 10.7Hz, 1H), 3.43(dd, J=8.4, 10.7Hz, 1H), 3.62(m, 1H), 7.85(A

2

B

2

q, J=8.7Hz, 2H), 7.88 (A

2

B

2

q, J=8.7Hz, 2H), 7.98(d, J=7.8Hz, 1H), 10.61(s, 1H)

31

R

69- 70

3700- 2200(br), 1671, 1329, 1163

2.69(dd, J=7.6, 13.5Hz, 1H), 2.93(dd, J=7.6, 13.5Hz, 1H), 3.77(t, J=7.6Hz, 1H), (CD

3

OD)

32

R

—

—

—

33

R

160- 162

3401, 3260, 1673, 1316, 1165

2.66(dd, J=7.5, 13.4Hz, 1H), 2.96(dd, J=7.6, 14.2Hz, 1H), 3.81(m, 1H)

TABLE 5

(Ib)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

34

R

—

—

—

35

RS

141- 145

3700- 2400(br), 1672, 1443, 1327, 1094

2.84-3.21(m, 2H), 4.29(m, 1H)

TABLE 6

(Ia)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

2

RS

159- 161

3276, 2503br, 1897br, 1724, 1344, 1170 (Nujol)

2.95(dd, J=9.0, 14.0Hz, 1H), 3.12(dd, J=5.4, 14.0Hz, 1H), 4.13(m, 1H), 7.29(d, J= 2.0Hz, 1H), 8.34(d, J= 8.6Hz, 1H), 8.88(d, J=2.0Hz, 1H), 12.79(br, 1H)

3

R

227- 229

3386, 3305, 1747, 1363, 1323, 1161, 1135(Nujol)

2.88(dd, J=8.0, 14.0Hz, 1H), 3.09(dd, J=6.0, 14.0Hz, 1H), 3.91(m, 1H), 8.23(m, 1H), 10.79(s, 1H), 12.70(br, 1H)

4

RS

181- 189

2400- 3700(br), 1734, 1484, 1327, 1160

2.75-3.06(m, 2H), 3.69(s, 3H), 3.90(m, 1H)

5

RS

198- 200

3446, 3065, 1594, 1397, 1303, 1154, 1094

3.17(dd, J=7.4, 13.8Hz, 1H), 3.57(dd, J=5.5, 13.9Hz, 1H), 3.80(t, J=5.6Hz, 1H), 8.11(d, J=7.4Hz, 1H)

6

R

213- 215

3184, 1723, 1337, 1317, 1156

2.77(dd, J=9.7, 13.7Hz, 1H), 3.03(dd, J=4.9, 13.3Hz, 1H), 3.93(m, 1H), 8.38(d, J=8.8Hz, 1H)

7

CF

3

CH

2

—

R

176- 177

3276, 1706, 1344, 1260, 1165

2.40-2.90(m, 2H), 4.05(m, 1H), 8.51(d, J=9.0Hz, 1H), 13.2(br, 1H)

8

RS

153- 156

3289, 1739, 1326, 1159, 1089

1.83(m, 2H), 2.52(m, 2H), 3.70(m, 1H), 8.32(d, J=9.0Hz, 1H)

11

R

103- 105

2200- 3700br, 3439, 3288, 1725, 1329, 1143

2.86(m, 1H), 2.87(s, 6H), 2.98(dd, J=5.1, 13.8Hz, 1H), 4.15(m, 1H), 5.54(m, 1H)

TABLE 7

(Ia)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

13

RS

212- 213

3113, 1724, 1520, 1345, 1158

2.86(dd, J=10.2, 13.2Hz, 1H), 3.14(dd, J=4.5, 13.7Hz, 1H), 4.02(m, 1H), 8.42(d, J=8.4Hz, 1H)

14

RS

164- 165

3426, 3114, 1715, 1509, 1224, 1159

2.71(dd, J=9.9, 13.7Hz, 1H), 2.96(dd, J=5.3, 13.5Hz, 1H), 3.89(m, 1H), 8.34(d, J=9.0Hz, 1H)

15

R

85- 87

2919, 1688, 1448, 1335, 1326, 1169

0.52-1.72(m, 13H), 3.68(m, 1H), 8.20(br.s, 1H)

16

RS

179- 183

3432, 3294, 1713, 1482, 1341, 1159

2.80-3.12(m, 2H), 3.61(s, 3H), 3.94 (m, 1H), 8.30(d, J=8.6Hz, 1H)

17

RS

115- 120

3419, 3397, 3291, 1736, 1482, 1336, 1321, 1165

2.28(s, 3H), 2.78- 3.10(m, 2H),3.91 (m, 1H, 8.29(d, J=8.3Hz, 1H)

18

RS

208- 211

3407, 3285, 1751, 1735, 1703, 1486, 1321, 1162

2.80—3.10(m, 2H), 3.92(m, 1H), 8.29(d, J=8.2Hz, 1H)

20

RS

197- 205

2600- 3700br, 1635, 1594, 1335, 1163, 1095

2.60-3.04(m, 2H), 3.98(m, 1H)

21

RS

196- 199

2200- 3700br, 1713br, 1345, 1125

3.24-3.56(m, 2H), 4.34(m, 1H)

TABLE 8

(Ia)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

22

RS

141- 143

3335, 3246, 1732, 1315, 1152

4.10(d, J=3.2Hz, 1H), 5.13(d, J= 3.2Hz, 1H)

23

R

211- 214

3316, 1734, 1325, 1159 (Nujol)

4.94(d, J=9.4Hz, 1H), 8.80(d, J=9.4Hz, 1H), 13.0(br.s, 1H)

28

HOOC—CH

2

—

R

171- 173

3353, 1752, 1326, 1155, 1096

2.45(dd, J=6.2, 16.4Hz, 1H)2.63(dd, J=6.6, 16.4Hz, 1H),

29

HOOC—CH

2

—CH

2

—

R

185- 187

3270, 1709, 1336, 1159, 1093

1.68(dd, J=7.9, 14.1Hz, 1H), 1.87(dd, J=6.0, 13.4Hz, 1H), 2.22(t, J=7.2Hz, 2H), 3.80(m, 1H),

30

HOCH

2

—

R

277- 279

2200- 3700br, 3430, 3292, 1728, 1324, 1162

3.51(dd, J=6.0, 12.9Hz, 1H), 3.55(dd, J=5.4, 12.9Hz, 1H), 3.80(m, 1H), 8.06(d, J=8.7Hz, 1H)

31

R

89-91

2200- 3700br, 3432, 3289, 1773, 1330, 1165

3.54(dd, J=4.8, 9.9Hz, 1H), 3.60(dd, J=5.7, 9.9Hz, 1H), 4.04(m, 1H), 4.39(s, 2H), 8.34(d, J=8.1Hz, 1H)

32

R

>270

3319, 3052, 1701, 1317, 1284, 1162

2.81(dd, J=9.7, 13.7Hz, 1H), 3.05(dd, J=4.8, 13.4Hz, 1H), 3.96(m, 1H), 8.40(d, J=9.0Hz, 1H), 12.88(br.s, 1H)

TABLE 9

(Ia)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

34

R

243- 246

3420, 1588, 1402, 1324, 1151

3.06(dd, J=5.4, 14.4Hz, 1H), 3.14 (dd, J=5.1, 14.4Hz, 1H), 3.65(t, J=5.4Hz, 1H), 6.92(m, 1H), 10.72(s, 1H)

35

RS

151- 156

2200- 3700br, 1734, 1334, 1161

3.17-3.50(m, 2H), 4.51(m, 1H)

TABLE 10

(Ia)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

36

RS

>145

1726, 1354 1326, 1161

—

37

RS

—

1732, 1594 1404, 1155

—

38

R

188- 190

1607, 1594 1294, 1153

C

24

H

22

N

2

O

5

S•0.5 H

2

O Calc. C:62.73 H:5.04 N:6.10 S:6.98 Foun. C:62.75 H:5.08 N:6.31 S:7.05

39

R

90- 93

1724, 1594 1326, 1159

C

24

H

22

N

2

O

5

S•0.8 H

2

O Calc. C:62.00 H:5.12 N:6.03 S:6.90 Foun. C:62.03 H:5.06 N:6.08 S:6.82

40

R

149- 152

1685, 1349 1166

—

41

R

104- 107

1725, 1599 1372, 1173

—

42

R

167- 169

1745, 1653 1391, 1147

—

43

(CH

3

)

2

CH—

R

155- 157

1714, 1594 1334, 1166

C

17

H

19

NO

4

S•0.1 CF

3

COOH Calc. C:59.99 H:5.58 N:4.06 S:9.30 Foun. C:60.37 H:5.74 N:4.13 S:9.76

TABLE 10

(Ia)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

44

(CH

3

)

2

CH—

R

196- 197

1724, 1340 1328, 1167

C

21

H

27

NO

4

S.0.3 H

2

O Calc. 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

45

(CH

3

)

2

CH—

R

241- 243

1734, 1719 1324, 1160

C

23

H

23

NO

4

S•0.3 H

2

O Cal. C:66.58 H:5.73 N:3.38 S:7.73 Foun. C:66.45 H:5.52 N:3.24 S:7.56

46

(CH

3

)

2

CH—

R

157- 159

1670, 1375 1148

—

47

(CH

3

)

2

CH—

R

175- 176

1717, 1694 1349, 1165

—

48

(CH

3

)

2

CH—

R

145- 147

1634, 1334 1158

C

17

H

18

FNO

4

S Calc. C: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

49

(CH

3

)

2

CH—

R

183- 186

1681, 1319 1162

—

50

R

183- 184

1725, 1340 1159

—

51

R

224- 226

1750, 1324 1159

C

27

H

23

NO

4

S.0.7 H

2

O Calc. C:68.98 H:5.23 N:2.98 S:6.82 Foun. C:69.08 H:5.09 N:2.91 S:6.73

TABLE 12

(Ia)

Ex-

mp

am-

(de-

ple

comp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

52

R

157- 160

1685, 1349 1166

—

53

R

111- 112

1691, 1567 1390, 1159

—

54

R

194- 195

1749, 1592 1232, 1164

—

55

(CH

3

)

2

CH—

R

197- 199

1746, 1337 1164

C

18

H

21

NO

4

S

2

•0.2 H

2

O Calc. C:56.43 H:5.63 N:3.66 S:16.74 Foun. C:56.74 H:5.67 N:3.86 S:16.35

56

R

108- 110

1649, 1337 1165

—

57

R

187- 190

1588, 1308 1141

—

58

R

239- 243

1744, 1592 1323, 1160

C

21

H

18

N

2

O

4

S

2

•0.3 H

2

O Calc. C:58.40 H:4.34 N:6.45 S:14.85 Foun. C:58.40 H:4.44 N:6.58 S:14.57

59

R

222- 224

1751, 1734 1537, 1347 1172

C

17

H

14

ClN

3

O

6

S•0.3 H

2

O Calc. C:47.48 H:3.44 Cl:8.39 N:9.65 S:7.52 Foun. C:47.57 H:3.43 Cl:8.26 N:9.79 S:7.47

TABLE 13

(Ia)

Ex-

mp

am-

(de-

IR (ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

60

R

foam

3700- 2400br, 3277, 1669, 1325, 1152

2.60(dd, J=8.7, 13.7Hz, 1H), 2.79(dd, J=6.0, 13.7Hz, 1H), 3.75(ddd, J=6.0, 8.7, 9.0, 1H), 6.94(d, J=8.9Hz, 2H)

61

R

115- 118

3302, 1667, 1324, 1153 (Nujol)

2.71(dd, J=7.0, 14.4Hz, 1H), 2.96(dd, J=7.0, 14.2Hz, 1H), 3.78(t, J=7.6Hz, 1H)

62

S

—

3406, 1670, 1582, 1325, 1153

2.71(dd, J=7.9, 14.4Hz, 1H), 2.96(dd, J=7.6, 14.4Hz, 1H), 3.78(dd, J=7.2, 7.3Hz, 1H)

63

(CH

3

)

2

CH—

R

149- 151

3268, 1634, 1584, 1336, 1157

0.76(d, J=6.6Hz, 6H), 1.77(m, 1H), 3.26(m, 1H)

64

RS

—

3314, 1669, 1582, 1420, 1328, 1154

2.71(dd, J=7.9, 14.2Hz, 1H), 2.93(dd, J=6.5, 14.3Hz, 1H), 3.65(s, 3H), 3.78 (dd, J=7.1, 7.2Hz, 1H)

65

RS

—

3405, 1671, 1582, 1487, 1324, 1154

2.34(s, 3H), 2.65(dd, J=7.8, 14.1Hz, 1H), 2.93(dd, J=7.6, 14.4Hz, 1H), 3.75(dd, J=6.8, 7.7Hz, 1H)

66

RS

—

3317, 1670, 1582, 1488, 1323, 1153

2.71(dd, J=8.9, 14.4Hz, 1H), 2.89(dd, J=6.6, 14.4Hz, 1H), 3.75(dd, J=6.5, 6.8Hz, 1H)

67

RS

—

3421, 1702, 1676, 1582, 1354, 1328, 1153

2.54(s, 3H), 2.69-2.89(m, 2H), 3.87(m,1H)

TABLE 14

(Ia)

Ex-

mp

am-

(de-

IR (ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

60

R

108- 109

2400- 3600br, 3345, 3213, 1735, 1700, 1346, 1163

2.72(dd, J=8.7, 13.6Hz, 1H), 2.94(dd, J=5.6, 13.6Hz, 1H), 3.84(ddd, J=5.6, 8.7, 8.7Hz, 1H), 8.23(d, J=8.7Hz, 1H)

61

R

82- 87

3410, 3276, 1724, 1582, 1488, 1331, 1152 (Nujol)

2.88(dd, J=7.4, 15.2Hz, 1H), 3.07(dd, J=6.2, 14.4Hz, 1H), 3.83(m, 1H), 8.08(m, 1H), 10.80(s, 1H), 12.70(br, 1H)

62

S

foam

3412, 1724, 1582, 1488, 1332, 1152

2.81-3.12(m, 2H), 3.88(m, 1H),8.19(d, J=8.4Hz, 1H)

63

(CH

3

)

2

CH—

R

137- 138

3154, 1720, 1688, 1583, 1488, 1251

0.89(d, J=7.0Hz, 3H), 0.98(d, J=6.8Hz, 3H), 2.12(m, 2H), 3.80(dd, J=4.7, 9.7Hz, 1H), 5.17(d, J=9.6Hz, 1H)

64

RS

—

3273, 1724, 1582, 1487, 1331, 1198, 1153

2.78-3.10(m, 2H), 3.67(s, 3H), 3.86(m, 1H)

65

RS

—

3409, 3281, 1725, 1582, 1331, 1197, 1153

2.34(s, 3H), 2.75-3.08(m, 2H), 3.86(m, 1H),8.19 (d, J=8.4Hz, 1H)

66

RS

—

3415, 1725, 1582, 1488, 1329, 1196, 1174, 1152

2.78-3.08(m, 2H), 3.85 (m, 1H), 8.18(d, J=8.6Hz, 1H)

67

RS

236- 237

3296, 1742, 1647, 1604, 1581, 1342, 1334, 1152

2.55(s, 3H), 2.79-3.11(m, 2H), 3.98(m, 1H)

TABLE 15

(Ia)

Ex-

mp

am-

(de-

IR (ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

68

R

>240

1608, 1590, 1507, 1232 1157

—

69

RS

—

1735, 1583, 1362, 1171

C

24

H

22

N

2

O

7

S

2

Calc. C:56.02 H:4.31 N:5.44 S:12.46 Foun. C:55.75 H.4.40 N:5.41 S:12.21

70

RS

—

1733, 1583 1150

—

TABLE 16

(Ib)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

71

R

129- 131

3700- 2400br, 3247, 1636, 1337, 1160

0.90(t, J=6.8Hz, 3H), 1.22-1.40(m, 4H), 1.52-1.67(m, 2H), 2.62(t, J=7.7Hz, 2H), 2.86(dd, J=8.4, 13.7Hz, 1H), 3.02(dd, J=5.7, 13.7Hz, 1H) (CDCl

3

)

72

CH

3

(CH

2

)

7

—

R

oil

3700- 2400br, 1663, 1320, 1145(film)

0.87(t, J=6.3Hz, 3H), 2.50(t, J=7.4Hz, 2H), 2.76(dd, J=9.6, 14.0Hz, 1H), 2.87(dd, J=5.8, 14.0Hz, 1H), 3.84(dd, J=5.8, 9.6Hz, 1H),

73

CH

3

(CH

2

)

3

—

R

oil

3600- 2400br, 3262, 1673, 1321, 1142 (CHCl

3

)

0.79(t, J=7.0Hz, 3H), 2.32-2.56(m, 2H), 2.92(m, 1H), 3.26(m, 1H),

74

R

—

—

—

75

R

85- 86

3700- 2200(br), 3262, 1639, 1332, 1156

2.80(m, 1H), 2.96(m, 1H), 3.94(s, 2H), 3.86(m, 1H), 6.80-7.52(m, 10H), 7.08(A

2

B

2

qJ=7.5Hz, 2H), 7.42(A

2

B

2

q, J=7.5Hz, 2H) (CDCl

3

)

76

R

—

—

—

TABLE 17

(Ib)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

77

R

138- 139

3700- 2400(br), 3312, 1629, 1329, 1144

2.79(dd, J=8.5, 13.4Hz, 1H), 2.89(dd, J=6.0, 13.4Hz, 1H), 3.81(dd, J=6.0, 8.5Hz, 1H), 6.55(d, J=15.5Hz, 1H)

78

R

69- 70

3700- 2200(br), 1670, 1318, 1152

2.78(dd, J=8.6, 13.4Hz, 1H), 2.91(dd, J=6.0, 13.4Hz, 1H), 3.92(ABq, J=13.5Hz, 1H), 3.90(m, 1H), 9.01(s, 1H), 10.78(s, 1H)

79

R

—

—

—

TABLE 18

(a)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

71

R

121- 122

2300- 3700br, 3426, 3318, 1713, 1330, 1159

0.89(t, J=6.7Hz, 3H), 2.62(t, J=7.6Hz, 2H), 2.96(dd, J=7.0, 13.9Hz, 1H), 3.10(dd, J=5.4, 13.9Hz, 1H), 4.19(dt, J=6.9, 8.2Hz, 1H), 5.30(d, J=8.2Hz, 1H),

72

CH

3

(CH

2

)

7

—

R

oil

2400- 3600br, 3340, 1736, 1334, 1142 (CHCl

3

)

0.88(t, J=6.9Hz, 3H), 2.55- 2.73(m, 2H), 2.97(dd, J=8.4, 13.8Hz, 1H), 3.24(dd, J=4.8, 13.8Hz, 1H), 4.35(m, 1H), 4.98(m, 1H) (CDCl

3

)

73

CH

3

(CH

2

)

3

—

R

89- 90

2300- 3700br, 3240, 1725, 1341, 1144

0.84(t, J=7.1Hz, 3H), 2.57- 2.70(m, 2H), 2.97(dd, J=8.4, 13.9Hz, 1H), 3.25(dd, J=4.8, 13.9Hz, 1H), 4.35(m, 1H), 4.96(d, J=9.6Hz, 1H) (CDCl

3

)

74

R

>250

3421, 1580, 1333, 1421, 1153

2.41(s, 3H), 3.01(dd, J=6.0, 14.4Hz, 1H), 3.12(dd, J=4.5, 14.4Hz, 1H), 3.67(t, J=5.4Hz, 1H), 6.79(m, 1H), 6.89(m, 1H), 10.59(s, 1H)

76

R

foam

3413, 1594, 1456, 1416, 1157

3.03(dd, J=6.5, 15.1Hz, 1H), 3.15(dd, J=4.7, 14.1Hz, 1H), 3.64(t, J=5.1Hz, 1H), 10.68(s, 1H)

77

R

—

2400- 3700br, 3252, 1765, 1725, 1301, 1140

2.81(dd, J=9.2, 13.7Hz, 1H), 3.03(dd, J=5.4, 13.7Hz, 1H), 3.94(dt, J=5.4, 9.2Hz, 1H), 6.66(d, J−15.2Hz, 1H), 7.16(d, J=15.2Hz, 1H), 8.01(d, J=9.2Hz, 1H)

78

R

—

2200- 3700br, 3268, 1726, 1321, 1152 (film)

2.81(dd, J=9.2, 13.7Hz, 1H), 3.00(dd, J=5.6, 13.7Hz, 1H), 4.01(ABq, J=13.7Hz, 2H), 4.01(m, 1H), 7.65(d, J=8.3Hz, 1H)

79

R

—

3413, 2931, 1720, 1585, 1455, 1421, 1313, 1144

0.90-1.68(m, 9H), 1.78 (m, 1H), 2.74(m, 1H), 3.00- 3.20(m, 2H), 3.77(m, 1H) 6.45(br.s, 1H), 6.77(br.s, 1H)

TABLE 19

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

80

R

153- 155

1704, 1596, 1349, 1164

—

81

n-C

8

H

17

—

R

>130

1576, 1356 1139

—

82

R

128- 130

1732, 1342 1167

C

24

H

19

N

3

O

5

S•1.3 H

2

O Calc. C:59.45 H:4.49 N:8.67 S:6.61 Foun. C:59.43 H:4.45 N:8.59 S:6.58

83

R

210- 214

1745, 1590 1316, 1157

—

84

R

198- 200

1594, 1456 1200, 1188

—

TABLE 20

(Ib)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

85

R

157- 160

3700- 2400br, 3273, 1633, 1338, 1166

2.65(dd, J=8.9, 13.6Hz, 1H), 2.82(dd, J=6.6, 13.6Hz, 1H), 3.86(m, 1H), 7.75(d, J=7.8Hz, 2H), 7.87(d, J=8.7Hz, 2H)

86

R

138- 142

3700- 2400br, 2921, 1672, 1314, 1165

2.62(dd, J=8.6, 13.5Hz, 1H), 2.81(dd, J=6.5, 13.6Hz, 1H), 3.09(s, 6H), 3.83(m, 1H), 6.86(d, J=9.0Hz, 2H), 7.83(d, J=8.8Hz, 2H)

87

S

206- 207

3700- 2400(br), 3357, 1686, 1641, 1314, 1155

2.57(dd, J=8.3, 13.6Hz, 1H), 2.79(dd, J=6.0, 13.6Hz, 1H), 3.76(m, 1H), 8.02(d, J=8.7Hz, 1H), 8.80(s, 1H), 8.85(d, J=1.7Hz, 1H), 9.06(s, 1H), 10.59(d, J=1.7Hz, 1H)

TABLE 21

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

1

H-NMR(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

85

R

172- 174

2400- 3600br, 3426, 3296, 1698,1350, 1167

2.75(dd, J=9.1, 13.7Hz, 1H), 2.98(dd, J=5.5, 13.7Hz, 1H), 3.96(ddd, J=5.5, 9.1, 9.1Hz, 1H), 8.51(d, J+9.1Hz, 1H)

86

R

93- 94

2200- 3700br, 3431, 1735, 1391, 1154

2.74(dd, J=9.1, 13.6Hz, 1H), 2.96(dd, J=5.7,13.6Hz, 1H), 3.09(s, 6H), 3.93(dt, J=5.7, 9.1Hz, 1H), 8.39(d, J=9.1Hz, 1H)

87

S

203- 204

2300- 3700br, 3358, 3262, 1718, 1686, 1660, 1313, 1159

2.71(dd, J−9.1, 13.7Hz, 1H), 2.93(dd, J=5.6, 13.7Hz, 1H), 3.84(dt, J=5.6, 9.1Hz, 1H), 8.11(d, J=9.1Hz, 1H), 8.78(s, 1H), 9.06(s, 1H)

TABLE 22

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

88

R

103- 106

1719, 1390 1229

—

89

(CH

3

)

2

CH—

R

96- 99

1734, 1461 1327, 1158

C

17

H

20

N

2

O

6

S

2

•0.9 Ethylether Calc. C:51.63 H:6.10 N:5.85 S:13.38 Foun. C:51.23 H:6.17 N:5.87 S:13.11

90

(CH

3

)

2

CH—

R

110- 112

1724, 1325 1168

C

18

H

21

N

3

O

6

S

2

•0.8 Ethylether Calc. C:51.05 H:5.86 N:8.42 S:12.86 Foun. C:50.75 H:5.89 N:8.15 S:12.47

91

R

98- 101

1735, 1598, 1327, 1185

C

21

H

19

BrN

2

O

6

S

2

•0.5 CF

3

COOH Calc. 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)

Process 1

To a solution of D-valine methylester hydrochloride (XV-2) (755 mg, 4.5 mmol) in dichloromethane (12 ml) was added N-methylmorpholine (1.49 ml, 3×4.5 mmol) and 5-bromo-2-thiophensulfonyl chloride (1.24 g, 1.05×4.5 mmol) was added under ice-cooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HCl, 5% NaHCO

3

, and water. The organic layer was concentrated in vacuo, and dried over Na

2

SO

4

. The residue was subjected to silica gel column chromatography and the fractions eluting with ethyl acetate/hexane=1/3 were collected and washed with n-hexane to give 1.32 g of the desired compound (XVII-1).

Yield 82%. mp. 109-110° C.

Elemental analysis C

10

H

14

BrNO

4

S

2

Calcd.: C; 33.71 H; 3.96 Br; 22.43 N; 3.93 S;1 8.00.

Found: C; 33.75 H; 3.89 Br; 22.43 N; 3.96 S; 17.86.

[α]

D

: −34.5±0.7(c=1.012 CHCl

3

25° C.)

IR(CHCl

3

, ν max cm

−1

)1737,1356,1164,1138

NMR (CDCl

3

, δ ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz, 3H), 2.00 (m, 1H), 3.60(s, 3H), 3.83(dd, J=5.2, 10.0 Hz, 1H), 5.20(d, J=10.0 Hz, 1H), 7.04(d, J=4.1 Hz, 1H), 7.32(d, J=4.1 Hz, 1H)

Process 2

To a degassed solution of 400 mg (1.12 mmol) of compound (XVII-1) in 5 ml of dimethylformamide was added 222 mg (1.5×1.12 mmol) of 4-methoxyphenylacetylene and 21 mg (0.1×1.12 mmol) of copper iodide (I) under an argon atmosphere. Then 39 mg (0.05×1.12 mmol) of bis(triphenylphosphine)palladium dichloride (II) and 0.47 ml (3×1.12 mmol) of triethylamine were added to the reaction mixture. The resulting mixture was degassed and stirred overnight under an argon atmosphere at 50° C. The reaction mixture was diluted with ethyl acetate. The organic later was washed with 1N HCl, 5% NaHCO

3

, and water, dried over Na

2

SO

4

, and concentrated in vacuo. The resulting residue was column chromatographed on silica gel. The fractions eluting 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. 131-132° C.

Elemental analysis C

19

H

21

NO

5

S

2

.0.2 H

2

O

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, ν max cm

−1

): 3268,2203,1736,1604,1524,1348,1164.

NMR(CDCl

3

, δ ppm): 0.90(d, J=6.6 Hz, 3H), 1.00(d, J=7.0 Hz, 3H), 2.00(m, 1H), 3.60(s, 3H), 3.84(s, 3H), 3.86(dd, J=5.0, 10.2 Hz, 1H), 5.21(d, J=10.2 Hz, 1H), 6.90(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).

Process 3

To a solution of 407 mg (1 mmol) of compound (XVII-1) in 8 ml of tetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH. The resulting mixture was stirred for 6 h at 60° 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 Na

2

SO

4

, and concentrated in vacuo to give 373 mg of compound (Ia-2-1). Yield 100%. mp. 147-148° C.

IR (KBr, ν max cm

−1

): 1710,1604,1351,1216.

Elemental analysis C

18

H

19

NO

5

S

2

.0.2H

2

O

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.

TABLE 23

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

93

R

165- 170

1590, 1316, 1137

—

94

R

223- 226

1747, 1323 1134

C

26

H

22

N

2

O

5

S Calc. C:65.81 H:4.67 N:5.90 S:6.76 Foun. C:65.34 H:4.90 N:5.56 S:6.40

95

R

216- 218

1724, 1325 1135

—

96

R

111- 114

1739, 1336 1163

—

97

R

178- 180

1710, 1511 1329, 1161

—

98

R

105- 108

1725, 1618 1373, 1163

—

99

R

>250

1706, 1606 1350, 1164

C

26

H

20

N

2

O

6

S• 0.4 H

2

O Calc. C:63.00 H:4.23 N:5.65 S:6.47 Foun. C:62.99 H:4.32 N:5.82 S:6.76

100

R

176- 177

1735, 1633 1321, 1173

C

25

H

21

N

3

O

4

S• 0.8 H

2

O Calc. C:63.36 H:4.81 N:8.87 S:6.77 Foun. C:63.45 H:4.92 N:8.77 S:6.57

TABLE 24

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

101

R

227- 229

1736, 1618 1398, 1168

C

26

H

22

N

2

O

4

S• 0.2 H

2

O Calc. C:67.57 H:4.89 N:6.06 S:6.94 Foun. C:67.66 H:4.77 N:6.09 S:6.71

102

R

230- 233

1735, 1654 1399, 1164

—

103

R

234- 236

1732, 1631 1372, 1148

—

104

R

>200 de- comp.

1600, 1558 1336, 1171

—

105

(CH

3

)

2

CH—

R

146- 149

1795, 1718 1331, 1166

—

106

(CH

3

)

2

CH—

R

231- 232

1719, 1595 1344, 1167

C

19

H

18

N

2

O

6

S• 0.1 H

2

O Calc. 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

107

(CH

3

)

2

CH—

R

166- 169

1728, 1631 1372, 1148

—

108

(CH

3

)

2

CH—

R

163- 165

1728, 1332 1172

—

TABLE 25

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

109

(CH

3

)

2

CH—

R

187- 189

1720, 1656 1319, 1165

—

110

(CH

3

)

2

CH—

R

111- 114

1724, 1635 1366, 1158

—

111

(CH

3

)

3

C—

R

161- 162

1711, 1683 1600, 1328 1159

C

21

H

23

NO

5

S• 1.3 H

2

O Calc. 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

112

CH

3

CH

2

(CH

3

)CH—

R

157- 159

1732, 1680 1329, 1167

—

113

R

133- 136

1735, 1651 1348, 1165

—

114

R

183- 185

1727, 1604 1335, 1182

—

115

R

166- 168

1725, 1663 1399, 1197

C

23

H

18

FNO

4

S• 0.3 H

2

O Calc. 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

116

(CH

3

)

2

CH

R

163- 165

1728, 1332 1172

—

TABLE 26

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

117

(CH

3

)

2

CH—

R

187- 189

1720, 1656 1319, 1165

—

118

R

111- 114

1724, 1635 1366, 1158

—

119

R

167- 169

1585, 1318 1153

—

120

R

—

1605, 1523 1340, 1151

—

121

R

—

1604, 1524 1336, 1173

—

122

R

103- 106

1721, 1620 1339, 1163

—

123

R

180- 182

1729, 1675 1340, 1168

—

124

(CH

3

)

2

CH—

R

147- 148

1710, 1604 1351, 1216

C

18

H

19

NO

5

S

2

• 0.2 H

2

O Calc. C:54.45 H:4.92 N:3.53 S:16.15 Foun. C:54.39 H:4.93 N:3.79 S:15.96

TABLE 27

(Ia)

Ex-

mp

am-

(de-

IR(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

125

(CH

3

)

2

CH—

R

157- 158

1712, 1350 1163

C

18

H

19

CO

4

S

2

• 0.2 H

2

O Calc. C:56.73 H:5.13 N:3.68 S:16.83 Foun. C:57.03 H:5.30 N:3.89 S:16.56

126

(CH

3

)

2

CH—

R

154- 156

1710, 1499 1356, 1165

—

127

R

149- 150

1695, 1334 1184

C

22

H

19

NO

5

S

2

• 0.2 H

2

O Calc. C:59.36 H: 4.39 N:3.15 S:14.41 Foun. C:59.43 H:4.61 N:3.25 S:14.02

128

R

161- 164

1710, 1329 1180

—

129

R

155- 158

1734, 1699 1324, 1105

C

21

H

16

FNO

4

S

2

O Calc. C:58.73 H:3.75 F:4.42 N:3.26 S:14.93 Foun. C:58.66 H:3.93 F:4.52 N:3.33 S:14.41

130

R

—

—

—

131

R

—

—

—

132

R

—

—

—

TABLE 28

(Ia)

Example

mp (decomp.)

IR (νcm

−1

)

Elemental

No.

R

1

R

18

*

(° C.)

(KBr)

analysis

133

R

—

—

—

134

R

—

—

—

135

R

—

—

—

136

R

—

—

—

137

R

—

—

—

138

R

—

—

—

139

R

—

—

—

140

R

—

—

—

TABLE 29

(Ia)

Example

mp (decomp.)

IR (νcm

−1

)

Elemental

No.

R

1

R

18

*

(° C.)

(KBr)

analysis

141

R

—

—

—

142

R

—

—

—

143

R

—

—

—

144

R

—

—

—

145

R

—

—

—

146

R

—

—

—

147

R

—

—

—

148

R

—

—

—

TABLE 30

(Ia)

Example

mp (decomp.)

IR (νcm

−1

)

Elemental

No.

R

1

R

18

*

(° C.)

(KBr)

analysis

149

R

—

—

—

150

R

—

—

—

151

R

—

—

—

152

R

—

—

—

153

R

—

—

—

154

R

—

—

—

155

R

—

—

—

156

R

—

—

—

EXAMPLE 157, 158

Process 1 (R

2

=CH

3

)

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 (5×0.33 mmol) of potassium carbonate and 0.1 ml (5×0.33 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 Na

2

SO

4

, and concentrated in vacuo to give 373 mg of N-methyl derivative as an oil. Yield 91%.

Elemental analysis C

24

H

23

NO

5

S

2

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 obtained the above process in 2 ml of methanol was added 0.6 ml of 1N NaOH, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over Na

2

SO

4

, and concentrated in vacuo to give 105 mg of compound (Ia-2-66) (R═Me). Yield 77%. mp. 185-186° C.

Elemental analysis C

23

H

21

NO

5

S

Calcd.: C; 60.64 H; 4.65 N; 3.07 S; 14.08.

Found: C; 60.56 H; 4.84 N; 3.01 S; 13.94.

IR (KBr, ν max cm

−1

): 3600-2300br, 3426, 2203, 1710, 1604, 1503, 1344, 1151.

NMR (d

6

-DMSO, δ 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

═CH

2

Ph) was synthesized in the same manner as those described in Example 157.

IR(KBr, ν max cm

−1

): 2200,1722,1340,1151.

NMR (d

6

-DMSO, δ ppm): 2.94(dd, J=7.6, 13.8 Hz, 1H), 3.19(dd, J=7.2, 14.4 Hz, 1H), 3.83(s, 3H), 4.29(d, J=16.2 Hz, 1H), 4.62(d, J=16.2 Hz, 1H) (Only characteristic peaks are shown.)

EXAMPLE 159

(Method C)

Process 1

To a solution of 500 mg (1.4 mmol) of compound(XVII-2) which was obtained Example 96 in 12 ml of dry tetrahydrofuran was added 387 mg (2×1.4 mmol) of powdery potassium carbonate, 319 mg (1.5×1.4 mmol) of 4-methoxyphenylboronic acid and 81 mg (0.05×1.4 mmol) of tetrakis(triphenylphosphine)palladium. The resulting mixture was stirred under argon atmosphere for 48 h at 75° C. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1N HCl, 5% NaHCO

3

aq., and water, dried over Na

2

SO

4

, 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. 122-123° C.

Elemental analysis C

17

H

21

NO

5

S

2

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.

[α]

D

−21.7±0.6 (c=1.000 DMSO 25° C.)

IR (KBr, ν max cm

−1

): 1735,1605,1505,1350,1167,1136

NMR (CDCl

3

, δ ppm): 0.90(d, J=7.0 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 2.10(m, 1H), 3.54(s, 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

To a solution of 390 mg (1.01 mmol) of compound (XIX-1) in 8 ml of tetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH, and resulting mixture was stirred at 60° C. for 6 h. The reaction mixture was concentrated in vacuo to remove an organic solvent. The resulting residue was diluted with ethyl acetate. The mixture was acidified with aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na

2

SO

4

, and concentrated in vacuo to give 373 mg of compound (Ia-3-1). Yield 100%. mp.: 174-176° C.

IR(KBr, ν max cm

−1

): 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.

TABLE 31

(Ia)

Ex-

mp

IR

am-

(de-

(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental anaylsis

160

R

93- 96

1667, 1337 1180

—

161

R

157- 159

1670, 1339 1194

—

162

R

168- 171

1725, 1598 1371, 1185

—

163

R

226- 230

1735, 1341 1159

C

22

H

20

N

2

O

4

S

3

.0.4 H

2

O Calc. C:55.07 H:4.37 N:5.84 S:20.05 Foun. C:55.35 H:4.43 N:6.04 S:1965

164

(CH

3

)

2

CH—

R

174- 176

1735, 1503 1343, 1163

—

165

(CH

3

)

2

CH—

R

165- 167

1713, 1353 1163

—

166

(CH

3

)

2

CH—

R

146- 147

1702, 1504 1352, 1168

C

15

H

16

FNO

4

S

2

.0.1 H

2

O Calc. 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

167

(CH

3

)

2

CH—

R

157- 159

1747, 1324 1159

C

16

H

19

NO

4

S

3

Calc. 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

TABLE 32

(Ia)

Ex-

mp

IR

am-

(de-

(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental anaylsis

168

R

161- 165

1735, 1698 1374, 1163

C

20

H

19

NO

5

S

2

Calc. C:57.54 H:4.59 N:3.35 S:15.36 Foun. C:57.62 H:4.73 N:3.52 S:15.27

169

R

166- 167

1713, 1609 1378, 1194

C

20

H

19

NO

4

S

2

Calc. C:59.83 H:4.77 N:3.49 S:15.97 Foun. C:59.77 H:4.86 N:3.61 S:15.86

170

R

174- 175

1721, 1654 1365, 1148

C

19

H

16

FNO

4

S

2

Calc. C:56.28 H:3.98 F:4.09 N:3.45 S:15.82 Foun. C:56.33 H:4.09 F:4.65 N:3.65 S:15.84

171

R

203- 205

1750, 1730 1428, 1325 1155

C

20

H

19

NO

4

S

3

.0.2 H

2

O Calc. C:54.95 H:4.47 N:3.20 S:22.00 Foun. C:55.05 H:4.52 N:3.34 S:22.04

172

R

—

—

—

173

R

—

—

—

174

R

—

—

—

175

R

—

—

—

EXAMPLE 176

(Method D)

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 (3×47.68 mmol) of N-methylmorpholine and 14.1 g (1.2×47.68 mmol) of 4-nitrobenzenesulfonyl chloride under ice-cooling. After being stirred for 5 h at room temperature the reaction mixture was washed with 2N HCl, 5% NaHCO

3

, water. The organic layer was dried over Na

2

SO

4

and concentrated in vacuo, and the resulting residue was recrystallized from dichloromethane/n-hexane to give 13.3 g of the desired compound (XX-1). Yield 77.8%. mp. 89-90° C.

Elemental analysis C

15

H

22

N

2

O

6

S

Calcd.: C; 50.27 H; 6.19 N; 7.82 S; 8.95.

Found: C; 50.04 H; 6.10 N; 7.89 S; 8.84.

[α]

D

−2.9±0.8(c=0.512 DMSO 23° C.)

IR(KBr, ν 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 (1 g) for 2 h 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 11.5 g of amine derivative (XXI-1). Yield 94.4%. mp. 164-166° C.

Elemental analysis C

15

H

24

N

2

O

4

S

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.

[α]

D

+10.3±1.0(c=0.515 DMSO 23° C.)

IR(KBr, ν max cm

−1

): 3461, 3375, 1716, 1638, 1598, 1344, 1313.

NMR(d-DMSO, δ 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)

Process 3

To a solution of 328 mg (1 mmol) of compound (XXI-1) in 10 ml of dichloromethane was added 0.33 ml (3×1 mmol) of N-methylmorpholine and 280 mg (1.5×1 mmol) of 4-(methylthio)benzoyl chloride under ice-cooling. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added ethyl ether and precipitation were collected and washed with ice-water and ethyl ether, The solid were recrystallized from acetone/ethyl ether to give 433 mg of the desired compound (XXII-1). Yield 90.5%. mp. 235-238° C.

Elemental analysis C

23

H

30

N

2

O

5

S

2

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.

[α]

D

+5.7±0.9(c=0.512 DMSO 25° C.)

IR(KBr, ν max cm

−1

): 3366, 3284, 1713, 1667, 1592, 1514, 1498, 1341, 1317.

NMR(d

6

-DMSO, δ 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 (s, 1H).

Process 4

To a solution of 405 mg (0.85 mmol) of compound (XXII-1) in 3 ml of dichloromethane was added 3.3 ml (50×0.85 mmol) of trifluoroacetic acid and resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was washed with ethyl ether to give 340 mg of the desired compound (Ia-4-1). Yield 94.7%. mp. 231-234° C.

IR(KBr, ν max cm

−1

): 1748, 1655, 1592, 1323, 1161.

Elemental analysis C

19

H

22

N

2

O

5

S

2

.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.

TABLE 33

(Ia)

mp (decomp.)

IR (ν cm

−1

)

Example No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

177

R

215-217

1732, 1641 1341, 1163

—

178

R

233-234

1726, 1655 1323, 1177

C

25

H

23

N

3

O

6

S.0.9 H

2

O Calc. C:58.91 H:4.90 N:8.24 S:6.29 Foun. C:58.97 H:5.07 N:7.95 S:6.10

179

R

216-218

1723, 1633 1361, 1149

—

180

R

211-213

1719, 1629 1340, 1156

C

24

H

20

N

4

O

7

S.1.1 H

2

O Calc. C:54.56 H:4.24 N:10.60 S:6.07 Foun. C:54.51 H:4.32 N:10.83 S:6.15

181

R

236-238

1732, 1653 1399, 1199

C

26

H

26

N

4

O

5

S.0.9 H

2

O Calc. C:59.73 H:5.36 N:10.72 S:6.13 Foun. C:59.58 H:5.23 N:10.84 S:6.15

182

R

240-244

1731, 165 1591, 1327 1160

C

25

H

23

N

3

O

5

S.0.9 H

2

O Calc. C:60.82 H:5.06 N:8.51 S:6.49 Foun. C:60.83 H:5.19 N:8.66 S:6.66

183

R

215-218

1727, 1668 1590, 1316 1154

C

24

H

20

BrN

3

O

5

S.0.6 H

2

O Calc. C:52.11 H:3.86 Br:14.44 N:7.60 S:5.80 Foun. C:52.13 H:4.04 BR:14.57 N:7.43 S:5.70

184

R

244-249

1728, 1653 1593, 1323 1159

C

25

H

23

N

3

O

5

S

2

.0.7 H

2

O Calc. C:57.50 H:4.71 H:8.05 S:12.28 Foun. C:57.63 H:4.79 N:8.00 S:12.08

TABLE 34

(Ia)

mp (decomp.)

IR (ν cm

−1

)

Example No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

185

R

170-175

1730, 1651 1603, 1333 1161

C

24

H

20

FN

3

O

5

S.0.6 H

2

O Calc. C:58.55 H:4.34 F:3.86 N:8.54 S:6.51 Foun.C:58.67 H:4.51 F:3.77 N:8.42 S:6.47

186

R

237-239

1723, 1651 1591, 1322 1161

C

23

H

22

N

2

O

6

S Calc. C:60.78 H:4.88 N:6.16 S:7.05 Foun. C:60.50 H:4.99 N:6.14 S:7.31

187

R

235-239

1719, 1672 1593, 1327 1159

C

22

H

19

N

2

O

6

S Calc. C:56.29 H:4.08 N:8.95 S:6.83 Foun. C:56.01 H:4.09 N:8.93 S:6.75

188

R

114-115

1748, 1658 1593, 1325 1159

C

22

H

20

N

2

O

5

S.0.5 CF

3

COOH Calc. C:57.37 H:4.29 N:5.82 S:6.66 Foun. C:57.53 H:4.45 N:5.75 S:7.11

189

R

242-243

1743, 1670 1591, 1335 1167

C

22

H

19

BrN

2

O

5

S.CF

3

COOH Calc. C:46.69 H:3.27 Br:12.94 N:4.54 S:5.19 Foun. C:46.79 H:3.41 Br:12.86 N:4.57 S:5.37

190

R

242-244

1752, 1726 1656, 1591 1324, 1160

C

23

H

22

N

2

O

5

S Calc. C:63.00 H:5.06 N:6.39 S:7.31 Foun. C:62.70 H:5.13 N:6.36 S:7.36

191

R

232-235

1742, 1667 1591, 1334 1161

C

23

H

22

N

2

O

5

S

2

.0.8 CF

3

COOH Calc. C:52.59 H:4.09 N:4.99 S:11.42 Foun. C:52.77 H:4.24 N:5.12 S:11.58

192

R

218-220

1737, 1651 1598, 1324 1160

C

22

H

19

FN

2

O

5

S Calc. C:59.72 H:4.33 F:4.29 N:6.33 S:7.25 Foun. C:59.59 H:4.42 F:4.30 N:6.37 S:7.24

TABLE 35

(Ia)

mp (decomp.)

IR (ν cm

−1

)

Example No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

193

R

201- 203

1724, 1673 1592, 1326 1156

C

21

H

18

ClN

3

O

5

S Calc. C:54.84 H:3.94 Cl:7.71 N:9.14 S:6.97 Foun. C:54.39 H:4.06 Cl:7.42 N:8.98 S:6.99

194

R

206- 208

1725, 1682 1592, 1332 1160

C

22

H

20

ClN

3

O

5

S.0.1 CF

3

COOH Calc. C:55.15 H:4.19 Cl:7.33 N:8.69 S:6.63 Foun. C:55.25 H:4.28 Cl:7.10 N:8.80 S:6.80

195

(CH

3

)

2

CH—

R

254- 256

1748, 1659 1590, 1324 1161

C

24

H

24

N

2

O

5

S.0.5 H

2

O Calc. C:62.46 H:5.46 N:6.07 S:6.95 Foun. C:62.42 H:5.54 N:6.26 S:6.97

196

(CH

3

)

2

CH—

R

227- 229

1749, 1659 1592, 1323 1161

C

19

H

22

N

2

O

5

S.0.2 H

2

O Calc. C:57.91 H:5.73 N:7.11 S:8.14 Foun. C:57.94 H:5.69 N:7.03 S:8.14

197

(CH

3

)

2

CH—

R

231- 234

1748, 1655 1592, 1323 1161

C

19

H

22

N

2

O

5

S.2.0. CF

3

COOH Calc. C:53.14 H:5.13 N:6.46 S:14.78 Foun. C:53.48 H:5.31 N:6.57 S:15.06

198

(CH

3

)

2

CH—

R

235- 236

1749, 1726 1668, 1597 1322, 1160

C

18

H

19

FN

2

O

5

S

2

.0.1 CF

3

COOH Calc. C: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

199

(CH

3

)

2

CH—

R

226- 227

1728, 1661 1591, 1317 1159

C

18

H

20

N

2

O

5

S.0.1 CF

3

COOH Calc. C:57.16 H:5.38 N:7.41 S:8.48 Foun. C:57.01 H:5.46 N:7.57 S:8.57

200

(CH

3

)

2

CH—

R

220- 221

1696, 1654 1591, 1317 1255

C

19

H

22

N

2

O

6

S.0.2 H

2

O Calc. C:55.65 H:5.51 N:6.83 S:7.82 Foun. C:55.63 H:5.48 N:7.03 S:7.75

TABLE 36

(Ia)

mp (decomp.)

IR (ν cm

−1

)

Example No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

201

(CH

3

)

2

CH—

R

240- 242

1726, 1688 1591, 1347 1166

C

18

H

19

N

3

O

7

S.0.4 H

2

O Calc. C:50.44 H:4.66 N:9.80 S:7.48 Foun. C:50.40 H:4.55 N:9.90 S:7.44

202

(CH

3

)

2

CH—

R

229- 230

1726, 1663 1592, 1318 1159

C

18

H

19

BrN

2

O

5

S.0.2 Ethylether Calc. C:48.03 H:4.50 Br:17.00 N:5.96 S:6.82 Foun. C:48.04 H:4.61 Br:16.83 N:5.96 S:6.86

203

(CH

3

)

3

C—

R

214- 216

1659, 1591 1316, 1159

C

20

H

24

N

2

O

6

S.0.4 H

2

O Calc. 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

204

R

236- 237

1723, 1679 1590, 1337 1162

C

21

H

20

N

4

O

5

S.0.25 CF

3

COOH Calc. C:55.06 H:4.35 N:11.95 S:6.84 Foun. C:54.80 H:4.90 N:12.16 S:7.10

205

R

272- 275

1719, 1672 1594, 1339 1165

C

21

H

19

N

3

O

5

S Calc. 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

206

R

214- 215

1733, 1685 1594, 1319 1154

C

20

H

19

N

3

O

6

S Calc. C:55.94 H:4.46 N:9.78 S:7.47 Foun. C:55.50 H:4.47 N:9.74 S:7.31

207

R

217- 220

1732, 1679 1592, 1312 1155

—

208

R

—

—

—

EXAMPLE 209

(Method E)

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 (2×99.8 mmol) of N-methylmorpholine and 20.27 g (99.8 mmol) of p-styrenesulfonyl chloride under ice-cooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HCl, 5% NaHCO

3

, water. The organic layer was dried over Na

2

SO

4

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. 118-120° C.

IR(KBr, ν max cm

−1

): 3419, 3283, 1716, 1348, 1168.

NMR(CDCl

3

, δ 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 −78° C. To this solution was added 22 ml (20×15 mmol) of methylsulfide, and the reaction mixture was allowed to warm to room temperature gradually over 80 min and concentrated in vacuo to give 6.03 g aldehyde derivative (XXIV-1).

IR(CHCl

3

, ν max cm

−1

) 3322, 1710, 1351, 1170.

NMR(CDCl

3

, δ ppm): 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.9 Hz, 3H), 1.22(s, 9H), 2.07(m, 1H), 3.69(dd, J=4.5, 9.9 Hz, 1H), 8.01(s, 4H), 10.08(s, 1H).

Process 3

To a solution of 6.02 g (15 mmol) of compound (XXIV- 1) in 60 ml of ethanol and 15 ml of tetrahydrofuran was added 2.72 g (1.05×15 mmol) of benzenesulfonyl hydrazide at room temperature. After being stirred for 2 h, the resulting mixture was concentrated in vacuo. The residue which was obtained by concentration in vacuo was column chromatographed on silica gel and the fractions eluting with chloroform/ethyl acetate=1/4 were collected and recrystallized from ethyl acetate to give 4.44 g of the desired compound (XXV-1). Yield from process 2 60%. mp. 163-164° C.

Elemental analysis C

22

H

29

N

3

O

6

S

2

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.

[α]

D

−11.6±1.0(c=0.509 DMSO 23.5° C.)

IR(KBr, ν max cm

−1

): 3430, 3274, 1711, 1364, 1343, 1172.

NMR(CDCl

3

δ ppm): 0.84(d, J=6.9 Hz, 3H), 0.99(d, J=6.6 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 3.63(dd, J=4.5, 9.9 Hz, 1H), 5.16(d, J=9.9 Hz, 1H), 7.50-7.68(m, 5H), 7.73(s, 1H), 7.78-7.84(m, 2H), 7.96-8.02(m, 2H), 8.16(brs, 1H).

Process 4

To a solution of 0.14 ml (1.11×1 mmol) of 4-(methylmercapto)aniline and 0.3 ml of conc. hydrochloric acid in 3 ml of aqueous 50% ethanol solution was added a solution of 78.4 mg (1.14×1 mmol) of sodium nitrite in 1 ml of water at 0 to 5° C. of the internal temperature and the reaction mixture was stirred for 15 min at the same temperature. To a solution of 496 mg (1 mmol) of compound (XXV-1) in 5 ml of dry pyridine was added the above reaction mixture over 8 min at −25° C. This reaction mixture was stirred for additional 4 h at −15° C. to rt, poured into water, and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCO

3

, and water, dried over Na

2

SO

4

, 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 C

23

H

29

N

5

O

4

S

2

.0.3H

2

O

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, ν max cm

−1

): 3422, 3310, 1705, 1345, 1171.

NMR(d

6

-DMSO, δ ppm): 0.83(d, J=6.9 Hz, 3H), 0.86(d, J=7.2 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 2.59(s, 3H), 3.54(dd, J=6.3, 9.6 Hz, 1H), 7.56(d, J=8.7 Hz, 2H), 8.00(d, J=8.6 Hz, 2H), 8.10(d, J=8.7 Hz, 2H), 8.33(d, J=9.6 Hz, 2H), 8.34(d, J=8.7 Hz, 2).

Process 5

A solution of 353 mg of compound (XXVI-1) in 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid was stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was washed with ethyl ether to give 308 mg of compound (Ia-5-1). Yield 98%. mp. 194-195° C.

IR(KBr, ν max cm

−1

): 1720, 1343, 1166.

Elemental analysis C

19

H

21

N

5

O

4

S

2

.1.1H

2

O

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.

TABLE 37

(Ib)

Ex-

mp

IR

am-

(de-

(ν

1

H-NMR

ple

comp.)

cm

−1

)

(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

210

R

—

—

—

211

R

194- 195

3700— 2200(br), 3278, 1634, 1337, 1160

2.65(dd, J=9.3, 13.1Hz, 1H), 2.82(dd, J=5.8, 13.1Hz, 1H), 3.86(dt, J=5.8 9.3Hz, 1H), 7.72 (A

1

B

2

q, J=8.1Hz, 2H), 8.19(A

2

B

2

q, J=8.1Hz, 2H), 8.49(d, J=9.3Hz, 1H), 8.88(s, 1H), 10.69(s, 1H)

TABLE 38

(Ia)

Ex-

mp

IR

am-

(de-

(ν

1

H-NMR

ple

comp.)

cm

−1

)

(δ ppm)

No.

R

1

R

18

*

(° C.)

(KBr)

d

6

-DMSO

210

R

—

—

—

211

R

215- 216

2400- 3700br, 3422, 3337, 1733, 1698, 1347, 1170

2.75(dd, J=9.3, 13.7Hz, 1H), 2.99(dd, J=5.3, 13.7Hz, 1H), 3.96(dt, J=5.3, 9.3Hz, 1H), 8.53(d, J=9.3Hz, 1H)

TABLE 39

(Ia)

mp (decomp.)

IR (ν cm

−1

)

Example No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

212

RS

199-202

1734, 1337 1161

C

25

H

22

N

6

O

4

S.0.5 Ethylether Calc. 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

213

RS

224-225

1728, 1338 1166

C

24

H

19

FN

6

O

4

S.0.4 Ethylether Calc C:57.35 H:4.32 F:3.54 N:15.67 S:5.98 Foun. C:58.74 H:4.37 F:3.47 N:15.17 S:568

214

(CH

3

)

2

CHCH

2

—

R

202-204

1720, 1595 1338, 1170

C

19

H

21

N

5

O

4

S Calc. C:54.93 H:5.09 N:16.86 S:7.72 Foun. C:54.75 H:5.14 N:16.81 S:7.55

215

(CH

3

)

2

CH—

R

221-222

1696, 1594 1349, 1173

C

18

H

19

N

5

O

4

S Calc. C:53.38 H:4.83 N:17.29 S:7.92 Foun. C:53.38 H:4.80 N:17.05 S:7.67

216

RS

145-148

1727, 1337 1163

—

217

R

203-205

1735, 1495 1336, 1160

C

28

H

23

N

5

O

4

S.0.6 H

2

O Calc. C:62.70 H:4.55 N:13.06 S:5.98 Foun. C:62.61 H:4.50 N:13.29 S:5.87

218

RS

225-227

1721, 1418 1344, 1163

C

26

H

21

N

5

O

4

S.0.2 H

2

O Calc. C:62.07 H:4.29 N:13.92 S:6.37 Foun. C:61.93 H:4.30 N:14.01 S:6.43

219

R

111-114

1727, 1703 1459, 1332 1165

C

25

H

20

N

6

O

5

S.H

2

O Calc. C:56.17 H:4.15 N:15.72 S:6.00 Foun. C:56.20 H:4.18 N:15.68 S:6.10

TABLE 40

(Ia)

mp (decomp.)

IR (ν cm

−1

)

Example No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

220

R

195-196

1749, 1719 1331, 1165

C

25

H

22

N

6

O

5

S Calc. C:57.91 H:4.28 N:16.21 S:6.18 Foun. C:57.77 H:4.29 N:16.01 S:6.37

221

CH

3

CH

2

(CH

3

)CH—

R

205-207

1730, 1693 1349, 1173

C

19

H

21

N

5

O

4

S Calc. C:54.93 H:5.09 N:16.86 S:7.72 Foun. C:54.71 H:5.09 N:16.70 S:7.56

222

CH

3

CH

2

(CH

3

)CH—

R

204-207

1729, 1693 1337, 1170

C

20

H

23

N

5

O

5

S:0.4 H

2

O 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

223

(CH

3

)

2

CH—

R

190 decomp.

1718, 1601 1385, 1162

—

224

(CH

3

)

2

CH—

R

195-197

1719, 1304 1162

C

20

H

23

N

5

O

5

S.0.4 H

2

O 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

225

(CH

3

)

2

CH—

R

227-228

1696, 1348 1171

C

18

H

18

BrN

5

O

4

S.0.8 H

2

O Calc. C:43.70 H:3.99 Br:16.15 N:14.16 S:6.48 Foun. C:43.93 H:3.85 Br:15.92 N:13.87 S:6.47

226

(CH

3

)

3

C—

R

204-207

1698, 1344 1168

—

227

R

203-205

1757, 1738 1331, 1163

—

TABLE 41

(Ia)

Ex-

mp

IR

am-

(de-

(ν

ple

comp.)

cm

−1

)

No

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

228

R

197- 199

1744, 1325 1154

—

229

R

197- 198

1738, 1707 1328, 1169

C

23

H

18

F

3

N

5

O

4

S Calc. C:53.38 H:3.51 F:11.01 N:13.53 S:6.20 Foun. C:53.11 H:3.55 F:10.89 N:13.66 S:6.31

230

R

190- 191

1730, 1597 1245, 1161

C

22

H

18

N

6

O

6

S.0.4 H

2

O Calc. C:52.67 H:3.78 N:16.73 S:6.39 Foun. C:53.11 H:3.92 N:16.53 S:6.55

231

R

205- 207

1730, 1509 1236, 1165

C

22

H

18

FN

5

O

4

S.0.2 H

2

O Calc. C:56.09 H:3.94 F:4.03 N:14.87 S:6.81 Foun. C:56.10 H:4.09 F:4.12 N:14.84 S:7.08

232

R

204- 206

1730, 1493 1346, 1164

C

22

H

18

ClN

5

O

4

S.0.6 H

2

O Calc. C:53.41 H:3.91 Cl:7.17 N:14.16 S:6.48 Foun. C:53.33 H:3.90 Cl:7.22 N:14.19 S:6.68

233

R

226- 227

1732, 1697 1509, 1373 1345, 1170

C

23

H

21

N

5

O

4

S.0.6 H

2

O Calc. C:56.94 H:4.86 N:14.44 S:6.61 Foun. C:56.88 H:4.49 N:14.31 S:6.72

234

R

214- 216

1732, 1697 1345, 1168

C

23

H

21

N

5

O

5

S.1.7 H

2

O Calc. C:54.15 H:4.82 N:13.73 S:6.29 Foun. C:54.04 H:4.35 N:13.60 S.6.77

235

R

190- 192

1731, 1605 1336, 1160

C

23

H

18

N

6

O

4

S.0.8 H

2

O Calc. C:56.50 H:4.04 N:17.19 S:6.56 Foun. C:56.52 H:4.16 N:17.00 S:6.52

TABLE 42

(Ia)

Example

mp (decomp.)

IR (ν cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

236

R

224-226

1738, 1328 1314, 1149

C

26

H

27

N

5

O

4

S Calc. C:61.77 H:5.38 N:13.85 S:6.34 Foun. C:61.59 H:5.45 N:13.89 S:6.27

237

R

225-227

1739, 1512 1329, 1178

C

28

H

29

N

5

O

4

S.0.3 H

2

O Calc. C:62.62 H:5.56 N:13.04 S:5.97 Foun. C:62.46 H:5.52 N:13.43 S:6.28

238

R

182-184

1587, 1506 1242, 1159

—

239

R

226-228

1713, 1514 1341, 1159

—

240

R

205-207

1744, 1716 1490, 1327 1159

C

24

H

19

BrN

6

O

4

S.1.7 H

2

O Calc. C:48.20 H:3.78 Br:13.36 N:14.05 S:5.36 Foun. C:48.27 H:3.75 Br:13.16 N:14.11 S:5.38

241

R

199-201

1718, 1685 1334, 1170

C

25

H

22

N

6

O

4

S.0.6 H

2

O Calc. C:58.49 H:4.56 N:16.37 S:6.25 Foun. C:58.52 H:4.69 N:16.71 S:5.90

242

(CH

3

)

2

CH—

R

206-207

1716, 1346 1165

C

19

H

21

N

5

O

4

S.0.8 H

2

O Calc. C:53.09 H:5.30 N:16.29 S:7.46 Foun. C:53.20 H:5.14 N:16.06 S:7.70

243

(CH

3

)

2

CH—

R

208-209

1746, 1726 1715, 1334 1159

C

18

H

18

FN

5

O

4

S.0.2 H

2

O Calc. C:51.11 H:4.38 F:4.49 N:16.55 S:7.58 Foun. C:50.90 H:4.37 F:4.89 N:16.28 S:7.46

TABLE 43

(Ia)

Ex-

mp

IR

am-

(de-

(ν

ple

comp.)

cm

−1

)

No.

R

1

R

18

*

(° C.)

(KBr)

Elemental analysis

244

(CH

3

)

2

CH—

R

223- 225

1696, 1348 1171

—

245

(CH

3

)

2

CH—

R

194- 195

1720, 1343 1166

C

19

H

21

N

5

O

4

S

2

.1.1H

2

O Calc. C:48.83 H:5.00 N:14.99 S:13.72 Foun. C:49.13 H:5.25 N:14.55 S:13.34

246

R

222- 224

1753, 1497 1325, 1165

C

23

H

21

N

5

O

4

S

2

.0.2H

2

O Calc. 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

247

R

213- 216

1718, 1677 1495, 1333 1170

C

25

H

22

N

6

O

4

S

2

.1.1H

2

O Calc. C:54.16 H:4.40 N:15.16 S:11.57 Foun. C:54.20 H:4.66 N:15.09 S:11.62

248

R

>220

1698, 1430 1327, 1163

C

18

H

16

N

6

O

4

S.0.4H

2

O Cal. C:51.52 H:4.04 N:20.03 S:7.64 Foun. C:51.43 H:3.96 N:19.76 S:8.02

249

R

—

—

—

250

R

—

—

—

251

R

—

—

—

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.

TABLE 44

(I)

Example

mp (decomp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No

R

1

R

18

R

19

R

20

*

(° C.)

(KBr)

d

6

-DMSO

252

(CH

3

)

2

CH—

—CH

—COOH

R

—

1715, 1583 1340, 1151

0.96(d, J=6.6Hz, 3H) 1.01(d, 6.8Hz, 3H) 2.87(s, 3H) 4.17(d, J=10.4Hz, 1H)

253

(CH

3

)

2

CH—

—CH

3

—CONHOH

R

110-111

3323, 1678 1328, 1150

0.71(d, J=6.6Hz, 3H) 0.88(d, 6.4Hz, 3H) 2.88(s, 3H) 3.48(d, J=10.8Hz, 1H)

254

(CH

3

)

2

CH—

—CONHOH

R

148-150

3344, 1684 1323, 1149

0.55(d, J=6.8Hz, 3H), 0.82(d, 6.6Hz, 3H) 3.74(s, 3H)

255

(CH

3

)

2

CH—

—(CH

2

)

4

NH

2

—COOH

R

—

3700-2400br 1681, 1319 1212

0.91(d, J=5.6Hz, 6H) 1.52-1.69(m, 4H) 3.84(d, J=10.4Hz, 1H)

256

(CH

3

)

2

CH—

—CH

3

—COOH

R

206-207

3300-2400br 1711, 1336 1185

0.95(d, J=6.6Hz, 3H) 0.97(d, 6.8Hz, 3H) 2.89(s, 3H) 4.20(d, J=1.0.6Hz, 1H)

257

(CH

3

)

2

CHCH

2

—

—CH

3

—COOH

R

132-132.5

3300-2400br 1736, 1717 1694, 1346 1162

0.92(d, J=6.6Hz, 3H) 0.97(D, 6.6Hz, 3H) 2.84(s, 3H) 4.73(t, J=7.4Hz, 1H)

258

—COOH

R

—

3640-2400br 1736, 1717 1694, 1346 1162

2.78(d, d, J=13.8, 7.2Hz, 1H) 3.14(d, d, J=14.8, 7.4Hz, 1H) 4.43(d, J=16.4Hz, 1H) 4.68(d, J=16.4Hz, 1H)

259

(CH

3

)

2

CH—

—CH

3

—COOH

R

141-144

3284br, 1745 1714, 1323 1131

0.96(d, J=6.4Hz, 3H) 0.97(d, J=6.4Hz, 3H) 2.52(s, 3H), 2.93(s, 3H

TABLE 45

(I)

Example

mp (decomp.)

IR (ν cm

−1

)

1

H-NMR(δ ppm)

No

R

1

R

18

R

19

R

20

*

(° C.)

(KBr)

d

6

-DMSO

260

(CH

3

)

2

CH—

—COOH

R

—

3600-2400br 1718, 1344 1151

0.72(d, J=6.4Hz, 3H)0.85(d, J= 6.4HZ, 3H)2.47(s, 3), 4.15(d, J=10.2Hz, 1H)4.51(d, J=15.5Hz, 1H)4.73(d,4J=15.5H, 1H)

261

—CH

3

—COOH

R

—

3600-2400br 1719, 1655 1592, 1320 1154

2.54(s, 3H), 2.78(s, 3H) 2.85(d, d, J=14.0, 9.4Hz, 1H) 3.16(d, d, J=14.0, 6.0Hz, 1H) 4.76(d, d, J=10.0, 5.8Hz, 1H)

262

—COOH

R

—

—

—

263

—(CH

2

)

4

NH

2

—COOH

R

—

—

—

264

CH

3

—COOH

R

—

—

—

265

—COOH

R

—

—

—

266

—(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.

TABLE 46

(I)

(I)

Ex-

mp

IR

am-

(de-

(ν

1

H-NMR

ple

comp.)

cm

−1

)

(δ ppm)

No.

R{hu 1

R

18

R

20

*

(° C.)

(KBr)

d

6

-DMSO

267

—CONHOH

R

156- 158

3700- 2400br, 3267, 2217, 1671, 1321, 1161

2.62(dd, J=8.4, 13.5Hz, 1H), 2.80(dd, J=6.0, 13.5Hz, 1H), 3.82(ddd, J=6.0, 8.4, 8.7Hz, 1H), 8.38(d, J=8.7Hz, 1H)

267

—COOH

R

176- 178

2200- 3700br, 3430, 3292, 1728, 1324, 1162

2.73(dd, J=9.3, 13.6Hz, 1H), 2.96(dd, J=5.4, 13.5Hz, 1H), 3.92(dt, J=5.4, 9.3Hz, 1H), 8.42(d, J= 9.3Hz, 1H)

Test examples on the compounds of the present invention are described below. The test compounds are the ones described in the Examples and Tables.

Test Example

(1) Isolation and Purification of MMP-9 (92 kDa, Gelatinase B)

Type IV collagenase (MMP-9) was purified according to the methods descrived in the following literature. Scott M. Wilhelm et al., J. Biol. Chem., 264, 17213-17221, (1989), SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV Collagenase Which Is Identical to That Secreted by Normal Human Macrophages; Yasunori Okada et al., J. Biol. Chem., 267, 21712-21719, (1992), Matrix Metalloproteinase 9 (92-kDa Gelatinase/Type IV Collagenase) from HT 1080 Human Fibrosarcoma Cells; Robin V. Ward et al., Biochem. J., (1991) 278, 179-187, The purification of tissue inhibitor of metalloproteinase-2 from its 72 kDa progelatinase complex.

MMP-9 is secreted from human fibrosarcoma cell line ATCC HT 1080, into its culture medium when it is stimulated with 12-tetradecanoylphorbol-13-acetate (TPA). The production of MMP-9 in this culture was verified by the gelatin zymography as described in the following literature (Hidekazu Tanaka et al., (1993) Biochem. Biophys. Res. Commun., 190, 732-740, Molecular cloning and manifestation of mouse 105-kDa gelatinase cDNA). The condition medium of the stimulated HT 1080 was concentrated and was purified with gelatin-Sepharose 4B, concanavalin A-sepharose, and Sephacryl S-200. The purified pro-MMP-9 (92 kDa, gelatinase B) thus obtained gave a single positive band in the gelatin zymography. Subsequently, activated MMP-9 was obtained by treating the pro-MMP-9 with trypsin.

(2) Assay Methods of Type IV Collagenase Inhibitors

Collagenase assay was performed using the activated MMP-9 described above and the substrate supplied in the type IV collagenase activity kit (YAGAI, inc.), according to the manufacturer's protocol. The following 4 assays are performed per compound (inhibitor).

(A) substrate (type IV collagenase), enzyme (MMP-9), inhibitor

(B) substrate (type IV collagenase), inhibitor

(C) substrate (type IV collagenase), enzyme (MMP-9)

(C) 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−(

A−B

)/(

C−D

)}×100

IC

50

is a concentration at which the percent inhibition reaches 50%. The results are shown in Tables 47 to 54.

TABLE 47

Example No.

Compound No.

IC

50

(μM)

Compound No.

IC

50

(μM)

1

1a-1-1

0.24

1b-1-1

0.030

2

1a-1-2

2.6

1b-1-2

0.04

3

1a-1-3

0.18

1b-1-3

0.005

4

1a-1-4

2.25

5

1a-1-5

0.81

1b-1-5

0.041

6

1a-1-6

0.68

1b-1-6

0.034

7

1b-1-7

0.028

8

1a-1-8

2.0

1b-1-8

2.0

9

1b-1-9

0.41

10

1b-1-10

2.1

11

1b-1-11

1.7

12

1b-1-12

0.085

13

1b-1-13

0.38

14

1a-1-14

3.7

1b-1-14

0.11

15

1b-1-15

0.027

16

1a-1-16

0.520

1b-1-16

0.0108

17

1a-1-17

0.205

1b-1-17

0.0203

18

1a-1-18

0.500

1b-1-18

0.0282

20

1b-1-20

0.134

21

1a-1-21

4.65

1b-1-21

0.0041

23

1b-1-23

0.073

24

1b-1-24

0.2

26

1b-1-26

1.3

27

1b-1-27

3.0

30

1a-1-30

1.16

1b-1-30

0.213

31

1b-1-31

0.0129

TABLE 48

Example No.

Compound No.

IC

50

(μM)

Compound No.

IC

50

(μM)

33

1a-1-33

0.24

1b-1-33

0.005

35

1a-1-35

2.6

1b-1-35

0.0216

38

1a-1-38

0.018

40

1a-1-40

0.076

41

1a-1-41

0.312

42

1a-1-42

0.0123

43

1a-1-43

0.625

44

1a-1-44

1.910

45

1a-1-45

0.040

46

1a-1-46

1.12

47

1a-1-47

0.389

48

1a-1-48

1.15

49

1a-1-49

0.249

50

1a-1-50

0.553

51

1a-1-51

0.110

52

1a-1-52

0.329

53

1a-1-53

1.8

54

1a-1-54

0.075

55

1a-1-55

0.0398

60

1a-1-60

1.31

1b-1-60

0.0012

61

1a-1-61

0.247

1b-1-61

0.247

62

1b-1-62

3.50

63

1a-1-63

1.05

1b-1-63

0.00039

64

1a-1-64

1.90

1b-1-64

0.0037

65

1a-1-65

0.291

1b-1-65

0.0035

TABLE 49

Example No.

Compound No.

IC

50

(μM)

Compound No.

IC

50

(μM)

67

1a-1-67

1b-1-67

0.0061

68

1a-1-68

0.231

80

1a-1-80

1.91

83

1a-1-83

1.77

85

1a-1-85

1.2

1b-1-85

0.013

86

1a-1-86

0.35

1b-1-86

0.0053

87

1b-1-87

0.940

93

1a-2-2

0.237

94

1a-2-3

0.0109

95

1a-2-4

0.0759

96

1a-2-5

0.123

97

1a-2-6

0.088

98

1a-2-7

0.0699

100

1a-2-9

0.0577

101

1a-2-10

0.023

102

1a-2-11

0.0475

103

1a-2-12

0.0981

104

1a-2-13

3.28

105

1a-2-14

2.98

106

1a-2-15

0.133

107

1a-2-16

0.325

109

1a-2-18

1.19

110

1a-2-19

0.203

111

1a-2-20

3.41

112

1a-2-21

3.74

114

1a-2-23

0.929

TABLE 50

Example No.

Compound No.

IC

50

(μM)

115

1a-2-24

0.161

117

1a-2-26

1.19

118

1a-2-27

0.088

119

1a-2-28

1.11

120

1a-2-29

1.53

121

1a-2-30

0.0736

122

1a-2-31

0.224

123

1a-2-32

0.0234

124

1a-2-33

0.0218

125

1a-2-34

0.0144

126

1a-2-35

0.156

127

1a-2-36

0.0243

128

1a-2-37

0.0922

129

1a-2-38

0.222

160

1a-3-2

0.040

161

1a-3-3

0.0108

162

1a-3-4

0.873

163

1a-3-5

0.0126

164

1a-3-6

0.0965

165

1a-3-7

0.230

166

1a-3-8

1.28

167

1a-3-9

0.014

168

1a-3-10

0.0083

169

1a-3-11

0.244

170

1a-3-12

2.03

171

1a-3-13

0.0395

TABLE 51

Example No.

Compound No.

IC

50

(μM)

177

1a-4-2

0.684

178

1a-4-3

0.0252

179

1a-4-4

2.36

180

1a-4-5

0.045

181

1a-4-6

0.0539

182

1a-4-7

0.0059

183

1a-4-8

0.0027

184

1a-4-9

0.00325

185

1a-4-10

0.0422

186

1a-4-11

0.0982

187

1a-4-12

0.177

188

1a-4-13

0.843

189

1a-4-14

0.0375

190

1a-4-15

0.0597

191

1a-4-16

0.0095

192

1a-4-17

0.324

193

1a-4-18

0.722

195

1a-4-20

1.1

196

1a-4-21

0.0573

197

1a-4-22

0.0161

198

1a-4-23

0.493

199

1a-4-24

2.06

200

1a-4-25

0.173

201

1a-4-26

0.252

202

1a-4-27

0.0114

203

1a-4-28

0.173

TABLE 52

Example No.

Compound No.

IC

50

(μM)

Compound No.

IC

50

(μM)

204

1a-4-29

3.95

207

1a-4-30

4.44

210

1a-5-2

0.024

211

1a-5-3

0.210

1b-211

0.00565

212

1a-5-4

0.393

213

1a-5-5

0.128

214

1a-5-6

0.832

215

1a-5-7

0.110

216

1a-5-8

0.107

218

1a-5-10

0.744

219

1a-5-11

0.574

220

1a-5-12

0.0167

221

1a-5-13

0.316

222

1a-5-14

0.078

223

1a-5-15

0.349

224

1a-1-16

0.0101

225

1a-5-17

0.0122

226

1a-5-18

0.166

227

1a-5-19

0.0198

228

1a-5-20

0.106

229

1a-5-21

0.215

230

1a-5-22

0.281

231

1a-5-23

0.197

232

1a-5-24

0.144

233

1a-5-25

0.0864

234

1a-5-26

0.153

TABLE 53

Example No.

Compound No.

IC

50

(μM)

Compound No.

IC

50

(μM)

235

1a-5-27

0.265

236

1a-5-28

0.304

237

1a-5-29

1.32

238

1a-5-30

2.85

239

1a-5-31

0.243

240

1a-5-32

0.0041

241

1a-5-33

0.0131

242

1a-5-34

0.0239

243

1a-5-35

0.0529

244

1a-5-36

0.0165

245

1a-5-37

0.0059

246

1a-5-38

0.0108

247

1a-5-39

0.0035

267

1a-2-66

1.5

1b-2-66

0.011

TABLE 54

Example No.

Compound No.

IC

50

(μM)

252

1-252

0.24

253

1-253

0.000039

254

1-254

0.00063

255

1-255

0.529

256

1-256

0.601

257

1-257

0.776

258

1-258

0.908

259

1-259

0.130

260

1-260

0.159

261

1-260

0.182

The compound of the present invention showed strong activity for inhibiting type IV collagenase.

Industrial Applicability

It is considered that the compound of the present invention is useful to prevent or treat osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, 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, because the compound of the present invention has strong inhibitory activity against metalloproteinase, especially MMP.

Number	Date	Country	Kind
8-30082	Jan 1996	JP
8-213555	Aug 1996	JP

Number	Name	Date
4666931	Ohishi et al.	May 1987
5445258	MacPherson et al.	Aug 1995
5650428	Ohmori et al.	Jul 1997
5756545	O'Brien et al.	May 1998
5900427	Vedejs et al.	May 1999

Number	Date	Country
0 468 231 A2	Jan 1992	EP
0 757 037	Feb 1997	EP
0 757 984	Feb 1997	EP
2508444	Dec 1982	FR
57-59969	Apr 1982	JP
9314069	Jul 1993	WO
9535276	Dec 1995	WO
9600214	Jan 1996	WO
9745402	Dec 1997	WO

	Number	Date	Country
Parent	PCT/JP97/00126	Jan 1997	US
Child	09/120197		US

Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

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US

International Classifications

Abstract

Description

Claims

Priority Claims (2)

Parent Case Info

US Referenced Citations (5)

Foreign Referenced Citations (9)

Non-Patent Literature Citations (24)

Continuations (1)