Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

TECHNICAL FIELD

[0001] This application relates to sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same.

BACKGROUND ART

[0002] 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

[0003] 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.

[0004] In the above situation, the inventors of the present invention found that a kind of sulfonamide derivatives have strong activity to inhibit MMP.

[0005] The present invention relates to a composition for inhibiting metalloproteinase which contains a compound of the formula I:

[0006] wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, -(CH2)m-, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(RA)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R2 is hydrogen atom when Y is —NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0007] Mentioned in more detail, the invention relates to the following a)-b), 1)-16), and A)-C).

[0008] a) A composition for inhibiting metalloproteinase which contains a compound of the formula I:

[0009] wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, -(CH2)m-, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(RA)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R2 is hydrogen atom when Y is —NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is —CO—NH— or —NH—CO—, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is tetrazol-diyl, R5 is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or heteroaryl substituted by lower alkyl or optionally substituted aryl when R3 is optionally substituted arylene and R4 is a bond, both of R3 and R4 are not a bond at the same time, and R4 is not —O— when R3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0010] b) A composition for inhibiting metalloproteinase as mentioned above, which is a composition for inhibiting type-IV collagenase.

[0011] Preferred embodiment of the present invention are as follows.

[0012] 1) A compound of the formula I:

[0013] wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, -(CH2)m-, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(RA)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted: aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R2 is hydrogen atom when Y is —NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is —CO—NH— or —NH—CO— (when R3 is phenylene and R4 is —CO—NH—, R1 is not methyl or phenyl and R5 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R5 is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is tetrazol-diyl, R5 is lower alkyl, aryl substituted with lower alkyl or optionally substituted aryl, or heteroaryl substituted with lower alkyl or optionally substituted aryl when R3 is optionally substituted arylene and R4 is a bond, both of R3 and R4 are not a bond at the same time, and R4 is not —O— when R3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

[0014] 2) A compound of the formula II:

[0015] wherein R6 is —CH═CH—, —C≡C—, —N═N—, —NH—CO—NH—, —S—, —SO2NH—, or —SO2—NH—N═CH—; R7 is optionally substituted aryl or optionally substituted heteroaryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; R1, R2, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0016] 3) A compound of the formula III:

[0017] wherein R10 is -(CH2)m-, —CO—, —CO—NH—, —N(RA)—, —NHCO—, or tetrazol-diyl; m is 1 or 2; R1, R2, R7, R8, R9, RA, and Y are as defined above, provided R1 is not methyl or phenyl and R7 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when R10 is —NH—CO—, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0018] 4) A compound of the formula IV:

[0019] wherein R11 is a bond, —CH═CH—, or —C≡C—; X is oxygen atom or sulfur atom, R1, R2, R7, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

[0020] 5) A compound of the formula I′:

[0021] wherein R1′ 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; R2′ is hydrogen atom, methyl, 4-aminobutyl, or benzyl; R3′ is 1,4-phenylene; R4′ is —O—; R5′ is phenyl or 4-hydroxy-phenyl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0022] 6) A compound of the formula I″:

[0023] wherein R1″ 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; R2″ is hydrogen atom; R3″ is 1,4-phenylene; R4″ is a bond; R5″ 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.

[0024] 7) A compound of the formula V:

[0025] wherein R12 is —CH═CH— or —C≡C—; R1, R2, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

[0026] 8) A compound of the formula VI:

[0027] wherein R2, R8, and R9 are as defined above, R13 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R14 is optionally substituted aryl, or optionally substituted heteroaryl; provided R13 is not methyl or phenyl and R14 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

[0028] 9) A compound of the formula VII:

[0029] wherein R1, R2, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0030] 10) A compound of the formula VIII:

[0031] wherein R1, R2, R7, and R11 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0032] 11) A compound of the formula VIII:

[0033] wherein R1, R2, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0034] 12) A compound of the formula X:

[0035] wherein R12 is —CH═CH— or —C≡C—; R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0036] 13) A compound of the formula XI:

[0037] wherein R8, R9, R13, and R14 are as defined above, provided R13 is not methyl or phenyl and R14 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0038] 14) A compound of the formula XII:

[0039] wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0040] 15) A compound of the formula XIII:

[0041] wherein R1, R7, and R11 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0042] 16) A compound of the formula XIV:

[0043] wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

[0044] A compound of the invention is more specifically illustrated below:

[0045] A) The compound of any one of above 1) to 16), wherein R1, R1′, R1″, and R13 are i-propyl, benzyl, or (indol-3-yl) methyl.

[0046] B) The compound of any one of above 1) to 4) and 7) to 16), wherein R5, R7, and R14 are phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.

[0047] C) The compound of any one of above 1) to 16), wherein a configuration of asymmetric carbon atoms bonding with R1, R1′, R1″, and R13 is R configuration.

[0048] 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)

[0049] All of compounds of above 1) to 16) and A) to C) have strong metalloproteinase inhibitory activity, and the following compound is more preferable:

[0050] 1) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl) methyl, R2 is hydrogen atom, R3 is 1,4-phenylene, R4 is —C≡C—, and R5 is optionally substituted phenyl.

[0051] 2) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl) methyl, R2 is hydrogen atom, R3 is optionally substituted 2,5-thiophen-diyl, R4 is —C≡C—, and R5 is optionally substituted phenyl.

[0052] 3) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl)methyl, R2 is hydrogen atom, R3 is 1,4-phenylene, R4 is tetrazol-diyl, and R5 is optionally substituted phenyl.

[0053] The term “alkyl” herein used means C1-C10 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.

[0054] The term “lower alkyl” herein used means C1-C6 straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, and the like.

[0055] The term “C3-C8 cycloalkyl” herein used is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0056] The term “aryl” herein used means monocyclic or condensed ring aromatic hydrocarbons. Examples of the aryl are phenyl, naphthyl, and the like.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] The term “halogen” herein used means fluoro, chloro, bromo, and iodo.

[0066] 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.

[0067] Substituents for “optionally substituted alkyl”, “optionally substituted C3-C8 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.

[0068] 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), cycloalky (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

[0069] 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.

[0070] Method A: A general synthetic method of the compound represented by the formula I.

[0071] Method B: A synthetic method of the compound wherein and R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is —C≡C—, and R5 is optionally substituted aryl or optionally substituted heteroaryl.

[0072] Method C: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is a bond, and R5 is optionally substituted aryl or optionally substituted heteroaryl.

[0073] Method D: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is —CO—NH—, and R5 is optionally substituted aryl or optionally substituted heteroaryl.

[0074] Method E: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is tetrazol-diyl, and R5 is optionally substituted aryl or optionally substituted heteroaryl.

[0075] Method F: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is —CH═CH—, and R5 is optionally substituted aryl or optionally substituted heteroaryl.

[0076] Details of these methods are explained as follows.

[0077] (Method A)

[0078] wherein R1, R2, R3, R4, and R5 are as defined above, R15 is hydrogen atom or a carboxy protective group, R16 is a hydroxy protective group, and Hal is halogen.

[0079] 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 R5—R4—R3—SO2Hal (R3, R4, and R5 are as defined above; and Hal is halogen) and then hydroxylamine. Each process will hereinafter be described in more detail.

[0080] (Process 1)

[0081] 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 R15 is hydrogen atom, preferable solvents for this sulfonylation are dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, or mixed solvents thereof. When a compound (XV) is an amino acid wherein R15 is a protective group such as an ester, a solvent for this sulfonylation is exemplified by the above solvents and mixed solvents of water-insoluble solvents (e.g., benzene and dichloromethane) and the above solvents. A base to be used in this sulfonylation is exemplified by organic bases such as triethylamine, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and the like. Usually this reaction can be carried out at ice-cooling to room temperature. When R1, R3, R4, R5, or R15 of compound (Ia-1) contains a functional 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 R2 is not hydrogen atom, compound (Ia-1) wherein R2 is hydrogen atom is further reacted with haloalkyl (e.g., methyl iodide, and ethyl iodide) or haloaralkyl (e.g., benzyl chloride, and benzyl bromide) in dimethylformamide, tetrahydrofuran, dioxane, and the like at a temperature range of ice-cooling to 80° C., preferably ice-cooling to room temperature, for 3-10 hours, preferably 10-20 hours to give the desired N—R2 derivative.

[0082] (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.

[0083] 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 R15 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.

[0084] (Process 3)

[0085] 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.

[0086] (Process 4)

[0087] 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.).

[0088] (Method B)

[0089] wherein R1, R2, R7, R15, and Hal are as defined above, R17 is optionally substituted aryl or optionally substituted heteroaryl.

[0090] 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 R17 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.

[0091] (Process 1)

[0092] This process may be carried out in the same manner as that described in process 1 of method A.

[0093] (Process 2)

[0094] 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(Ph3P)2Cl2), 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.

[0095] (Process 3)

[0096] This process may be carried out in the same manner as that described in process 1 of method A.

[0097] (Process 4)

[0098] This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

[0099] (Method C)

[0100] wherein R1, R2, R7, R15, R17, and Hal are as defined above.

[0101] 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 R17 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.

[0102] (Process 1)

[0103] 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(Ph3P)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.

[0104] (Process 2)

[0105] This process may be carried out in the same manner as that described in process 1 of method A.

[0106] (Process 3)

[0107] This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

[0108] (Method D)

[0109] wherein R1 , R2, R7, R15, R17, and Hal are as defined above.

[0110] 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 R17 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 R17 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.

[0111] (Process 1)

[0112] This process may be carried out in the same manner as that described in process 1 of method A.

[0113] (Process 2)

[0114] 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, PtO2, 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.

[0115] (Process 3)

[0116] 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.

[0117] (Process 4)

[0118] This process may be carried out in the same manner as that described in process 1 of method A.

[0119] (Process 5)

[0120] This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

[0121] (Method E)

[0122] wherein R1, R2, R7, R15, R17, and Hal are as defined above.

[0123] 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 R17 is converted into an aldehyde group (process 2). Conversion of compound (XXI 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.

[0124] (Process 1)

[0125] This process may be carried out in the same manner as that described in process 1 of method A.

[0126] (Process 2)

[0127] 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.

[0128] (Process 3)

[0129] 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.

[0130] (Process 4)

[0131] 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.

[0132] (Process 5)

[0133] This process may be carried out in the same manner as that described in process 1 of method A.

[0134] (Process 6)

[0135] This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

[0136] (Method F)

[0137] wherein R1, R2, R7, R15, R17, and Hal are as defined above.

[0138] 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 R17 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.

[0139] (Process 1)

[0140] Compound (XXIV) is reacted with ylide derivatives of optionally substituted aryl or optionally substituted heteroaryl such as Ph3P═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.

[0141] (Process 2)

[0142] This process may be carried out in the same manner as that described in process 1 of method A.

[0143] (Process 3)

[0144] This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

[0145] 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.

[0146] The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] The following examples are provided to further illustrate the present invention and are not to be constructed as limiting the scope thereof.

[0152] Abbreviations described below are used in the following examples.

[0153] p-TsOH: p-toluenesulfonic acid

[0154] DMSO: dimethylsulfoxide

[0155] Me: methyl

[0156]

t
Bu: tert-butyl

EXAMPLE 1

Method A

[0157]

[0158] 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% NaHCO3, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl3/MeOH=40/1 to 20/1 were collected to yield 1.70 g of compound (Ib-1-1) as a foam. Yield 43%. mp. 169-170° C. Elemental analysis (%) C21H20N2O4S 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 νmax (cm−1) (Nujol): 3365, 3295, 3266, 1674, 1320, 1159. NMR (δppm) d6-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′

[0159] Another synthetic method of compound (Ib-1-1)

[0160] Process 1

[0161] 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% NaHCO3 and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl3/MeOH=40/1 to 20/1 were collected and crystallized from dichloromethane/hexane to give 2.32 g of compound (Ia-1-1′). Yield 84.1%. mp. 130-131° C. Elemental analysis (%) C28H25NO4S 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 νmax (cm−1) (Nujol) : 3352, 1732, 1341, 1190, 1163. NMR (δppm) (CDCl3): 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)

[0162] Process 2

[0163] 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 (%) C21H19NO4S 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 νmax (cm−1) (Nujol): 3408, 3305, 1751, 1325, 1161, 1134. NMR (δppm) (CDCl3): 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)

[0164] Process 3

[0165] 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 NaHCO3 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% NaHCO3, and water, and concentrated in vacuo to give compound (Ia-1) (969 mg). Yield 93.3%.

[0166] Process 4

[0167] 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% NaHCO3, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CH2Cl2/hexane=1/1 were collected and recrystallized from dichloromethane/hexane to give 2.04 g of compound (XVI-1). Yield 80%. mp. 171-173° C. Elemental analysis (%) C28H26N2O4S 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 νmax (cm−1) (Nujol) : 3248, 1661, 1594, 1333, 1163. NMR (δppm) (CDCl3): 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)

[0168] Process 5

[0169] 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

[0170] The compounds which were shown in Tables 1 to 22 were synthesized in a manner similar to those described in Example 1′

1TABLE 1(Ib)

Ex-mpample(decomp.)IR (ν cm−1)1H-NMR (δ ppm)No.R1R18*(° C.)(KBr)d6-DMSO2

RS173>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

R203-2063403, 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

RS124-1263277, 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

R139-1413262, 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)7CF3CH2—

R167-1693265, 1676 1642, 1337, 1161 (Nujol)2.2-2.7(m, 2H), 3.99(t, J=7.0Hz, 1H)8

RS172-1733403, 3261, 1669, 1321, 11601.68(m, 2H), 2.37(m, 2H), 3.64(t, J=6.9Hz, 1H)9

R144-1463700-2200br, 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),

[0171]

2

TABLE 2

(Ib)

Ex-

mp

ample

(decomp.)
IR (ν cm−1)

1
H-NMR (δ ppm)

No.
R1
R18
*
(° C.
(KBr)
d6-DMSO

10

R
116-118
3600-24O0br, 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
(CH3)2CH—

R
178-179
3268, 1632, 1598, 1336, 1162
0.71(d, J=6.8z, 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), 3.90(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
3404, 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)

[0172]

3

TABLE 3

(Ib)

Ex-

mp

ample

(decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
(d6-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
3404, 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), (CD3OD)

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), (CD3OD)

[0173]

4

TABLE 4

(Ib)

Ex-

mp

ample

(decomp.)
IR (δ cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-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(A2B2qJ=8.9Hz, 2H), 8.20(A2B2q, J=8.9Hz, 2H), 8.72(d, J=9.0Hz, 1H), 8.86(s, 1H), 10.7(s, 1H)

28
HOOC—CH2—

R
—
—
—

29
HOOC—CH2—CH2—

R
—
—
—

30
HOCH2—

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(A2B2q, J=8.7Hz, 2H), 7.88(A2B2q, J=8.7Hz, 2H), 7.98 (d, J=7.8Hz, 1H), 10.61(s, 1H)

31

R
69-70
3700-220(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), (CD3OD)

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)

[0174]

5

TABLE 5

(Ib)

Ex-

mp

ample

(decomp.)
IR (ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

34

R
—
—
—

35

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

[0175]

6

TABLE 6

(Ia)

Ex-

mp

ample

(decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-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), 7.39(d, J=2.0Hz, 1H), 8.34(d, J=8.6Hz, 1H), 8.88(d, J=2.0Hz, 1H), 12.79(br, 1H)

3

100

101

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

102

103

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

104

105

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

106

107

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
CF3CH2—

108

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

109

110

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

111

112

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)

[0176]

7

TABLE 7

(Ia)

113

mp

Example

(decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

13

114

115

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

116

117

RS
164-165
3246, 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

118

119

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

120

121

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

122

123

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

124

125

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

126

127

RS
197-205
2600-3700br, 1635, 1594, 1335, 1163, 1095
2.60-3.0(m, 2H), 3.98(m, 1H)

21

128

129

RS
196-199
2200-3700br, 1713br, 1345, 1125
3.24-3.56(m, 2H), 4.34 (m, 1H)

[0177]

8

TABLE 8

(Ia)

130

mp

Example

(decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

22

131

132

RS
141-143
3335, 3246, 1732, 1315, 1152
4.10(d, J=3.2Hz, 1H), 5.13(d, J=3.2Hz, 1H)

23

133

134

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—CH2—

135

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—CH2—CH2—

136

R
185-187
3270, 1709, 1336, 1159, 1093
1.68(dd, J=7.9, 14.1Hz, 1H), 18.7 (dd, J=6.0, 13.4Hz, 1H), 2.22(t, J=7.2Hz, 2H), 3.80(m, 1H),

30
HOCH2—

137

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

138

139

R
89-91
2200-3700br, 3432, 3289, 1733, 1330, 1165
3.54(dd, J=4.8, 9.9Hz, 1H), 3.60 (dd, J=5.7, 9.9Hz, 1H), 4.0(m, 1H), 4.39(s, 2H), 8.34(d, J=81Hz, 1H)

32

140

141

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)

[0178]

9

TABLE 64

(Ia)

142

mp

Example

(decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

34

143

144

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

145

146

RS
151-156
2200-3700br, 1734, 1334, 1161
3.17-3.50(m, 2H), 4.51(m, 1H)

[0179]

10

TABLE 10

(Ia)

147

mp

Example

(decomp.)
IR(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

36

148

149

RS
>145
1726, 1354, 1326, 1161
—

37

150

151

RS
—
1732, 1594 1404, 1155
—

38

152

153

R
188-190
1607, 1594 1294, 1153
C24H22N2O5.0.5H2O 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

154

155

R
90-93
1724, 1594 1326, 1159
C24H22N2O5S.0.8H2O 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

156

157

R
149-152
1685, 1349 1166
—

41

158

159

R
104-107
1725, 1599 1372, 1173
—

42

160

161

R
167-169
1745, 1653 1391, 1147
—

43
(CH3)2CH—

162

R
155-157
1714, 1594 1334, 1166
C17H19NO4S.0.1CF3COOH 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

[0180]

11

TABLE 11

(Ia)

163

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

44
(CH3)2CH—

164

R
196-197
1724, 1340 1328, 1167
C21H27NO4S.0.3H2O 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
(CH3)2CH—

165

R
241-243
1734, 1719 1324, 1160
C23H23NO4S.0.3H2O Calc. 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
(CH3)2CH—

166

R
157-159
1670, 1375 1148
—

47
(CH3)2CH—

167

R
175-176
1717, 1694 1349, 1165
—

48
(CH3)2CH—

168

R
145-147
1634, 1334 1158
C17H18FNO4S 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
(CH3)2CH—

169

R
183-186
1681, 1319 1162
—

50

170

171

R
183-184
1725, 1340 1159
—

51

172

173

R
224-226
1750, 1324 1159
C27H23NO4S. 0.7H2O 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

[0181]

12

TABLE 12

(Ia)

174

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

52

175

176

R
157-160
1685, 1349 1166
—

53

177

178

R
111-112
1691, 1567 1390, 1159
—

54

179

180

R
194-195
1749, 1592 1323, 1164
—

55
(CH3)2CH—

181

R
197-199
1746, 1337 1164
C18H21NO4S2.0.2H2O 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

182

183

R
108-110
1649, 1337 1165
—

57

184

185

R
187-190
1588, 1308 1141
—

58

186

187

R
239-243
1744, 1592 1323, 1160
C21H18N2O4S2.0.3H20 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

188

189

R
222-224
1751, 1734 1537, 1347 1172
C17H14ClN3O6S.0.3H2O 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

[0182]

13

TABLE 13

(Ib)

190

Exam-

mp

ple

(decomp.)
IR (ν cm−1)

1
H-NMR (δ-DMSO

60

191

192

R
foam
3700-2400 br, 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

193

194

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

195

196

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
(CH3)2CH—

197

R
149-151
3268, 1634, 1584, 1336, 1157
0.76(d, J=6.6Hz, 6H), 1.77(m, 1H), 3.26(m, 1H)

64

198

199

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

200

201

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

202

203

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

204

205

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

[0183]

14

TABLE 14

(Ia)

206

Exam-

mp

ple

(decomp.)
IR (ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

60

207

208

R
108-109
2400-3600 br, 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

209

210

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

211

212

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
(CH3)2CH—

213

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

214

215

RS
—
3273, 1724, 1582, 1487, 1331, 1198, 1153
2.78-3.10(m, 2H), 3.67(s, 3H), 3.86(m, 1H)

65

216

217

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

218

219

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

220

221

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)

[0184]

15

TABLE 15

(Ia)

222

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

68

223

224

R
>240
1608, 1590 1507, 1232 1157
—

69

225

226

RS
—
1735, 1583 1362, 1171
C24H22N2O7S2 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

227

228

RS
—
1733, 1583 1150
—

[0185]

16

TABLE 16

(Ib)

229

mp
IR

Example

(decomp.)
(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

71

230

231

R
129-131
3700-2400 br, 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) (CDCl3)

72

232

CH3(CH2)7—
R
oil
3700-2400 br, 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

233

CH3(CH2)3—
R
oil
3600-2400 br, 3262, 1673, 1321, 1142 (CHCl3)
0.79(t, J=7.0Hz, 3H), 2.32-2.56(m, 2H), 2.92(m, 1H), 3.26 (m, 1H),

74

234

235

R
—
—
—

75

236

237

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(A2B2qJ=7.5Hz, 2H), 7.42(A2B2q, J=7.5Hz, 2H)(CDCl3)

76

238

239

R
—
—
—

[0186]

17

TABLE 17

(Ib)

240

mp
IR

Example

(decomp.)
(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

77

241

242

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

243

244

R
69-70
3700-220 (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

245

246

R
—
—
—

[0187]

18

TABLE 18

(Ia)

247

mp
IR

Example

(decomp.)
(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

71

248

249

R
121-122
2300-3700 br, 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

250

CH3(CH2)7—
R
oil
2400-3600 br, 3340, 1736, 1334, 1142 (CHCl3)
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) (CDCl3)

73

251

CH3(CH2)3—
R
89-90
2300-3700 br, 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) (CDCl3)

74

252

253

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

254

255

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

256

257

R
—
2400-3700 br, 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

258

259

R
—
2200-3700 br, 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=137.7Hz, 2H), 4.01(m, 1H), 7.65(d, J=8.3Hz, 1H)

79

260

261

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)

[0188]

19

TABLE 19

(Ia)

262

Exam-

mp
IR

ple

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

80

263

264

R
153-155
1704, 1596 1349, 1164
—

81

265

n-C8H17—
R
>130
1576, 1356 1139
—

82

266

267

R
128-130
1732, 1342 1167
C24H19N3O5S.1.3H2O Calc. C: 59.45 H: 4.49 N: 6.67 S: 6.61 Foun. C: 59.43 H: 4.45 N: 8.59 S: 6.58

83

268

269

R
210-214
1745, 1590 1316, 1157
—

84

270

271

R
198-200
1594, 1456 1200, 1188
—

[0189]

20

TABLE 20

(Ib)

272

Exam-

mp

ple

(decomp.)
IR (ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

85

273

274

R
157-160
3700-2400 br, 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

275

276

R
138-142
3700-2400 br, 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

277

278

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)

[0190]

21

TABLE 21

(Ia)

279

mp

Example

(decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

85

280

281

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

282

283

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

284

285

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)

[0191]

22

TABLE 22

(Ia)

286

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KRr)
Elemental analysis

88

287

288

R
103-106
1719, 1390 1229
—

89
(CH3)2CH—

289

R
96-99
1734, 1461 1327, 1158
C17H20N2O6S2.0.9Ethylether 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
(CH3)2CH—

290

R
110-112
1724, 1325 1168
C18H21N3O6S2.0.8Ethylether 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

291

292

R
98-101
1735, 1598 1327, 1185
C21H19BrN2O6S2.0.5CF3COOH 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

[0192]

293

[0193] Process 1

[0194] 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% NaHCO3, and water. The organic layer was concentrated in vacuo, and dried over Na2SO4. The residue was subjected to silica gel column chromatography and the fractions eluting with ethyl acetate/hexane=⅓ 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 C10H14BrNO4S2 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 CHCl3 25° C.) IR(CHCl3, νmax cm−1)1737,1356,1164,1138 NMR (CDCl3, δppm): 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)

[0195] Process 2

[0196] 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% NaHCO3, and water, dried over Na2SO4, 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 C19H21NO5S2·0.2 H2O 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, νmax cm−1) : 3268,2203,1736,1604,1524,1348,1164. NMR(CDCl3, δppm): 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).

[0197] Process 3

[0198] To a solution of 407 mg (1 mmol) of compound (XVII-1) in 8 ml of tetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH. The resulting mixture was stirred for 6 h at 60° C. The reaction mixture was concentrated in vacuo to remove an organic solvent, and the residue was diluted with ethyl acetate. The mixture was acidified with aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 373 mg of compound (Ia-2-1). Yield 100%. mp. 147-148° C. IR (KBr, νmax cm−1) 1710,1604,1351,1216. Elemental analysis C18H19NO5S2·0.2H2O 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

[0199] The compounds which were shown in Tables 23 to 30 were synthesized in a manner similar to those described in Example 92.

23TABLE 23(Ia)

294

mpIRExample(decomp.)(ν cm−1)No.R1R18*(° C.)(KBr)Elemental analysis93

295

296

R165-1701590, 1316 1137—94

297

298

R223-2261747, 1323 1134C26H22N2O5S Calc. C: 65.81 H: 4.67 N: 5.90 S: 6.76 Foun. C: 65.34 H: 4.90 N: 5.56 S: 6.4095

299

300

R216-2181724, 1325 1135—96

301

302

R111-1141739, 1336 1163—97

303

304

R178-1801710, 1511 1329, 1161—98

305

306

R105-1081725, 1618 1373, 1163—99

307

308

R>2501706, 1606 1350, 1164C26H20N2O6.0.4H2O Calc. C: 63.00 H: 4.23 N: 5.65 S: 6.47 Foun. C: 62.99 H: 4.32 N: 5.82 S: 6.76100

309

310

R176-1771735, 1633 1321, 1173C25H21N3O4S.0.8H2O 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

[0200]

24

TABLE 24

(Ia)

311

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

101

312

313

R
227-229
1736, 1618 1398, 1168
C26H22N2O4S.0.2H2O 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

314

315

R
230-233
1735-1654 1399, 1164
—

103

316

317

R
234-236
1732, 1631 1372, 1148
—

104

318

319

R
>200 decomp.
1600, 1558 1336, 1171
—

105
(CH3)2CH—

320

R
146-149
1795, 1718 1331, 1166
—

106
(CH3)2CH—

321

R
231-232
1719, 1595 1344, 1167
C19H18N2O6S.0.1H2O 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
(CH3)2CH—

322

R
166-169
1728, 1631 1372, 1148
—

108
(CH3)2CH—

323

R
163-165
1728, 1332 1172
—

[0201]

25

TABLE 25

(Ia)

324

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

109
(CH3)2CH—

325

R
187-189
1720, 1656 1319, 1165
—

110
(CH3)2CH—

326

R
111-114
1724, 1635 1366, 1158
—

111
(CH3)3C—

327

R
161-162
1711, 1683 1600, 1328 1159
C21H23NO5S.1.3H2O 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
CH3CH2(CH3)CH—

328

R
157-159
1732, 1680 1329, 1167
—

113

329

330

R
133-136
1735, 1651 1348, 1165
—

114

331

332

R
183-185
1727, 1604 1335, 1182
—

115

333

334

R
166-168
1725, 1663 1399, 1197
C23H18FNO4S.0.3H2O 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
(CH3)2CH—

335

R
163-165
1728, 1332 1172
—

[0202]

26

TABLE 26

(Ia)

336

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

117
(CH3)2CH—

337

R
187-189
1720, 1656 1319, 1165
—

118

338

339

R
111-114
1724, 1635 1366, 1158
—

119

340

341

R
167-169
1585, 1318 1153
—

120

342

343

R
—
1605, 1523 1340, 1151
—

121

344

345

R
—
1604, 1524 1336, 1173
—

122

346

347

R
103-106
1721, 1620 1339, 1163
—

123

348

349

R
180-182
1729, 1675 1340, 1168
—

124
(CH3)2CH—

350

R
147-148
1710, 1604 1351, 1216
C18H19NO5S2.0.2H2O 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

[0203]

27

TABLE 27

(Ia)

351

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

125
(CH3)2CH—

352

R
157-158
1712, 1350 1163
C18H19NO4S2.0.2H2O 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
(CH3)2CH—

353

R
154-158
1710, 1499 1356, 1165
—

127

354

355

R
149-150
1695, 1334 1184
C22H19NO5S2.0.2H2O 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

356

357

R
161-164
1710, 1329 1180
—

129

358

359

R
155-158
1734, 1699 1324, 1105
C21H16FNO4S2Calc. 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

360

361

R
—
—
—

131

362

363

R
—
—
—

132

364

365

R
—
—
—

[0204]

28

TABLE 28

(Ia)

366

Example

mp (decomp.)
IR (ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

133

367

368

R
—
—
—

134

369

370

R
—
—
—

135

371

372

R
—
—
—

136

373

374

R
—
—
—

137

375

376

R
—
—
—

138

377

378

R
—
—
—

139

379

380

R
—
—
—

140

381

382

R
—
—
—

[0205]

29

TABLE 29

(Ia)

383

Ex-

ample

mp (decomp.)
IR (ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

141

384

385

R
—
—
—

142

386

387

R
—
—
—

143

388

389

R
—
—
—

144

390

391

R
—
—
—

145

392

393

R
—
—
—

146

394

395

R
—
—
—

147

396

397

R
—
—
—

148

398

399

R
—
—
—

[0206]

30

TABLE 30

(Ia)

400

Example

mp (decomp.)
IR (ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

149

401

402

R
—
—
—

150

403

404

R
—
—
—

151

405

406

R
—
—
—

152

407

408

R
—
—
—

153

409

410

R
—
—
—

154

411

412

R
—
—
—

155

413

414

R
—
—
—

156

415

416

R
—
—
—

EXAMPLE 157, 158

[0207]

417

[0208] Process 1 (R2═CH3)

[0209] 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 Na2SO4, and concentrated in vacuo to give 373 mg of N-methyl derivative as an oil. Yield 91%. Elemental analysis C24H23NO5S2 Calcd. : C; 61.39 H; 4.94 N; 2.98 S; 13.66 Found: C; 61.22 H; 5.18 N; 2.93 S; 13.27

[0210] 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 Na2SO4, and concentrated in vacuo to give 105 mg of compound (Ia-2-66) (R=Me). Yield 77%. mp. 185-186° C. Elemental analysis C23H21NO5S 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, νmax cm−1) : 3600-2300 br, 3426, 2203, 1710, 1604, 1503, 1344, 1151. NMR (d6-DMSO, δppm): 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).

[0211] The compound (Ia-2-67) (R2═CH2Ph) was synthesized in the same manner as those described in Example 157. IR(KBr, νmax cm−1) : 2200,1722,1340,1151. NMR (d6-DMSO, δppm): 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

[0212]

418

[0213] Process 1

[0214] 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% NaHCO3 aq., and water, dried over Na2SO4, and concentrated in vacuo. The residue was column chromatographed on silica gel. The fractions eluting with n-hexane/ethyl acetate=3/1 were collected and recrystallized from n-hexane to give 447 mg of the desired compound (XIX-1). Yield 83%. mp. 122-123° C. Elemental analysis C17H21NO5S2 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, νmax cm−1): 1735,1605,1505,1350,1167,1136 NMR (CDCl3, δppm): 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).

[0215] Process 2

[0216] 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 Na2SO4, and concentrated in vacuo to give 373 mg of compound (Ia-3-1). Yield 100%. mp. :174-176° C. IR(KBr, νmax cm−1): 1735, 1503, 1343, 1163.

Example 160-175

[0217] The compounds which were shown in Tables 31 to 32 were synthesized in a manner similar to those described in Example 159.

31TABLE 31(Ia)

419

mpIRExample(decomp.)(ν cm−1)No.R1R18*(° C.)(KBr)Elemental Analysis160

420

421

R93-961667, 1337 1180—161

422

423

R157-1591670, 1339 1194—162

424

425

R168-1711725, 1598 1371, 1185—163

426

427

R226-2301735, 1341 1159C22H20N2O4S3.0.4H2O Calc. C: 55.07 H: 4.37 N: 5.84 S: 20.05 Foun. C: 55.35 H: 4.43 N: 6.04 S: 19.65164(CH3)2CH—

428

R174-1781735, 1503 1343, 1163—165(CH3)2CH—

429

R165-1671713, 1353 1163—166(CH3)2CH—

430

R146-1471702, 1504 1352, 1168C15H16FNO4S2.0.1H2O 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: 17.77167(CH3)2CH—

431

R157-1591747, 1324 1159C16H19NO4S3Calc. 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

[0218]

32

TABLE 32

(Ia)

432

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

168

433

434

R
161-165
1735, 1698 1374 1163
C20H19NO5S2Calc. C: 57.54 H: 4.59 N: 3.35 S: 15.36 Foun. C: 57.62 H: 4.72 N: 3.52 S: 15.27

169

435

436

R
166-167
1713, 1609 1378, 1194
C20H19NO4S2Calc. 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

437

438

R
174-175
1721, 1654 1365, 1148
C19H16FNO4S2Calc. 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

439

440

R
203-205
1750, 1730 1428, 1325 1155
C20H19NO4S3.0.2H2O 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

441

442

R
—
—
—

173

443

444

R
—
—
—

174

445

446

R
—
—
—

175

447

448

R
—
—
—

EXAMPLE 176

Method D

[0219]

449

[0220] Process 1

[0221] 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% NaHCO3, water. The organic layer was dried over Na2SO4 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 C15H22N2O6S 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, νmax cm−1) 3430 br, 3301, 1722, 1698, 1525, 1362, 1348, 1181, 1174, 1159.

[0222] Process 2

[0223] 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 analysisC15H24N2O4S 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, νmax cm−1): 3461, 3375, 1716, 1638, 1598, 1344, 1313. NMR(d-DMSO, δppm) : 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)

[0224] Process 3

[0225] 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 analysisC23H30N2O5S2 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, νmax cm−1): 3366, 3284, 1713, 1667, 1592, 1514, 1498, 1341, 1317. NMR(d6-DMSO, δppm) : 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).

[0226] Process 4

[0227] 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, νmax cm−1):1748, 1655, 1592, 1323, 1161. Elemental analysis C19H22N2O5S2·0.1CF3COOH 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

[0228] The compounds which were shown in Tables 33 to 36 were synthesized in a manner similar to those described in Example 176.

33TABLE 33(Ia)

450

mpIRExample(decomp.)(ν cm−1)No.R1R18*(° C.)(KBr)Elemental analysis177

451

452

R215-2171732, 1641 1341, 1163—178

453

454

R233-2341726, 1655 1323, 1177C25H23N3O6S.0.9H2O Calc. C: 58.91 H: 4.90 N: 8.24 S: 6.29 Foun. C: 58.97 H: 5.07 N: 7.95 S: 6.10179

455

456

R216-2181723, 1633 1361, 1149—180

457

458

R211-2131719, 1629 1340, 1156C24H20N4O7S.1.1H2O Calc. C: 54.50 H: 4.24 N: 10.60 S: 6.07 Foun. C: 54.51 H: 4.32 N: 10.83 S: 6.15181

459

460

R236-2381732, 1653 1399, 1199C26H26N4O5S.0.9H2O Calc. C: 59.73 H: 5.36 N: 10.72 S: 6.13 Foun. C: 59.58 H: 5.23 N: 10.85 S: 6.47182

461

462

R240-2441731, 1656 1591, 1327 1160C25H23N3O5S.0.9H2O Calc. C: 60.82 H: 5.06 N: 8.51 S: 6.49 Foun. C: 60.83 H: 5.19 N: 8.66 S: 6.66183

463

464

R215-2181727, 1668 1590, 1316 1154C24H20BrN3O5S.0.6H2O 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: 5.70184

465

466

R244-2491728, 1653 1593, 1323, 1159C25H23N3O5S2.0.7H2O Calc. C: 57.50 H: 4.71 N: 8.05 S: 12.28

[0229]

34

TABLE 34

(Ia)

467

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental anaylsis

185

468

469

R
170-175
1730-1651 1603, 1333 1161
C24H20FN3O5S.0.6H2O 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

470

471

R
237-239
1723, 1651 1591, 1322 1161
C23H22N2O6S 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

472

473

R
235-239
1719, 1672 1593, 1327 1159
C22H19N3O7S 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

474

475

R
114-115
1748, 1658 1592, 1325 1159
C22H20N2O5S.0.5CF3COOH 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

476

477

R
242-243
1743, 1670 1591, 1335 1167
C22H19BrN2O5S.CF3COOH 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

478

479

R
242-244
1752, 1726 1656, 1591 1324, 1160
C23H22N2O5S 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

480

481

R
232-235
1742, 1667 1591, 1334 1161
C23H22N2O5S2.0.8CF3COOH 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

482

483

R
218-220
1737, 1651 1598, 1324 1160
C22H19FN2O5S 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

[0230]

35

TABLE 35

(Ia)

484

Exam-

IR

Exam-

mp
(ν

ple

(decomp.)
cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

193

485

486

R
201-203
1724, 1673 1592, 1326 1156
C21H18ClN3O5S 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

487

488

R
206-208
1725, 1682 1592, 1332 1160
C22H20ClN3O5S.0.1CF3COOH 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
(CH3)2CH—

489

R
254-256
1748, 1659 1590, 1324 1161
C24H24N2O5S.0.5H2O 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
(CH3)2CH—

490

R
227-229
1749, 1658 1592, 1323 1161
C19H22N2O5S.0.2H2O 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
(CH3)2CH—

491

R
231-234
1748, 1655 1592, 1323 1161
C19H22N2O5S2.0.1CF3COOH 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
(CH3)2CH—

492

R
235-236
1749, 1726 1668, 1597 1322, 1160
C18H19FN2O5S.0.1CF3COOH 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
(CH3)2CH—

493

R
226-227
1728, 1661 1591, 1317 1159
C18H20N2O5S.0.1H2O 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
(CH3)2CH—

494

R
220-221
1696, 1654 1591, 1317 1255
C19H22N2O6S.0.2H2O 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

[0231]

36

TABLE 36

(Ia)

495

IR

mp
(ν

Exam-

cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

201
(CH3)2CH—

496

R
240-242
1726, 1688 1591, 1347 1166
C18H19N3O7S.0.4H2O 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
(CH3)2CH—

497

R
229-230
1726, 1663 1592, 1318 1159
C18H19BrN2O5S.0.2Ethylether 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
(CH3)3C—

498

R
214-216
1659, 1591 1316, 1159
C20H24N2O6S.0.4H2O 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

499

500

R
236-237
1723, 1679 1590, 1337 1162
C21H20N4O5S.0.25CF3COOH 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

501

502

R
272-275
1719, 1672 1594, 1339 1165
C21H19N3O5S 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

503

504

R
214-215
1733, 1685 1594, 1319 1154
C20H19N3O6S 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

505

506

R
217-220
1732, 1679 1592, 1312 1155
—

208

507

508

R
—
—
—

EXAMPLE 209

Method E

[0232]

509

[0233] Process 1

[0234] 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% NaHCO3, water. The organic layer was dried over Na2SO4 and concentrated in vacuo, and the resulting residue was column chromatographed on silica gel. The fractions eluting with ethyl acetate/n-hexane/chloroform=⅓/1 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, νmax cm−1): 3419, 3283, 1716, 1348, 1168. NMR(CDCl3, δppm): 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).

[0235] Process 2

[0236] 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(CHCl3, νmax cm−1): 3322, 1710, 1351, 1170. NMR(CDCl3, δppm): 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).

[0237] Process 3

[0238] 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=¼ 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 C22H29N3O6S2 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, νmax cm−1): 3430, 3274, 1711, 1364, 1343, 1172. NMR(CDCl3δppm): 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).

[0239] Process 4

[0240] 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 (XXVV-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% NaHCO3, and water, dried over Na2SO4, and concentrated in vacuo. The residue was column chromatographed on silica gel and the fractions eluting with chloroform/ethyl acetate={fraction (1/9)} were collected to give 374 mg of the desired compound (XXVI-1). Yield 74%. Elemental analysis C23H29N5O4S2·0.3H2O Calcd. : C; 54.27 H; 5.86 N; 13.76 S; 12.60 Found: C; 54.25 H; 5.77 N; 13.87 S; 12.52 IR(KBr, νmax cm−1): 3422, 3310, 1705, 1345, 1171. NMR(d6-DMSO, δppm) : 0.83(d, J=6.9 Hz, 3H), 0.86(d, J=7.2 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 2.59(s, 3H), 3.54(dd, J=6.3, 9.6 Hz, 1H), 7.56(d, J=8.7 Hz, 2H), 8.00(d, J=8.6 Hz, 2H), 8.10(d, J=8.7 Hz, 2H), 8.33(d, J=9.6 Hz, 2H), 8.34(d, J=8.7 Hz, 2H).

[0241] Process 5

[0242] 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, νmax cm−1): 1720, 1343, 1166. Elemental analysis C19H21N5O4S2·1.1H2O 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

[0243] The compounds which were shown in Tables 37 to 43 were synthesized in a manner similar to those described in Example 209.

37TABLE 37(Ib)

510

mpExample(decomp.)IR(ν cm−1)1H-NMR(δ ppm)No.R1R18*(° C.)(KBr)d6-DMSO210

511

512

R———211

513

514

R194-1953700-2200 (br), 3278, 1634, 1337, 11602.65(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(A2B2q, J=8.1Hz, 2H), 8.19(A2B2q, J=8.1Hz, 2H), 8.49(d, J=9.3Hz, 1H), 8.88(s, 1H), 10.69(s, 1H)

[0244]

38

TABLE 38

(Ia)

515

mp

Example

(decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO

210

516

517

R
—
—
—

211

518

519

R
215-216
2400-3700 br, 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)

[0245]

39

TABLE 39

(Ia)

520

IR

Exam-

mp
(ν

ple

(decomp.)
cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental anaylsis

212

521

522

RS
199-202
1734, 1337 1161
C25H22N6O4S.0.5Ethylether 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

523

524

RS
224-225
1728, 1338 1166
C24H19FN6O4S.0.4Ethylether Calc C: 57.35 H: 4.32 F: 3.54 N: 15.67 S: 5.98 Foun. C: 56.74 H: 4.37 F: 3.47 N: 15.17 S: 568

214
(CH3)2CHCH2—

525

R
202-204
1720, 1595 1338, 1170
C19H21N5O4S 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
(CH3)2CH—

526

R
221-222
1696, 1594 1349, 1173
C18H19N5O4S 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

527

528

RS
145-148
1727, 1337 1163
—

217

529

530

R
203-205
1735, 1495 1336, 1160
C28H23N5O4S.0.6H2O 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

531

532

RS
225-227
1721, 1418 1344, 1163
C26H21N5O4S.0.2H2O 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

533

534

R
111-114
1727, 1703 1459, 1332 1165
C25H20N6O5S.H2O 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

[0246]

40

TABLE 40

(Ia)

535

IR

Exam-

mp
(ν

ple

(decomp.)
cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

220

536

537

R
195-196
1749, 1719 1331, 1165
C25H22N6O5S 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
CH3CH2(CH3)CH—

538

R
205-207
1730, 1693 1349, 1173
C19H21N5O4S 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
CH3CH2(CH3)CH—

539

R
204-207
1729, 1693 1337, 1170
C20H23N5O5S.0.4H2O 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
(CH3)2CH—

540

R
190 decomp.
1718, 1601 1385, 1162
—

224
(CH3)2CH—

541

R
195-197
1719, 1304 1162
C20H23N5O5S.0.4H2O 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
(CH3)2CH—

542

R
227-228
1696, 1348 1171
C18H18BrN5O4S.0.8H2O 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
(CH3)3C—

543

R
204-207
1698, 1344 1168
—

227

544

545

R
203-205
1757, 1738 1331, 1163
—

[0247]

41

TABLE 41

(Ia)

546

mp
IR

Example

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

228

547

548

R
197-199
1744, 1325 1154
—

229

549

550

R
197-198
1738-1707 1328, 1169
C23H18F3N5O4S 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

551

552

R
190-191
1730, 1597 1345, 1161
C22H18N6O6S.0.4H2O Calc. C: 52.67 H: 3.78 N: 16.73 S: 6.39 Foun. C: 52.73 H: 3.92 N: 16.53 S: 6.55

231

553

554

R
204-207
1730, 1509 1236, 1165
C22H18FN5O4S.0.2H2O Calc. C: 56.09 H: 3.94 F: 4.03 N: 14.87 S: 6.81

232

555

556

R
204-206
1730, 1493 1346, 1164
C22H18ClN5O4S. 0.6H2O 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

557

558

R
226-227
1732, 1697 1509, 1373 135, 1170
C23H21N5O4S.1.2H2O 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

559

560

R
214-216
1732, 1697 1345, 1168
C23H21N5O5S.1.7H2O Calc. C: 54.15 H: 4.82 N: 13.73 S: 6.29 Foun. C: 54.05 H: 4.35 N: 13.60 S: 6.77

235

561

562

R
190-192
1731, 1605 1336, 1160
C23H18N6O4S.0.8H2O 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

[0248]

42

TABLE 42

(Ia)

563

Exam-

mp
IR

ple

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental anaylsis

236

564

565

R
224-226
1738, 1328 1314, 1149
C26H27N5O4S 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

566

567

R
225-227
1739, 1512 1329, 1178
C28H29N5O4S.0.3H2O 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

568

569

R
182-184
1587, 1506 1242, 1159
—

239

570

571

R
226-228
1713, 1514 1341, 1159
—

240

572

573

R
205-207
1744, 1716 1490, 1327 1159
C24H19BrN6O4S.1.7H2O 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

574

575

R
199-201
1718, 1685 1334, 1170
C25H22N6O4S.0.6H2O 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
(CH3)2CH—

576

R
206-207
1716, 1346 1165
C19H21N5O4S.0.8H2O 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
(CH3)2CH—

577

R
208-209
1746, 1726 1715, 1334 1159
c18H18FN5O4S.0.2H2O 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

[0249]

43

TABLE 43

(Ia)

578

Exam-

mp
IR

ple

(decomp.)
(ν cm−1)

No.
R1
R18
*
(° C.)
(KBr)
Elemental analysis

244
(CH3)2CH—

579

R
223-225
1696, 1348 1171
—

245
(CH3)2CH—

580

R
194-195
1720, 1343 1166
C19H21N5O4S2.1.1H2O Calc. C: 48.83 H: 5.00 N: 14.99 S: 1372 Foun. C: 49.13 H: 5.25 N: 14.55 S: 13.34

246

581

582

R
222-224
1753, 1497 1325, 1165
C23H21N5O4S2.0.2H2O 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

583

584

R
213-216
1718, 1677 1495, 1333 1170
C25H22N6O4S2.1.1H2O 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

585

586

R
>220
1698, 1430 1327, 1163
C18H16N6O4S.0.4H2O Calc. C: 51.52 H: 3.96 N: 19.76 S: 8.02

249

587

588

R
—
—
—

250

589

590

—
—
—

251

591

592

R
—
—
—

EXAMPLE 252-266

[0250] The compounds which were shown in Tables 44 to 45 were synthesized in a manner similar to those described in Example 157.

44TABLE 44(I)

593

ExampleNo.R1R18R19252(CH3)2CH—

594

—CH3253(CH3)2CH—

595

—CH3254(CH3)2CH—

596

597

255(CH3)2CH—

598

—(CH2)4NH2256(CH3)2CH—

599

—CH3257(CH3)2CHCH2—

600

—CH3258

601

602

603

259(CH3)2CH—

604

—CH3Examplemp (decomp.)IR(ν cm−1)1H-NMR(δ ppm)No.R20*(° C.)(KBr)d6-DMSO252—COOHR—1715, 15830.96(d, J=6.6Hz, 3H)1340, 11511.01(d, 6.8Hz, 3H)2.87(s, 3H)4.17(d, J=10.4Hz, 1H)253—CONHOHR110-1113323, 16780.71(d, J=6.6Hz, 3H)1328, 11500.88(d, 6.4Hz, 3H)2.88(s, 3H)3.48(d, J=10.8Hz, 1H)254—CONHOHR148-1503344, 16840.55(d, J=6.8Hz, 3H)1323, 11490.82(d, 6.6Hz, 3H)3.74(s, 3H)255—COOHR—3700-2200 br0.91(d, J=5.6Hz, 6H)1681, 13191.52-1.69(m, 4H)12123.84(d, J=10.4Hz, 1H)256—COOHR206-2073300-2400 br0.95(d, J=6.6Hz, 3H)1711, 13360.97(d, 6.8Hz, 3H)11852.89(s, 3H)4.20(d, J=10.6Hz, 1H)257—COOHR132-132.53300-2400 br0.92(d, J=6.6Hz, 3H)1719, 13400.97(d, 6.6Hz, 3H)11532.84(s, 3H)4.73(t, J=7.4Hz, 1H)258—COOHR—3640-2400 br2.78(d.d, J=13.8, 7.2Hz, 1H)1736, 17173.14(d.d, J=14.8, 7.4Hz, 1H)1694, 13464.43(d, J=16.4Hz, 1H)11624.68(d, J=16.4Hz, 1H)259—COOHR141-144328 br, 17450.96(d, J=6.4Hz, 3H)1714, 13230.97(d, J=6.4Hz, 3H)11312.52(s, 3H), 2.93(s, 3H)

[0251]

45

TABLE 45

(I)

605

Example

No.
R1
R18
R19

260
(CH3)2CH—

606

607

261

608

609

—CH3

262

610

611

612

263

613

614

—(CH2)4NH2

264

615

616

—CH3

265

617

618

619

266

620

621

—(CH2)4NH2

Example

mp (decomp.)
IR(ν cm−1)

1
H-NMR(δ ppm)

No.
R20
*
(° C.)
(KBr)
d6-DMSO

260
—COOH
R
—
3600-2400 br
0.72(d, J=6.4Hz, 3H) 0.85(d, J=

1718, 1344
6.4Hz, 3H) 2.47(s, 3), 4.15(d,

1151
J=10.2Hz, 1H), 4.51(d, J=15.5

Hz, 1H) 4.73(d, J=15.5Hz, 1H)

261
—COOH
R
—
3600-2400 br
2.54(s, 3H), 2.78(s, 3H)

1719, 1655
2.85(d.d, J=14.0, 9.4Hz, 1H)

1592, 1320
3.16(d.d, J=14.0, 6.0Hz, 1H)

1154
4.76(d.d, J=10.0, 5.8Hz, 1H)

262
—COOH
R
—
—
—

263
—COOH
R
—
—
—

264
—COOH
R
—
—
—

265
—COOH
R
—
—
—

266
—COOH
R
—
—
—

EXAMPLE 267

[0252] The compounds which were shown in Tables 46 were synthesized in a manner similar to those described in Example 92.

46TABLE 46(I)

622

mpExample(decomp.)IR(ν cm−1)1H-NMR(δ ppmNo.R1R18R20*(° C.)(KBr)d6-DMSO267

623

624

—CONHOHR156-1583700-2400 br, 3267, 2217, 1671, 1321, 11612.62(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

625

626

—COOHR176-1782200-3700 br, 3430, 3292, 1728, 1324, 11622.73(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)

[0253] 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

[0254] (1) Isolation and Purification of MMP-9 (92 kDa, Gelatinase B)

[0255] 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.

[0256] 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.

[0257] (2) Assay Methods of Type IV Collagenase Inhibitors

[0258] 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).

[0259] (A) substrate (type IV collagenase), enzyme (MP-9), inhibitor

[0260] (B) substrate (type IV collagenase), inhibitor

[0261] (C) substrate (type IV collagenase), enzyme (MMP-9)

[0262] (D) substrate (type IV collagenase)

[0263] 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

[0264] IC50 is a concentration at which the percent inhibition reaches 50%. The results are shown in Tables 47 to 54.

47TABLE 47Example No.Compound No.IC50 (μM)Compound No.IC50 (μM)11a-1-1 0.241b-1-1 0.03021a-1-2 2.61b-1-2 0.0431a-1-3 0.181b-1-3 0.00541a-1-4 2.2551a-1-5 0.811b-1-5 0.04161a-1-6 0.681b-1-6 0.03471b-1-7 0.02881a-1-8 2.01b-1-8 2.091b-1-9 0.41101b-1-102.1111b-1-111.7121b-1-120.085131b-1-130.38141a-1-143.71b-1-140.11151b-1-150.027161a-1-160.5201b-1-160.0108171a-1-170.2051b-1-170.0203181a-1-180.5001b-1-180.0282201b-1-200.134211a-1-214.651b-1-210.0041231b-1-230.073241b-1-240.2261b-1-261.3271b-1-273.0301a-1-301.161b-1-300.213311b-1-310.0129

[0265]

48

TABLE 48

Example No.
Compound No.
IC50 (μM)
Compound No.
IC50 (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

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

[0266]

49

TABLE 49

Example No.
Compound No.
IC50 (μM)
Compound No.
IC50 (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

[0267]

50

TABLE 50

Example No.
Compound No.
IC50 (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

[0268]

51

TABLE 51

Example No.
Compound No.
IC50 (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

[0269]

52

TABLE 52

Example No.
Compound No.
IC50 (μM)
Compound No.
IC50 (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

[0270]

53

TABLE 53

Example No.
Compound No.
IC50 (μM)
Compound No.
IC50 (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

[0271]

54

TABLE 54

Example No.
Compound No.
IC50 (μM)

252
1-252
0.24

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

[0272] The compound of the present invention showed strong activity for inhibiting type IV collagenase.

Industrial Applicability

[0273] 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	Date	Country
Parent	09120383	Jul 1998	US
Child	10290245	Nov 2002	US

Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

Information

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Date Filed

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Inventors

Original Assignees

CPC

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Abstract

Description

Claims

Priority Claims (2)

Continuations (1)