Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

Information

  • Patent Grant
  • 6881727
  • Patent Number
    6,881,727
  • Date Filed
    Wednesday, July 3, 2002
    22 years ago
  • Date Issued
    Tuesday, April 19, 2005
    19 years ago
Abstract
Compounds having a metalloproteinase inhibitory activity, represented by the formula (I), its optically active isomers, their pharmaceutically acceptable salts, or hydrates thereof.
Description
TECHNICAL FIELD

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


BACKGROUND ART

An extracellular matrix consists of collagen, proteoglycan, etc., has a function to support tissues, and plays a role in a maintaining of a cell functions, for example propagation, differentiation, adhesion, or the like. Matrix metalloproteinases (MMP) such as gelatinase, stromelysin, collagenase, and the like have an important role in degradation of an extracellular matrix, and these enzymes work for growth, tissue remodeling, etc. under physiological conditions. Therefore, it is considered that these enzymes participate in progression of various kind of diseases involving breakdown and fibrosis of tissues, such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (for example, HIV infection). At the present time, it is not clear which enzyme participates in the above diseases seriously, but it is considered that these enzymes at least participate in tissue breakdown. As metalloproteinase inhibitors of amino acid derivatives, for example hydroxamic acid derivatives of amino acids (JP-A-6-2562939), carboxylic acid derivatives of amino acid and/or their hydroxamic acid derivatives (WO95/35276), etc. are disclosed.


DISCLOSURE OF INVENTION

If it is able to inhibit the activity of MMP, it is considered that MMP inhibitors contribute to an improvement and prevention of-the above diseases caused by or related to its activity. Therefore, development of MMP inhibitors has long been desired.


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


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


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


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


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


Preferred embodiment of the present invention are as follows.


1) A compound of the formula I:
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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.


2) A compound of the formula II:
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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


3) A compound of the formula III:
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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.


4) A compound of the formula IV:
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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.


5) A compound of the formula I′:
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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.


6) A compound of the formula I″:
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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; R41 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.


7) A compound of the formula V:
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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.


8) A compound of the formula VI:
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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.


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


10) A compound of the formula VIII:
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wherein R1, R2, R7, and R11 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.


11) A compound of the formula VIII:
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wherein R1, R2, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.


12) A compound of the formula X:
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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.


13) A compound of the formula XI:
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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.


14) A compound of the formula XII:
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wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.


15) A compound of the formula XIII:
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wherein R1, R7, and R11 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.


16) A compound of the formula XIV:
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wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.


A compound of the invention is more specifically illustrated below:


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


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


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


Further, this invention relates to a pharmaceutical composition, a composition for inhibiting metalloproteinase, and a composition for inhibiting type IV collagenase which contain the compound above 1) to 16) and A) to C)


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


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.


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.


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.


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.


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


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


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


The term “heteroaryl” herein used means a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring and may be fused with a carbocyclic ring or other heterocyclic ring at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 2-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl, (e.g. 2-benzothiazolyl), furyl (e.g., 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. The aryl part of the above heteroaryl is optionally substituted.


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


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


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


The term “non-aromatic heterocyclic group” herein used means 5 to 6 membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and may bind at any possible positin. Examples of the non-aromatic heterocyclic group are morpholino, piperidino, pyrrolidino, and the like.


The term “alkoxy” herein used means alkoxy of which alkyl part is the above mentioned alkyl. Examples of the alkoxy are methoxy, ethoxy, propoxy, butoxy, pentyloxy, and the like.


The term “lower alkoxy” herein used means alkoxy of which alkyl part is the above mentioned lower alkyl. Examples of the lower alkoxy are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, and the like.


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


The term “alkylthio” herein used means alkylthio whose alkyl part is the above mentioned lower alkyl. Examples of the alkylthio are methylthio, ethylthio, and the like.


Substituents for “optionally substituted alkyl”, “optionally substituted 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.


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







BEST MODE FOR CARRYING OUT THE INVENTION

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


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


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


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


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


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


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


Details of these methods are explained as follows.
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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.


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.


(Process 1)


Some of amino acids represented by the formula (XV) or its acidic salts (e.g., hydrochloride, p-toluenesulfonate, and trifluoroacetate) which are starting materials are commercially available. The other are able to be synthesized in accordance with a method described in Zikkenkagakukoza, vol. 22, IV (nihonkagakukai), J. Med. Chem. 38, 1689-1700, 1995, Gary M. Ksander et. al., etc. some of sulfonating agents are commercially available and the other are synthesized in accordance with a method described Shin-zikkenkagakukoza, vol. 14, 1787, 1978, Synthesis 852-854, 1986, etc. A carboxyl protective group is exemplified by esters (e.g., methyl ester, tert-butyl ester and benzyl ester). Deprotection of this protective group may be carried out by hydrolysis with acid (e.g., hydrochloride and trifluoroacetic acid) or base (e.g., sodium hydroxide) depending on the type of the group, or by catalytic reduction, e.g., under 10% palladium-carbon catalyst condition. To obtain a compound (Ib-1), the esters may directly be converted to hydroxamic acid by the method of process 2. When a compound (XV) is an amino acid wherein 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.


(Process 2)


A hydroxylamine is reacted with compound (Ia-1) or its reactive derivatives to give hydroxamic acid derivatives (Ib-1). A hydroxylamine is usually used as its acidic salts (e.g., hydrochloride, and phosphate, sulfate: commercially available) in the presence of a base. A base to be used in this reaction is exemplified by organic bases such as triethylamine, N,N-dimethylaniline, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. When compound (Ia-1) is used as a starting material of conversion to hydroxamic acid, this reaction is carried out in the presence of a peptide condensing agent (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-carbonyldiimidazole, or a mixture of one of the above agents with 1-hydroxybenzotriazole, N-hydroxy sucinicimide, etc.). A solvent for this reaction may be dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, and mixed solvent thereof. This reaction is carried out at −20° C. to 40° C., preferably ice-cooling to room temperature, for 1 to 16 hours.


Acid anhydrides (especially, mixed acid anhydrides), acid halides, acid azides, and esters can be utilized in this reaction as a reactive derivative of compound (Ia-1). These reactive derivatives are produced by usual methods. For example, the acid anhydride derivatives can be produced by a reaction of compound (Ia-1) with acid halide derivatives (e.g., ethyl chlorocarbonate) in the presence of a base (e.g., triethylamine), and acid halide derivatives can be produced by a reaction of compound (Ia-1) with a halogenation agent (e.g., oxalylchloride, and thionylchloride). Ester derivatives may be inactive or active. Sulfonyl derivatives converted from a compound (XV) wherein 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.


(Process 3)


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


(Process 4)


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

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


Conversion of compound (XV) to compound (XVII) is performed by sulfonation of an amino group of compound (XV) (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XVII) to compound (XVIII) is performed by Heck reaction (K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 4467(1975) etc.) wherein halogen of 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.


(Process 1)


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


(Process 2)


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


(Process 3)


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


(Process 4)


This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
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wherein R1, R2, R7, R15, R17, and Hal are as defined above.


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


(Process 1)


Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having a B(OH)2 (otherwise B(Et)2) group such as phenylboronic acid in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(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.


(Process 2)


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


(Process 3)


This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
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wherein R1, R2, R7, R15, R17, and Hal are as defined above.


Conversion of compound (XV) to compound (XX) is sulfonation of an amino group of the compound (XV) (process 1) and this process may be carried out in the same manner as that described in process 1 of method A. Conversion of compound (XX) to compound (XXI) is reduction of a nitro group of 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.


(Process 1)


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


(Process 2)


Compound (XX) is treated with hydrogen in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, etc. in the presence of a catalyst (e.g., Pd—C, 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.


(Process 3)


Compound (XXI) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an acid halide (otherwise an active ester) group such as benzoyl chloride in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, xylene, toluene, benzene, dichloromethane, etc. in the presence of a base (e.g., triethylamine, N-methylmorpholine, potassium carbonate etc.) to give the desired compound (XXII). This reaction is carried out at a temperature under ice-cooling to 100° C., preferably room temperature to 60° C., and is completed for 3 to 30 hours, preferably 10 to 25 hours.


(Process 4)


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


(Process 5)


This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
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wherein R1, R2, R7, R15, R17, and Hal are as defined above.


Conversion of compound (XV) to compound (XXIII) is performed by sulfonating an amino group of the compound (XV) (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XXIII) to compound (XXIV) is done by the reduction wherein an ethenyl group of R17 is converted into an aldehyde group (process 2). Conversion of compound (XXIV) to compound (XXVI) is performed by a tetrazole ring formation reaction (processes 3 and 4). Conversion of compound (XXVI) to compound (Ia-5) is N-alkylation, deprotection of a carboxyl protective group, etc. of compound (XXVI) (process 5), and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-5) to compound (Ib-5) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 6), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.


(Process 1)


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


(Process 2)


A compound (XXIII) is treated with ozone in a solvent such as dichloromethane, ethyl acetate, methanol, etc. to form an ozonide, and then a reagent such as zinc-acetic acid, triethylphosphate, dimethylsulfide, etc. is added to this reaction mixture for reduction to give the desired aldehyde derivatives (XXIV) The reduction can also be carried out by catalytic hydrogenation. This reaction is carried out at −100° C. to room temperature, preferably −78° C. to a temperature under ice-cooling, and is completed for 0.5 to 10 hours, preferably 1 to 3 hours.


(Process 3)


A compound (XXIV) is reacted with benzensulfonylhydrazide in a solvent such as tetrahydrofuran, ether, etc. mixed with a solvent such as methanol, ethanol, etc. to give the desired compound (XXV). This reaction is carried out at a temperature under ice-cooling to 80° C., preferably room temperature to 50° C., and is completed for 3 to 30 hours, preferably 10 to 20 hours.


(Process 4)


Optionally substituted aryl or optionally substituted heteroaryl having amino group such as aniline is dissolved in a mixed solvent such as alcohol (e.g., ethanol) and water. To this mixture conc. hydrochloric acid and a diazotizing agent such as a sodium nitrite aqueous solution are added at −20° C. to 10° C., preferably 0° C. to 5° C., to give a diazonium salt. The reaction time is 5 min to 1 hr, preferably 10 to 30 min. This reaction mixture is added to a pyridine solution of compound (XXV) and allowed react for 1 to 10 hr, preferably 2 to 5 hr, at −30° C. to 50° C., preferably −15° C. to room temperature to give the desired compound (XXVI). When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)), and then deprotected at an appropriate step.


(Process 5)


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


(Process 6)


This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
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wherein R1, R2, R7, R15, R17, and Hal are as defined above.


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


(Process 1)


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.


(Process 2)


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


(Process 3)


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


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


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


The compound of the present invention has an excellent activity for inhibiting metalloproteinase, especially activity for inhibiting MMP, and inhibits matrix dissolution, as described in the following test example. Therefore, the compound of the present invention is useful to treat or prevent diseases which are caused by MMP and relative enzymes such as TNF-α converting enzyme, etc.


Definitely, the compounds of the present invention are useful in the prevention or treatment of diseases such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, and gastric ulcer.


When the compound of the present invention is administered to a person for treatment or prevention of the above diseases, they can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, and liquid medicine, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation, or the like. An effective dose of the compound of the invention is formulated by being mixed with medicinal admixture such as excipient, penetrant, disintegrators, lubricant, and the like if necessary. When parenteral injection is prepared, the compound of the invention and an appropriate carrier are sterilized to prepare it.


An appropriate dosage varies with the conditions of the patients, an administration route, their age, their body weight and the like and should be determined by a physician in the end. In the case of oral administration, a daily dosage can generally be between 0.1-100 mg/kg/day, preferably 1-20 mg/kg/day. In the case of parenteral administration, the daily dosage can generally be between 0.01-10 mg/kg/day, preferably 0.1-1 mg/kg/day. The daily dosage can be administrated in one to several divisions.


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


Abbreviations described below are used in the following examples.


p-TsOH: p-toluenesulfonic acid


DMSO: dimethylsulfoxide


Me: methyl



tBu: tert-butyl
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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-11) 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 ν max (cm−1) (Nujol): 3365, 3295, 3266, 1674, 1320, 1159. NMR (δ ppm) 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)
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Process 1


To a solution of (R)-phenylalanine benzyl ester tosylate (compound XV-1′, 2.5 g (5.85 mmol)) in 60 ml of dichloromethane was added triethylamine (1.8 ml, 12.87 mmol) and 4-biphenylsulfonyl chloride(1.63 g, 6.44 mmol) under ice-cooling. After being stirred for 2 h at room temperature, the reaction mixture was washed with 2N HCl, 5% 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 ν max (cm−1) (Nujol): 3352, 1732, 1341, 1190, 1163. NMR (δ ppm) (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)


Process 2


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


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 ν max (cm−1) (Nujol): 3408, 3305, 1751, 1325, 1161, 1134. NMR (δ ppm) (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)


Process 3


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


Process 4


To a solution of compound (Ia-1-1″, 2.0 g, 5.24 mmol) which was obtained process 2 in dimethylformamide (20 ml) was added 1-hydroxybenzotriazole hydrate (0.7 g, 5.24 mmol), N-methylmorpholine (2.9 ml, 26.2 mmol), 1-ethyl-3-(3-diisopropylamino) carbodiimide hydrochloride (8 mmol), and O-benzylhydroxylamine hydrochloride (1.67 g, 10.48 mmol), and the resulting mixture was stirred for 6 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% 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 ν max (cm−1) (Nujol): 3248, 1661, 1594, 1333, 1163. NMR (δ ppm) (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)


Process 5


A solution of compound (XVI-1) (1.97 g) which was obtained process 4 in a 60 ml of mixed solvents of methanol/ethyl acetate=1/1 was hydrogenated using 10% Pd—C (200 mg) for 3.5 h. The reaction mixture was filtered off, and the filtrate was concentrated in vacuo. The residue was recrystallized from dichloromethane/hexane to give 1.35 g of compound (Ib-1-1). Yield 84.4%.


EXAMPLE 2-91

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










TABLE 1








(Ib)




embedded image















Exam-



mp
IR



ple



(decomp.)
(ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





2


embedded image




embedded image


RS
173>
3258, 1650, 1377, 1348, 1163 (Nujol)
2.87(dd, J=5.6, 14.2Hz, 1H), 2.98(dd, J=8.4, 14.2Hz, 1H), 4.02(dd, J=2.2, 8.6Hz, 1H), 7.24(d, J=2.0Hz, 1H), 8.83(d, J=2.2Hz, 1H)


3


embedded image




embedded image


R
203-206
3403, 3386, 3265, 1673, 1320, 1162 (Nujol)
2.72(dd, J=7.2, 13.8Hz, 1H), 2.97(dd, 7.0, 14.8Hz, 1H), 3.81(m, 1H),


4


embedded image




embedded image


RS





5


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RS
124-126
3277, 1669, 1397, 1322, 1159,
3.12(dd, J=10.3, 14.3Hz, 1H), 3.89(dd, J=3.3, 13.5Hz, 1H), 4.20(m, 1H), 5.90(brs, 1H)


6


embedded image




embedded image


R
139-141
3262, 1663, 1322, 1157,
2.67(dd, J=9.2, 13.1Hz, 1H), 2.84(dd, J=5.3, 13.5Hz, 1H), 3.82(m, 1H)


7
CF3CH2


embedded image


R
167-169
3265, 1676, 1642, 1337, 1161 (Nujol)
2.2-2.7(m, 2H), 3.99(t, J= 7.0Hz, 1H)


8


embedded image




embedded image


RS
172-173
3403, 3261, 1669, 1321, 1160
1.68(m, 2H), 2.37(m, 2H), 3.64(t, J=6.9Hz, 1H)


9


embedded image




embedded image


R
144-146
3700-2200 br, 3264, 1635, 1342, 1164,
2.61(dd, J=9.4, 13.8Hz, 1H), 2.78(dd, J=6.0, 13.8Hz, 1H), 3.78(m, 1H), 7.43(d, J=8.2Hz, 2H), 7.60(d, J=8.2Hz, 2H),


















TABLE 2









(Ib)









embedded image















Ex-








am-



mp



ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





10


embedded image




embedded image


R
116-118
3600- 2400 br, 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


embedded image




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R
91-92
3700- 2100 br, 3176, 1664, 1320, 1143,
2.70-2.93(m, 2H), 2.82(s, 6H), 3.75(m, 1H),


12
(CH3)2CH—


embedded image


R
178-179
3268, 1632, 1598, 1336, 1162
0.71(d, J=6.8Hz, 3H), 0.74(d, J= 5.4Hz, 3H), 1.73(m, 1H), 1.73(m, 1H), 3.22(m, 1H), 3.82(s, 3H), 7.05(d, J=9.0Hz, 2H), 7.69(d, J= 9.0Hz, 2H)


13


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


R
165-166
3278, 2920, 1632, 1337, 1161
0.50-1.62(m, 13H), 3.56(t, J= 7.4Hz, 1H)


16


embedded image




embedded image


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


embedded image




embedded image


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)


















TABLE 3









(Ib)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





18


embedded image




embedded image


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


embedded image




embedded image


RS





20


embedded image




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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


embedded image




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RS
111-115
3700- 2400 br, 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


embedded image




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RS

3455, 3362, 1672, 1398, 1162
3.86(d, J=3.6Hz, 1H), 4.91(d, J=3.6Hz, 1H)


23


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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


embedded image




embedded image


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


embedded image




embedded image


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)


















TABLE 4









(Ib)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





26


embedded image




embedded image


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, lH), 3.76(m, 1H)


27


embedded image




embedded image


R
70-71
3700- 2200 br, 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


embedded image


R





29
HOOC—CH2—CH2


embedded image


R





30
HOCH2


embedded image


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


embedded image




embedded image


R
69-70
3700-2200 (br), 1671, 1329, 1163
2.69(dd, J=7.6, 13.5Hz, 1H), 2.93(dd, J=7.6, 13.5Hz, 1H), 3.77(t, J=7.6Hz, 1H), (CD3OD)


32


embedded image




embedded image


R





33


embedded image




embedded image


R
160-162
3401, 3260, 1673, 1316, 1165
2.66(dd, J=7.5, 13.4Hz, 1H), 2.96(dd, J=7.6, 14.2Hz, 1H), 3.81(m, 1H)


















TABLE 5









(Ib)









embedded image















Example



mp (decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





34


embedded image




embedded image


R





35


embedded image




embedded image


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


















TABLE 6









(Ia)









embedded image















Ex-








am-


ple



mp (decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO
















2


embedded image




embedded image


RS
159-161
3276, 2503 br, 1897 br, 1724, 1344, 1170(Nujol)
2.95(dd, J=9.0, 14.0Hz, 1H), 3.12(dd, J=5.4, 14.0Hz, 1H), 4.13(m, 1H), 7.29(d, J=2.0Hz, 1H), 8.34(d, J=8.6Hz, 1H), 8.88(d, J=2.0Hz, 1H), 12.79(br, 1H)


3


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


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


embedded image


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


embedded image




embedded image


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


embedded image




embedded image


R
103-105
2200- 3700 br, 3439, 3288, 1725, 1329, 1143
2.86(m, 1H), 2.87(s, 6H), 2.98(dd, J=5.1, 13.8Hz, 1H), 4.15(m, 1H), 5.54(m, 1H)


















TABLE 7









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





13


embedded image




embedded image


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


embedded image




embedded image


RS
164-165
3426, 3114, 1715, 1509, 1224, 1159
2.71(dd, J=9.9, 13.7Hz, 1H), 2.96(dd, J=5.3, 13.5Hz, 1H), 3.89(m, 1H), 8.34(d, J=9.0Hz, 1H)


15


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


RS
197-205
2600- 3700 br, 1635, 1594, 1335, 1163, 1095
2.60-3.04(m, 2H), 3.98(m, 1H)


21


embedded image




embedded image


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


















TABLE 8









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





22


embedded image




embedded image


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


23


embedded image




embedded image


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


embedded image


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


embedded image


R
185-187
3270. 1709, 1336, 1159, 1093
1.68(dd, J=7.9, 14.1Hz, 1H), 1.87(dd, J=6.0, 13.4Hz, 1H), 2.22(t, J=7.2Hz, 2H), 3.80(m, 1H),


30
HOCH2


embedded image


R
277-279
2200-3700 br, 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


embedded image




embedded image


R
89-91
2200-3700 br, 3432, 3289, 1733, 1330, 1165
3.54(dd, J=4.8, 9.9Hz, 1H), 3.60(dd, J=5.7, 9.9Hz, 1H), 4.04(m, 1H), 4.39(s, 2H), 8.34(d, J=8.1Hz, 1H)


32


embedded image




embedded image


R
>270
3319, 3052, 1701, 1317, 1284, 1162
2.81(dd, J=9.7, 13.7Hz, 1H), 3.05(dd, J=4.8, 13.4Hz, 1H), 3.96(m, 1H), 8.40(d, J=9.0Hz, 1H), 12.88(br.s, 1H)


















TABLE 9









(Ia)









embedded image















Exam-



mp




ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





34


embedded image




embedded image


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


embedded image




embedded image


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


















TABLE 10









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





36


embedded image




embedded image


RS
>145
1726, 1354 1326, 1161



37


embedded image




embedded image


RS

1732, 1594 1404, 1155



38


embedded image




embedded image


R
188-190
1607, 1594 1294, 1153
C24H22N2O5S.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


embedded image




embedded image


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


embedded image




embedded image


R
149-152
1685, 1349 1166



41


embedded image




embedded image


R
104-107
1725, 1599 1372, 1173



42


embedded image




embedded image


R
167-169
1745, 1653 1391, 1147



43
(CH3)2CH—


embedded image


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


















TABLE 11









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





44
(CH3)2CH—


embedded image


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—


embedded image


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—


embedded image


R
157-159
1670, 1375 1148



47
(CH3)2CH—


embedded image


R
175-176
1717, 1694 1349, 1165



48
(CH3)2CH—


embedded image


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—


embedded image


R
183-186
1681, 1319 1162



50


embedded image




embedded image


R
183-184
1725, 1340 1159



51


embedded image




embedded image


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


















TABLE 12









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





52


embedded image




embedded image


R
157-160
1685,1349 1166



53


embedded image




embedded image


R
111-112
1691, 1567 1390, 1159



54


embedded image




embedded image


R
194-195
1749, 1592 1323, 1164



55
(CH3)2CH—


embedded image


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


embedded image




embedded image


R
108-110
1649, 1337 1165



57


embedded image




embedded image


R
187-190
1588, 1308 1141



58


embedded image




embedded image


R
239-243
1744, 1592 1323, 1160
C21H18N2O4S2.0.3H2O 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


embedded image




embedded image


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


















TABLE 13









(Ib)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





60


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


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—


embedded image


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


64


embedded image




embedded image


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


embedded image




embedded image


RS

3405, 1671, 1582, 1487, 1324, 1154
2.34(s, 3H), 2.65(dd, J=7.6, 14.1Hz, 1H), 2.93(dd, J=7.6, 14.4Hz, 1H), 3.75(dd, J=6.8, 7.7Hz, 1H)


66


embedded image




embedded image


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


embedded image




embedded image


RS

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


















TABLE 14









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





60


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


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—


embedded image


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


embedded image




embedded image


RS

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


65


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


RS
236-237
3296, 1742, 1647, 1604, 1581, 1342, 1334, 1152
2.55(s, 3H), 2.79-3.11(m, 2H), 3.98(m, 1H)


















TABLE 15









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





68


embedded image




embedded image


R
>240
1608, 1590 1507, 1232 1157



69


embedded image




embedded image


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


embedded image




embedded image


RS

1733, 1583 1150



















TABLE 16









(Ib)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





71


embedded image




embedded image


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


embedded image


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


embedded image


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


embedded image




embedded image


R





75


embedded image




embedded image


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


embedded image




embedded image


R





















TABLE 17









(Ib)









embedded image















Exam-



mp




ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





77


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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


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R
69-70
3700-2200(br), 1670, 1318, 1152
2.78(dd, J=8.6, 13.4Hz, 1H), 2.91(dd, J=6.0, 13.4Hz, 1H), 3.92(ABq, J= 13.5Hz, 1H), 3.90(m, 1H), 9.01(s, 1H), 10.78(s, 1H)


79


embedded image




embedded image


R





















TABLE 18









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





71


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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


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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


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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


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embedded image


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


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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


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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


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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=13.7Hz, 2H), 4.01(m, 1H), 7.65(d, J=8.3Hz, 1H)


79


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R

3413, 2931, 1720, 1585, 1455, 1421, 1313, 1144
0.90-1.68(m, 9H), 1.78(m, 1H), 2.74(m, 1H), 3.00-3.20(m, 2H), 3.77(m, 1H) 6.45(br.s, 1H), 6.77(br.s, 1H)


















TABLE 19









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





80


embedded image




embedded image


R
153-155
1704, 1596 1349, 1164



81


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n-C8H17
R
>130
1576, 1356 1139



82


embedded image




embedded image


R
128-130
1732, 1342 1167
C24H19N3O5S.1.3H2O Calc. C: 59.45 H: 4.49 N: 8.67 S: 6.61 Foun. C: 59.43 H: 4.45 N: 8.59 S: 6.58


83


embedded image




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R
210-214
1745, 1590 1316, 1157



84


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R
198-200
1594, 1456 1200, 1188



















TABLE 20









(Ib)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





85


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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


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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


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S
206-207
3700- 2400(br), 3357, 1686, 1641, 1314, 1155
2.57(dd, J=8.3, 13.6Hz, 1H), 2.79(dd, J=6.0, 13.6Hz, 1H), 3.76(m, 1H), 8.02(d, J=8.7Hz, 1H), 8.80(s, 1H), 8.85(d, J= 1.7Hz, 1H), 9.06(s, 1H), 10.59(d, J=1.7Hz, 1H)


















TABLE 21









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





85


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R
172-174
2400- 3600 br, 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


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R
93-94
2200- 3700 br, 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


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S
203-204
2300- 3700 br, 3358, 3262, 1718, 1686, 1660, 1313, 1159
2.71(dd, J=9.1, 13.7Hz, 1H), 2.93(dd, J=5.6, 13.7Hz, 1H), 3.84(dt, J=5.6, 9.1Hz, 1H), 8.11(d, J=9.1Hz, 1H), 8.78(s, 1H), 9.06(s, 1H)


















TABLE 22









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





88


embedded image




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R
103-106
1719, 1390 1229



89
(CH3)2CH—


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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—


embedded image


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


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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)




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Process 1


To a solution of D-valine methylester hydrochloride (XV-2) (755 mg, 4.5 mmol) in dichloromethane (12 ml) was added N-methylmorpholine (1.49 ml, 3×4.5 mmol) and 5-bromo-2-thiophensulfonyl chloride (1.24 g, 1.05×4.5 mmol) was added under ice-cooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HCl, 5% 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=1/3 were collected and washed with n-hexane to give 1.32 g of the desired compound (XVII-1).


Yield82%. mp. 109-110° C. Elemental analysis C10H14BrNO4S2 Calcd.: C; 33.71 H; 3.96 Br; 22.43 N; 3.93 S;18.00 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, ν max cm−1)1737,1356,1164,1138 NMR (CDCl3, δ ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz, 3H), 2.00(m, 1H), 3.60(s, 3H), 3.83(dd, J=5.2, 10.0 Hz, 1H), 5.20(d, J=10.0 Hz, 1H), 7.04(d, J=4.1 Hz, 1H), 7.32(d, J=4.1 Hz, 1H).


Process 2


To a degassed solution of 400 mg (1.12 mmol) of compound (XVII-1) in 5 ml of dimethylformamide was added 222 mg (1.5×1.12 mmol) of 4-methoxyphenylacetylene and 21 mg(0.1×1.12 mmol) of copper iodide (I) under an argon atmosphere. Then 39 mg (0.05×1.12 mmol) of bis(triphenylphosphine)palladium dichloride (II) and 0.47 ml (3×1.12 mmol) of triethylamine were added to the reaction mixture. The resulting mixture was degassed and stirred overnight under an argon atmosphere at 50° C. The reaction mixture was diluted with ethyl acetate. The organic later was washed with 1N HCl, 5% 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, ν max cm−1): 3268, 2203, 1736, 1604, 1524, 1348, 1164. NMR (CDCl3, δ ppm): 0.90(d, J=6.6 Hz, 3H), 1.00(d, J=7.0 Hz, 3H), 2.00(m, 1H), 3.60(s, 3H), 3.84(s, 3H), 3.86(dd, J=5.0, 10.2 Hz, 1H), 5.21(d, J=10.2 Hz, 1H), 6.90(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).


Process 3


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

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











TABLE 23









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)
Elemental


No.
R1
R18
*
(° C.)
(KBr)
analysis
















93


embedded image




embedded image


R
165-170
1590, 1316 1137



94


embedded image




embedded image


R
223-226
1747, 1323 1134
C26H22N2O5S Calc. C: 65.81 H: 4.67 N: 5.90 S: 6.76 Foun. C: 65.34 H: 4.90 N: 5.56 S: 6.40


95


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embedded image


R
216-218
1724, 1325 1135



96


embedded image




embedded image


R
111-114
1739, 1336 1163



97


embedded image




embedded image


R
178-180
1710, 1511 1329, 1161



98


embedded image




embedded image


R
105-108
1725, 1618 1373, 1163



99


embedded image




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R
>250
1706, 1606 1350, 1164
C26H20N2O6S. 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: 6.76


100


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R
176-177
1735, 1633
C25H21N3O4S. 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


















TABLE 24









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)
Elemental


No.
R1
R18
*
(° C.)
(KBr)
analysis





101


embedded image




embedded image


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


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embedded image


R
230-233
1735, 1654 1399, 1164



103


embedded image




embedded image


R
234-236
1732, 1631 1372, 1148



104


embedded image




embedded image


R
>200 decomp.
1600, 1558 1336, 1171



105
(CH3)2CH—


embedded image


R
146-149
1795, 1718 1331, 1166



106
(CH3)2CH—


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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—


embedded image


R
166-169
1728, 1631 1372, 1148



108
(CH3)2CH—


embedded image


R
163-165
1728, 1332 1172



















TABLE 25









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





109
(CH3)2CH—


embedded image


R
187-189
1720, 1656 1319, 1165



110
(CH3)2CH—


embedded image


R
111-114
1724, 1635 1366, 1158



111
(CH3)3C—


embedded image


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—


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R
157-159
1732, 1680 1329, 1167



113


embedded image




embedded image


R
133-136
1735, 1651 1348, 1165



114


embedded image




embedded image


R
183-185
1727, 1604 1335, 1182



115


embedded image




embedded image


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—


embedded image


R
163-165
1728, 1332 1172



















TABLE 26









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





117
(CH3)2CH—


embedded image


R
187-189
1720, 1656 1319, 1165



118


embedded image




embedded image


R
111-114
1724, 1635 1366, 1158



119


embedded image




embedded image


R
167-169
1585, 1318 1153



120


embedded image




embedded image


R

1605, 1523 1340, 1151



121


embedded image




embedded image


R

1604, 1524 1336, 1173



122


embedded image




embedded image


R
103-106
1721, 1620 1339, 1163



123


embedded image




embedded image


R
180-182
1729, 1675 1340, 1168



124
(CH3)2CH—


embedded image


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


















TABLE 27









(Ia)









embedded image















Ex-








am-



mp


ple



(decomp.)
IR (ν cm−1)


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





125
(CH3)2CH—


embedded image


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—


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R
154-156
1710, 1499 1356, 1165



127


embedded image




embedded image


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


embedded image




embedded image


R
161-164
1710, 1329 1180



129


embedded image




embedded image


R
155-158
1734, 1699 1324, 1105
C21H16FNO4S2 Calc. C: 58.73 H: 3.75 F: 4.42 N: 3.26 S: 14.93 Foun. C: 58.66 H: 3.93 F: 4.52 N: 3.33 S: 14.41


130


embedded image




embedded image


R





131


embedded image




embedded image


R





132


embedded image




embedded image


R





















TABLE 28









(Ia)









embedded image















Example



mp (decomp.)
IR (ν cm−1)



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





133


embedded image




embedded image


R





134


embedded image




embedded image


R





135


embedded image




embedded image


R





136


embedded image




embedded image


R





137


embedded image




embedded image


R





138


embedded image




embedded image


R





139


embedded image




embedded image


R





140


embedded image




embedded image


R





















TABLE 29









(Ia)









embedded image



















mp




Example



(decomp.)
IR (ν cm−1)


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





141


embedded image




embedded image


R





142


embedded image




embedded image


R





143


embedded image




embedded image


R





144


embedded image




embedded image


R





145


embedded image




embedded image


R





146


embedded image




embedded image


R





147


embedded image




embedded image


R





148


embedded image




embedded image


R





















TABLE 30









(Ia)









embedded image















Example



mp (decomp.)
IR (ν cm−1)



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





149


embedded image




embedded image


R





150


embedded image




embedded image


R





151


embedded image




embedded image


R





152


embedded image




embedded image


R





153


embedded image




embedded image


R





154


embedded image




embedded image


R





155


embedded image




embedded image


R





156


embedded image




embedded image


R













Example 157, 158




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Process 1 (R2═CH3)


To a solution of 150 mg (0.33 mmol) of compound (XVIII-2) in 2 ml of dimethylformamide which was synthesized the same manner as those described in Example 96 was added 227 mg (5×0.33 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


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, ν max cm−1): 3600-2300br, 3426, 2203, 1710, 1604, 1503, 1344, 1151. NMR (d6-DMSO, δ ppm): 2.88(s, 3H), 2.93(dd, J=12.0, 10.2 Hz, 1H), 3.19 (dd, J=14.2, 5.6 Hz, 1H), 3.81(s, 3H), 4.74(dd, J=5.4, 10.2 Hz, 1H), 6.99-7.04(m, 2H), 7.20-7.35(m, 7H), 7.52-7.56(m, 2H), 6.90(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).


The compound (Ia-2-67) (R2═CH2Ph) was synthesized in the same manner as those described in Example 157.


IR (KBr, ν max cm−1): 2200,1722,1340,1151. NMR (d6-DMSO, δ ppm): 2.94(dd, J=7.6, 13.8 Hz, 1H), 3.19(dd, J=7.2, 14.4 Hz, 1H), 3.83(s, 3H), 4.29(d, J=16.2 Hz, 1H), 4.62(d, J=16.2 Hz, 1H) (Only characteristic peaks are shown.)
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Process 1


To a solution of 500 mg (1.4 mmol) of compound (XVII-2) which was obtained Example 96 in 12 ml of dry tetrahydrofuran was added 387 mg (2×1.4 mmol) of powdery potassium carbonate, 319 mg (1.5×1.4 mmol) of 4-methoxyphenylboronic acid and 81 mg (0.05×1.4 mmol) of tetrakis(triphenylphosphine)palladium. The resulting mixture was stirred under argon atmosphere for 48 h at 75° C. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1N HCl, 5% 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; 53.26H; 5.50 N; 3.69 S; 16.63 [α]D−21.7±0.6 (c=1.000 DMSO 25° C.) IR (KBr, ν max cm−1): 1735,1605,1505,1350,1167,1136 NMR (CDCl3, δ ppm): 0.90(d, J=7.0 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 2.10(m, 1H), 3.54(s, 3H), 3.85(s, 3H), 3.87(dd, J=5.0, 10.2 Hz, 1H), 5.20(d, J=10.2 Hz, 1H), 6.94(d, J=9.0 Hz, 2H), 7.52(d, J=9.0 Hz, 2H), 7.11(d, J=4.0 Hz, 1H), 7.49(d, J=4.0 Hz, 1H).


Process 2


To a solution of 390 mg (1.01 mmol) of compound (XIX-1) in 8 ml of tetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH, and resulting mixture was stirred at 60° C. for 6 h. The reaction mixture was concentrated in vacuo to remove an organic solvent. The resulting residue was diluted with ethyl acetate. The mixture was acidified with aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 373 mg of compound (Ia-3-1). Yield 100%. mp.:174-176° C.


IR(KBr, ν max cm−1): 1735, 1503, 1343, 1163.


EXAMPLE 160-175

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











TABLE 31









(Ia)









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mp
IR



Example



(decomp.)
(ν cm−1)


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





160


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R
93-96
1667, 1337 1180



161


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R
157-159
1670, 1339 1194



162


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R
168-171
1725, 1598 1371, 1185



163


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R
226-230
1735, 1341 1159
C22H20N2O4S3.0.4H2O Calc. C:55.07 H:4.37 N:5.84 S:20.05 Foun. C:55.35 H:4.43 N:6.04 S:19.65


164
(CH3)2CH—


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R
174-176
1735, 1503 1343, 1163



165
(CH3)2CH—


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R
165-167
1713, 1353 1163



166
(CH3)2CH—


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R
146-147
1702, 1504 1352, 1168
C15H16FNO4S2.0.1H2O 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:17.77


167
(CH3)2CH—


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R
157-159
1747, 1324 1159
C16H19NO4S3 Calc. C:49.85 H:4.97 N:3.63 S:24.95 Foun. C:49.70 H:5.00 N:3.93 S:24.96
















TABLE 32







(Ia)









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Example



mp (decomp.)
IR (v cm−1)



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





168


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R
161-165
1735,1698 1374,1163
C20H19NO5S2 Calc. 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


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R
166-167
1713,1609 1378,1194
C20H19NO4S2 Calc. C:59.83 H:4.77 N:3.49 S:15.97 Foun. C:59.77 H:4.86 N:3.61 S:15.86


170


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R
174-175
1721,1654 1365,1148
C19H16FNO4S2 Calc. C:56.28 H:3.98 F:4.09 N:3.45 S:15.82 Foun. C:56.33 H:4.09 F:4.65 N:3.65 S:15.84


171


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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


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R





173


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R





174


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R





175


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R














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Process 1


To a solution of 10 g (47.68 mmol) of D-valine tert-butyl ester hydrochloride (XV-3) in 100 ml of dichloromethane was added 15.7 ml (3×47.68 mmol) of N-methylmorpholine and 14.1 g(1.2×47.68 mmol) of 4-nitrobenzenesulfonyl chloride under ice-cooling. After being stirred for 5 h at room temperature the reaction mixture was washed with 2N HCl, 5% 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, ν max cm−1): 3430br, 3301, 1722, 1698, 1525, 1362, 1348, 1181, 1174, 1159.


Process 2


A solution of 13.29 g (37.08 mmol) of compound (XX-1) in 200 ml of methanol was hydrogenated using 10% Pd/C (1 g) for 2 h at room temperature. The reaction mixture was filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized from acetone/n-hexane to give 11.5 g of amine derivative (XXI-1). Yield 94.4%. mp. 164-166° C.


Elemental analysis C15H24N2O4S Calcd.: C; 54.86 H; 7.37 N; 8.53 S; 9.76 Found: C; 54.84 H; 7.33 N; 8 63 S; 9.50 [α]D+10.3±1.0(c=0.515 DMSO 23° C.) IR(KBr, ν max cm−1): 3461, 3375, 1716, 1638, 1598, 1344, 1313. NMR(d-DMSO, δ ppm): 0.80(d, J=6.8 Hz, 3H), 0.82(d, J=6.6 Hz, 3H), 1.23(s, 9H), 1.83(m, 1H), 3.30(m, 1H), 5.86(s, 2H), 6.56(d, J=8.8 Hz, 2H), 7.36(d, J=8.6 Hz, 2H), 7.47(d, J=9.6 Hz, 1H)


Process 3


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


Elemental analysis C23H30N2O5S2 Calcd.: C; 57.72 H; 6.32 N; 5.85 S; 13.40 Found: C; 57.63 H; 6.28 N; 5.86 S; 13.20 [α]D+5.7±0.9(c=0.512 DMSO 25° C.) IR(KBr, ν max cm−1): 3366, 3284, 1713, 1667, 1592, 1514, 1498, 1341, 1317. NMR(d6-DMSO, δ ppm): 0.82(d, J=6.6 Hz, 3H), 0.84(d, J=6.8 Hz, 3H), 1.22(s, 9H), 1.91(m, 1H), 2.55(s, 3H), 3.32(s, 3H), 3.44(dd, J=6.2, 8.6 Hz, 1H), 7.40(d, J=8.6 Hz, 2H), 7.73(d, J=8.6 Hz, 2H), 7.90-8.01(m, 5H), 10.48(s, 1H).


Process 4


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


IR(KBr, ν max cm−1): 1748, 1655, 1592, 1323, 1161. Elemental analysis 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

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











TABLE 33









(Ia)









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Example



mp (decomp.)
IR (ν cm)



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





177


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R
215-217
1732, 1641 1341, 1163



178


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R
233-234
1726, 1655 1323, 1177
C25H23N3O6S·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:6.10


179


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R
216-218
1723, 1633 1361, 1149



180


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R
211-213
1719, 1629 1340, 1156
C24H20N4O7S·1.1H2O Calc. C:54.56 H:4.24 N:10.60 S:6.07 Foun.C:54.51 H:4.32 N:10.83 S:6.15


181


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R
236-238
1732, 1653 1399, 1199
C26H26N4O5S·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:6.47


182


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R
240-244
1731, 1656 1591, 1327 1160
C25H23N3O5S·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:6.66


183


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R
215-218
1727, 1668 1590, 1316 1154
C14H20BrN3O5.0.6H2O 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:5.70


184


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R
244-249
1728, 1653 1593, 1323 1159
C15H23N3O5S2.0.7H2O Calc. C:57.50 H:4.71 N:8.05 S:12.28 Foun.C:57.63 H:4.79 N:8.00 S:12.08






















TABLE 34





Example



mp (decomp.)
IR (ν cm−1)



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







185


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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


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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


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R
235-239
1719, 1672 1593, 1327 1159
C22H19N3O7S Calc. C:56.29 H:4.08 N:8.95 S:6.83 Foun.C:5601 H:4.09 N:8.93 S:6.75


188


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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


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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


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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


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R
232-235
1742, 1667 1591, 1334 1161
C23H22N2O5S2.0.5CF3COOH 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


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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


















TABLE 35









(Ia)









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Example



mp (decomp.)
IR (ν cm)



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





193


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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


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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—


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R
254-256
1748, 1659 1590, 1324 1161
C24H24N2O4S.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—


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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—


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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—


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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—


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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—


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R
220-221
1696, 1654 1591, 1317 1255
C19H22N2O6S·0.2H2O Calc. C:55.65 H5.51 N:6.83 S:7.82 Foun.C:55.63 H:5.48 N:7.03 S:7.75

















TABLE 36








(Ia)




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Example



mp (decomp.)
IR (ν cm−1)



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





201
(CH3)2CH—


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R
240-242
1726,1688 1591,1347 1166
C18H19N3O7S.0.4 H2O 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—


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R
229-230
1726,1663 1592,1318 1159
C18H19BrN2O5S.0.2 Ethylether Calc. C:48.03 H:4.50 Br:17.00 N:5.96 S:6.82 Foun. C:48.04 H:4.61 Br:16.83 N: 5.96 S:6.86


203
(CH3)3C—


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


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


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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


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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


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R
217-220
1732,1679 1592,1312 1155



208


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R














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Process 1


To a solution of 20.94 g (99.8 mmol) of D-valine tert-butyl ester hydrochloride (XV-3) in 200 ml of dichloromethane was added 22 ml (2×99.8 mmol) of N-methylmorpholine and 20.27 g (99.8 mmol) of p-styrenesulfonyl chloride under ice-cooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HCl, 5% 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=1/3/1 were collected and washed with n-hexane to give 28.93 g of the desired compound (XXIII-1).


Yield 85%. mp. 118-120° C. IR(KBr, ν max cm−1): 3419, 3283, 1716, 1348, 1168. NMR(CDCl3, δ ppm): 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 1.21(s, 9H), 2.04(m, 1H), 3.62(dd, J=9.8, 4.5 Hz, 1H), 5.09(d, J=9.8 Hz, 1H), 5.41(dd, J=0.5, 10.9 Hz, 1H), 5.84(dd, J=0.5, 17.6 Hz, 1H), 6.72(dd, J=10.9, 17.6 Hz, 1H), 7.49(d, J=8.4 Hz, 2H), 7.79(d, J=8.4 Hz, 2H).


Process 2


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


IR(CHCl3, ν max cm−1): 3322, 1710, 1351, 1170. NMR(CDCl3, δ ppm): 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.9 Hz, 3H), 1.22(s, 9H), 2.07(m, 1H), 3.69(dd, J=4.5, 9.9 Hz, 1H), 8.01(s, 4H), 10.08(s, 1H).


Process 3


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


Elemental analysis 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, ν max cm−1): 3430, 3274, 1711, 1364, 1343, 1172. NMR(CDCl3 δ ppm): 0.84(d, J=6.9 Hz, 3H), 0.99(d, J=6.6 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 3.63(dd, J=4.5, 9.9 Hz, 1H), 5.16(d, J=9.9 Hz, 1H), 7.50-7.68(m, 5H), 7.73(s, 1H), 7.78-7.84(m, 2H), 7.96-8.02(m, 2H), 8.16(brs, 1H).


Process 4

To a solution of 0.14 ml (1.11×1 mmol) of 4-(methylmercapto)aniline and 0.3 ml of conc. hydrochloric acid in 3 ml of aqueous 50% ethanol solution was added a solution of 78.4 mg (1.14×1 mmol) of sodium nitrite in 1 ml of water at 0 to 5° C. of the internal temperature and the reaction mixture was stirred for 15 min at the same temperature. To a solution of 496 mg (1 mmol) of compound (XXV-1) in 5 ml of dry pyridine was added the above reaction mixture over 8 min at −25° C. This reaction mixture was stirred for additional 4 h at −15° C. to rt, poured into water, and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCO3, and water, dried over Na2SO4, and concentrated in vacuo. The residue was column chromatographed on silica gel and the fractions eluting with chloroform/ethyl acetate=1/9 were collected to give 374 mg of the desired compound (XXVI-1). Yield 74%.


Elemental analysis 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, ν max cm−1): 3422, 3310, 1705, 1345, 1171. NMR(d6-DMSO, δ ppm): 0.83(d, J=6.9 Hz, 3H), 0.86(d, J=7.2 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 2.59(s, 3H), 3.54(dd, J=6.3, 9.6 Hz, 1H), 7.56(d, J=8.7 Hz, 2H), 8.00(d, J=8.6 Hz, 2H), 8.10(d, J=8.7 Hz, 2H), 8.33(d, J=9.6 Hz, 2H), 8.34(d, J=8.7 Hz, 2H).


Process 5


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


IR(KBr, ν max 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

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











TABLE 37









(Ib)









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mp
IR



Example



(decomp.)
(ν cm−1)

1H—NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





210


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R





211


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R
194-195
3700- 2200(br), 3278, 1634, 1337, 1160
2.65(dd, J=9.3, 13.1Hz, 1H), 2.82(dd, J=5.8, 13.1Hz, 1H), 3.86(dt, J=5.8, 9.3 Hz, 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)


















TABLE 38









(Ia)









embedded image



















mp
IR



Example



(decomp.)
(ν cm−1)

1H—NMR(δ ppm)



No.
R1
R18
*
(° C.)
(KBr)
d6-DMSO





210


embedded image




embedded image


R





211


embedded image




embedded image


R
215-216
2400-3700br, 3422, 3337, 1733, 1698, 1347, 1170
2.75(dd, J=9.3, 13.7Hz, 1H), 2.99(dd, J=5.3, 13.7Hz, 1H), 3.96(dt, J= 5.3, 9.3Hz, 1H), 8.53(d, J=9.3Hz, 1H)


















TABLE 39









(Ia)









embedded image



















mp
IR



Example



(decomp.)
(ν cm−1)


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





212


embedded image




embedded image


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


embedded image




embedded image


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


embedded image


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—


embedded image


R
221-222
1696, 1594 1349, 1173
C18H19N4O4S 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


embedded image




embedded image


RS
145-148
1727, 1337 1163



217


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


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


















TABLE 40









(Ia)









embedded image















Example



mp (decomp.)
IR (ν cm−1)



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





220


embedded image




embedded image


R
195-196
1749, 1719 1334, 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—


embedded image


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—


embedded image


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—


embedded image


R
190 decomp.
1718, 1601 1385, 1162



224
(CH3)2CH—


embedded image


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—


embedded image


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—


embedded image


R
204-207
1698, 1344 1168



227


embedded image




embedded image


R
203-205
1757, 1738 1331, 1163



















TABLE 41









(Ia)









embedded image















Example



mp (decomp.)
IR (ν cm−1)



No.
R1
R1a
*
(° C.)
(KBr)
Elemental analysis





228


embedded image




embedded image


R
197-199
1744, 1325 1154



229


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


R
205-207
1730, 1509 1236, 1165
C22H18FN5O4S.0.2HO2O Calc. C: 56.09 H: 3.94 F: 4.03 N: 14.87 S: 6.81 Foun. C: 56.10 H: 4.09 F: 4.12 N: 14.84 S: 7.08


232


embedded image




embedded image


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


embedded image




embedded image


R
226-227
1732, 1697 1509, 1373O 1345, 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


embedded image




embedded image


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


embedded image




embedded image


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


















TABLE 42









(Ia)









embedded image















Example



mp (decomp.)
IR (ν cm−1)



No.
R1
R1B
*
(° C.)
(KBr)
Elemental analysis





236


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


R
182-184
1587, 1506 1242, 1159



239


embedded image




embedded image


R
226-228
1713, 1514 1341, 1159



240


embedded image




embedded image


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


embedded image




embedded image


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—


embedded image


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—


embedded image


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


















TABLE 43









(Ia)









embedded image















Example



mp (decomp.)
IR (ν cm−1)



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





244
(CH3)2CH—


embedded image


R
223-225
1696, 1348 1171



245
(CH3)2CH—


embedded image


R
194-195
1720, 1343 1166
C19H21N5O4S2.1.1H2O Calc. C: 48.83 H: 5.00 N: 14.99 S: 13.72 Foun. C: 49.13 H: 5.25 N: 14.55 S: 13.34


246


embedded image




embedded image


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


embedded image




embedded image


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


embedded image




embedded image


R
>220
1698, 1430 1327, 1163
C18H16N6O4S.0.4H2O Calc. C: 51.52 H: 4.04 N: 20.03 S: 7.64 Foun. C: 51.34 H: 3.96 N: 19.76 S: 8.02


249


embedded image




embedded image


R





250


embedded image




embedded image


R





251


embedded image




embedded image


R












EXAMPLE 252-266

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











TABLE 44









(I)









embedded image

















Ex-










am-





mp


ple





(decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
R19
R20
*
(° C.)
(KBr)
d6-DMSO





252
(CH3)2CH—


embedded image


—CH3
—COOH
R

1715, 1583 1340, 1151
0.96(d, J=6.6Hz, 3H) 1.01(d, 6.8Hz, 3H) 2.87(s, 3H) 4.17(d, J=10.4Hz, 1H)


253
(CH3)2CH—


embedded image


—CH3
—CONHOH
R
110-111
3323, 1678 1328, 1150
0.71(d, J=6.6Hz, 3H) 0.88(d, 6.4Hz, 3H) 2.88(s, 3H) 3.48(d, J=10.8Hz, 1H)


254
(CH3)2CH—


embedded image




embedded image


—CONHOH
R
148-150
3344, 1684 1323, 1149
0.55(d, J=6.8Hz, 3H) 0.82(d, 6.8Hz, 3H) 2.87(s, 3H) 4.17(d, J=10.4Hz, 1H)


255
(CH3)2CH—


embedded image


—(CH2)4NH2
—COOH
R

3700, 2200br 1681, 1319 1212
0.91(d, J=5.6Hz, 6H) 1.52-1.69(m, 4H) 3.84(d, J=10.4Hz, 1H)


256
(CH3)2CH—


embedded image


—CH3
—COOH
R
206-207
3300, 2400br 1711, 1336 1185
0.95(d, J=6.6Hz, 3H) 0.97(d, 6.8Hz, 3H) 2.89(s, 3H) 4.20(d, J=10.6Hz, 1H)


257
(CH3)2CHCH2


embedded image


—CH3
—COOH
R
132-132.5
3300, 2400br 1719, 1340 1153
0.92(d, J=6.6Hz, 3H) 0.97(d, 6.6Hz, 3H) 2.84(s, 3H) 4.73(t, J=7.4Hz, 1H)


258


embedded image




embedded image




embedded image


—COOH
R

3640, 2400br 1736, 1717 1694, 1346 1162
2.78(d.d, J=13.8, 7.2Hz, 1H) 3.14(d.d, J=14.8, 7.4Hz, 1H) 4.43(d, J=16.4Hz, 1H) 4.68(d, J=16.4Hz, 1H)


259
(CH3)2CH—


embedded image


—CH3
—COOH
R
141-144
3284br, 1745 1714, 1323 1131
0.96(d, J=6.4Hz, 3H) 0.97(d, J=6.4Hz, 3H) 2.52(s, 3H), 2.93(s, 3H)


















TABLE 45









(I)









embedded image

















Example





mp (decomp.)
IR (ν cm−1)

1H-NMR(δ ppm)



No.
R1
R18
R19
R20
*
(° C.)
(KBr)
d6-DMSO





260
(CH3)2CH—


embedded image




embedded image


—COOH
R

3600-2400br 1718, 1344 1151
0.72(d, J=6.4Hz, 3H)0.85(d, J=6.4Hz, 3H)2.47(s, 3), 4.15(d, J=10.2Hz, 1H)4.51(d, J=15.5 Hz, 1H)4.73(d, J=15.5Hz, 1H)


261


embedded image




embedded image


—CH3
—COOH
R

3600-2400br 1719, 1655 1592, 1320 1154
2.54(s, 3H), 2.78(s, 3H) 2.85(d.d, J=14.0, 9.4Hz, 1H) 3.16(d.d, J=14.0, 6.0Hz, 1H) 4.76(d.d, J=10.0, 5.8Hz, 1H)


262


embedded image




embedded image




embedded image


—COOH
R





263


embedded image




embedded image


—(CH2)4NH2
—COOH
R





264


embedded image




embedded image


—CH3
—COOH
R





265


embedded image




embedded image




embedded image


—COOH
R





266


embedded image




embedded image


—(CH2)4NH2
—COOH
R












EXAMPLE 267

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











TABLE 46









(I)









embedded image
















Example






No.
R1
R18
R20
*





267


embedded image




embedded image


—CONHOH
R


267


embedded image




embedded image


—COOH
R















Example
mp (decomp.)
IR(ν cm−1)

1H-NMR(δ ppm)




No.
(° C.)
(KBr)
d6-DMSO







267
156-158
3700-2400br, 3267
2.62(dd, J=8.4, 13.5Hz, 1H), 2.80(dd,





2217, 1671, 1321, 1161
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
176-178
2200-3700br, 3430
2.73(dd, J=9.3, 13.6Hz, 1H), 2.96(dd,





3292, 1728, 1324, 1161
J=5.4, 13.5Hz, 1H), 3.92(dtd, J=5.4,






9.3Hz, 1H), 8.42(d, J=9.3Hz, 1H)










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


Test Example

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


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


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


(2) Assay Methods of Type IV Collagenase Inhibitors


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

    • (A) substrate (type IV collagenase), enzyme (MMP-9), inhibitor
    • (B) substrate (type IV collagenase), inhibitor
    • (C) substrate (type IV collagenase), enzyme (MMP-9)
    • (D) substrate (type IV collagenase)


According to the manufacturer's protocol, fluorescent intensity was measured and percent inhibition was determined by the following equation.

Inhibition (%)={1−(A−B)/(C−D)}×100


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













TABLE 47





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



















1
1a-1-1
0.24
1b-1-1
0.030


2
1a-1-2
2.6
1b-1-2
0.04


3
1a-1-3
0.18
1b-1-3
0.005


4
1a-1-4
2.25


5
1a-1-5
0.81
1b-1-5
0.041


6
1a-1-6
0.68
1b-1-6
0.034


7


1b-1-7
0.028


8
1a-1-8
2.0
1b-1-8
2.0


9


1b-1-9
0.41


10


1b-1-10
2.1


11


1b-1-11
1.7


12


1b-1-12
0.085


13


1b-1-13
0.38


14
1a-1-14
3.7
1b-1-14
0.11


15


1b-1-15
0.027


16
1a-1-16
0.520
1b-1-16
0.0108


17
1a-1-17
0.205
1b-1-17
0.0203


18
1a-1-18
0.500
1b-1-18
0.0282


20


1b-1-20
0.134


21
1a-1-21
4.65
1b-1-21
0.0041


23


1b-1-23
0.073


24


1b-1-24
0.2


26


1b-1-26
1.3


27


1b-1-27
3.0


30
1a-1-30
1.16
1b-1-30
0.213


31


1b-1-31
0.0129




















TABLE 48





Example No.
Compound No.
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


44
1a-1-44
1.910


45
1a-1-45
0.040


46
1a-1-46
1.12


47
1a-1-47
0.389


48
1a-1-48
1.15


49
1a-1-49
0.249


50
1a-1-50
0.553


51
1a-1-51
0.110


52
1a-1-52
0.329


53
1a-1-53
1.8


54
1a-1-54
0.075


55
1a-1-55
0.0398


60
1a-1-60
1.31
1b-1-60
0.0012


61
1a-1-61
0.247
1b-1-61
0.247


62


1b-1-62
3.50


63
1a-1-63
1.05
1b-1-63
0.00039


64
1a-1-64
1.90
1b-1-64
0.0037


65
1a-1-65
0.291
1b-1-65
0.0035




















TABLE 49





Example No.
Compound No.
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


















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


















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




















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




















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


















TABLE 54





Example No.
Compound No.
IC50 (μM)

















252
1-252
0.24


253
1-253
0.000039


254
1-254
0.00063


255
1-255
0.529


256
1-256
0.601


257
1-257
0.776


258
1-258
0.908


259
1-259
0.130


260
1-260
0.159


261
1-260
0.182









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


Industrial Applicability


It is considered that the compound of the present invention is useful to prevent or treat osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, and gastric ulcer, because the compound of the present invention has strong inhibitory activity against metalloproteinase, especially MMP.

Claims
  • 1. A composition for inhibiting metalloproteinase which comprises a compound of the formula I: wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is optionally substituted arylene; R4 is —CH═CH—, —C≡C—, —SO2—NH—N═CH—, or tetrazol-diyl; R5 is optionally substituted aryl; and Y is —NHOH or —OH; provided R2 is a hydrogen atom when Y is —NHOH; or an optically active substance, a pharmaceutically acceptable salt, or hydrate thereof.
  • 2. A composition for inhibiting metalloproteinase which comprises a compound of the formula I: wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is optionally substituted arylene; R4 is —CH═CH—, —C≡C—, —SO2—NH—N═CH—, or tetrazol-diyl; R5 is optionally substituted aryl; and Y is —NHOH or —OH; provided R2 is a hydrogen atom when Y is —NHOH; or an optically active substance, a pharmaceutically acceptable salt, or hydrate thereof.
  • 3. A compound of the formula I: wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is optionally substituted arylene; R4 —(CH2)m—, —CH═CH—, —C≡C—, SO2—NH—N═CH—, or tetrazol-diyl; R5 is optionally aryl; Y is —NHOH or —OH; and m is 1 or 2; provided R2 is hydrogen atom when Y is —NHOH, R4 is not —O— when R3 is optionally substituted arylene, R3 is not 1,2-phenylene or an optically active substance, a pharmaceutically acceptable salt, or hydrate thereof.
  • 4. A compound of the formula II: wherein R6 is —SO2—NH—N═CH—; R7 is optionally substituted aryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; Y is —NHOH or —OH; or an optically active substance, a pharmaceutically acceptable salt, or hydrate thereof.
  • 5. A compound of the formula III: wherein R10 is tetrazol-diyl; R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R7 is optionally substituted aryl; R8 and R9 are each independently a hydrogen atom, lower alkoxy, or nitro; Y is —NHOH or —OH; or an optically active substance, a pharmaceutically acceptable salt, or hydrate thereof.
  • 6. A compound of formula I′: wherein R1′ is benzyl, (indol-3-yl)methyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-fluoroindol-3-yl)methyl, (1-acetylindol-3-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, (1-alkoxycarbonyl-3-yl)methyl, (1-ethoxycarbonyl-3-yl)methyl or (1-isopropoxycarbonyl-3-yl)methyl; R2′ is hydrogen atom, methyl, 4-aminobutyl, or benzyl; R3′ is 1,4-phenylene; R4′ is —O—; R5′ is phenyl or 4-hydroxyphenyl; and Y is —NHOH or —OH, its optically active form, pharmaceutically acceptable salt, or hydrate thereof.
  • 7. A compound of formula V: wherein R12 is —CH═CH— or —C≡C—; R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R7 is optionally substituted aryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.
  • 8. A compound of formula VII: 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; R7 is optionally substituted aryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; its optically active form, pharmaceutically acceptable salt, or hydrate thereof.
  • 9. A compound of formula X: wherein R12 is —CH═CH— or —C≡C—; R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R7 is optionally substituted aryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; its optically active form, pharmaceutically acceptable salt, or hydrate thereof.
  • 10. A compound of formula XII: R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R7 is optionally substituted aryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; its optically active form, pharmaceutically acceptable salt, or hydrate thereof.
  • 11. The compound of claim 3, wherein R1 is isopropyl or benzyl.
  • 12. The compound of claim 3, wherein R5 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.
  • 13. The compound of claim 3, wherein a configuration of asymmetric carbon atoms bonding with R1 is R configuration.
  • 14. A pharmaceutical composition comprising a compound of claim 3.
  • 15. A pharmaceutical composition comprising a compound of claim 11.
  • 16. A pharmaceutical composition comprising a compound of claim 12.
  • 17. A pharmaceutical composition comprising a compound of claim 13.
  • 18. A method of inhibiting the activity of a metalloproteinase to treat a disease selected from the group consisting of osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection, 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, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, malaria, Crohn's disease, meningitis, and gastric ulcer, comprising administering to a subject in need of an effective amount of a compound of formula I: wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond or optionally substituted arylene; R4 is —(CH2)m—, —CH═CH—, —C≡C—, —N═N—, —N(RA), —O—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl; R5 is optionally substituted aryl; 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, or an optically active substance, a pharmaceutically acceptable salt, or hydrate thereof.
  • 19. A method of inhibiting the activity of a type-IV collagenase, to treat a disease selected from the group consisting of osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection, 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, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, malaria, Crohn's disease, meningitis, and gastric ulcer, comprising administering to a subject in need of an effective amount of a compound of formula I: wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond or optionally substituted arylene; R4 is —(CH2)m—, —CH═CH—, —C≡C—, ——N═N—, —N(RA)—, —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, or an optically active substance, a pharmaceutically acceptable salt, or hydrate thereof.
  • 20. The compound of claim 6, wherein R1′ is isopropyl or benzyl.
  • 21. The compound of claim 4, wherein R7 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.
  • 22. The compound of claim 6, wherein a configuration of asymmetric carbon atoms bonding with R1′ is R configuration.
  • 23. The compound according to claim 3, wherein R4 is —(CH2)m—, —CH═CH—, or —C≡C—; and m is 1 or 2, its optically active form, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • 24. The compound according to claim 3, wherein R1 is optionally substituted lower alkyl; R2 is hydrogen or optionally substituted lower alkyl; R3 is optionally substituted arylene; R4 is —(CH2)m—, —CH═CH—, —C≡C—; R5 is optionally substituted aryl or optionally substituted heteroaryl; and m is 1 or 2, its optically active form, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • 25. A compound of the formula: wherein R12 is —CH═CH—, —C≡C—, —O— or R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R7 is optionally substituted aryl or optionally substituted heteroaryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; its optically active form, pharmaceutically acceptable salt, or hydrate thereof.
Priority Claims (2)
Number Date Country Kind
8-30082 Jan 1996 JP national
8-21355 Aug 1996 JP national
Parent Case Info

This application is a divisional of application Ser. No. 09/710,904, filed Nov. 14, 2000, now U.S. Pat. No. 6,441,021, which is a divisional of application Ser. No. 09/120,197, filed Jul. 22, 1998, now U.S. Pat. No. 6,207,698, which is a continuation of PCT/JP97/00126, filed Jan. 22, 1997, which claims priority to Japanese Applications 8-21355 and 8-30082, filed Aug. 13, 1996 and Jan. 23, 1996, respectively, all of which are incorporated herein in their entirety.

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Related Publications (1)
Number Date Country
20030139379 A1 Jul 2003 US
Divisions (2)
Number Date Country
Parent 09710904 Nov 2000 US
Child 10188115 US
Parent 09120197 Jul 1998 US
Child 09710904 US
Continuations (1)
Number Date Country
Parent PCTJP97/00126 Jan 1997 US
Child 09120197 US