Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

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: 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 allyl, 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(R^A)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂NH—, —SO₂—NH—N═CH—, or tetrazol-diyl; R⁵ is optionally substituted lower alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R^A is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R² is hydrogen atom when Y is —NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

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: wherein R¹ is optionally substituted lower alky, 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(R^A)—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂NH—, —SO₂—NH—N═CH—, or tetrazol-diyl; R⁵ is optionally substituted lower alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R^A is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R² is hydrogen atom when Y is —NHOH, R⁵ is optionally substituted aryl or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R⁴ is —CO—NH— or —NH—CO—, R⁵ is optionally substituted aryl or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R⁴ is tetrazol-diyl, 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: 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(R^A)—, NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂NH—, —SO₂—NH—N═CH—, or tetrazol-diyl; R⁵ is optionally substituted lower alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryt or an optionally substituted non-aromatic heterocyclic group; R^A is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R² is hydrogen atom when Y is —NHOH, R⁵ is optionally substituted aryl or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R⁴ is —CO—NH— or —NH—CO— (when R³ is phenylene and R⁴ is —CO—NH—, R¹ is not methyl or phenyl and R⁵ is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R⁵ is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R¹ 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 R¹ 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: 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: wherein R¹⁰ is —(CH₂)m-, —CO—, —CO—NH—, N(R^A)—, —NHCO—, or tetrazol-diyl; m is 1 or 2; R¹, R², R⁷, R⁸, R⁹, R^A, 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: 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′: 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-pbenylene; 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″: wherein R¹″ is 4-thiazolylmethyl, (indol-3-yl)methyl, (5-methoxyindol-3-yl)methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-biphenylylmetbyl, 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-methylaulfonylindol-3-yl)methyl, or (1-ethoxycarbonylindol-3-yl)methyl; R²″ is hydrogen atom; R³″ is 1,4-phenylene; R⁴″ is a bond; R⁵″ is phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methylthiophenyl, 4-biphenylyl, 2-thienyl, benzoxazol-2-yl, benzothiazol-2-yl, or tetrazol-2-yl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
• 7) A compound of the formula V: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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 R¹⁸ is R configuration.

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

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

• 1) A compound wherein 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, R¹ 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-C₁₀ 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-imidazolyi), 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 position. 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, etbylthio, 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. 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-metbylmorpholine, 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 hydroxylarnine 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-dimnethylaniline, 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 (a-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.). 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. 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. 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. 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 −16° C. to room temperature to give the desired compound (XXVI). When optionally substituted aryl or optionally substituted heteroaryl has a subsitituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)), and then deprotected at an appropriate step.

(Process 5)

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

(Process 6)

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

EXAMPLE 1

(Method A)

 

To a suspension of (R)-(+)-phenylalanine (compound XV-1, 1.65 g (10 mmol)) in 50 ml of dimethylformamide and 35 ml of water was stirred and treated with 2.78 ml (20 mmol) of triethylamine under ice-cooling. Then, 2.52 g (1⁰ mmol) of 4-biphenylsulfonyl chloride in 10 ml of dimethylformamide was added dropwise to the mixture over 5 min. After the reaction mixture was stirred for 2 h at the same temperature, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 2.1 g (11 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3.47 g (50 mmol) of hydroxylamine hydrochloride, and 7 ml (50 mmol) of triethylamine were added to the mixture. After being stirred for 16 h at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCO₃, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl₃/MeOH=40/1 to 20/1 were collected to yield 1.70 g of compound (Ib-1-1) as a foam.

Yield 43%. mp. 169-170° C.

Elemental analysis (%) C₂₁H₂₀N₂O₄S; Calcd.: C; 63.62, H; 5.08, N; 7.07, S; 8.09. Found: C; 63.61, H; 5.12, N; 6.98, S; 8.06.

IR 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).

EXAMPLE 1

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

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 (%) C₂₆H₂₅NO₄S; 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° C.

Elemental analysis (%) C₂₁H19NO₄S; Calcd.: C; 66.12, H; 5.02, N; 3.67, S; 8.41. Found: C; 65.97, H; 5.06, N; 3.61, S; 8.48.

IR ν max (cm⁻¹) (Nujoil): 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; 68.86, 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%.

EXAMPLES 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
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
2			RS	173>	3258, 1650, 1377, 1348, 1163 (Nujol)	2.87(dd, J=5.6, 14.2 Hz, 1H), 2.98 (dd, J=8.4, 14.2 Hz, 1H), 4.02(dd, J=2.2, 8.6 Hz, 1H), 7.24(d, J=2.0 Hz, 1H), 8.83(d, J=2.2 Hz, 1H)
3			R	203-206	3403, 3386, 3265, 1673, 1320, 1162 (Nujol)	2.72(dd, J=7.2, 13.8 Hz, 1H), 2.97 (dd, 7.0, 14.8 Hz, 1H), 3.81(m, 1H)
4			RS	—	—	—
5			RS	124-126	3277, 1669, 1397, 1322, 1159	3.12(dd, J=10.3, 14.3 Hz, 1H), 3.89(dd, J=3.3, 13.5 Hz, 1H), 4.20 (m, 1H), 5.90 (brs, 1H)
6			R	139-141	3262, 1663, 1322, 1157	2.67(dd, J=9.2, 13.1 Hz, 1H), 2.84 (dd, J=5.3, 13.5 Hz, 1H), 3.82 (m, 1H)
7	CF3CH2—		R	167-169	3265, 1676, 1642, 1337, 1161 (Nujol)	2.2-2.7(m, 2H), 3.99(t, J=7.0 Hz, 1H)
8			RS	172-173	3403, 3261, 1669, 1321, 1160	1.68(m, 2H), 2.37(m, 2H), 3.64(t, J=6.9 Hz, 1H)
9			R	144-146	3700-2200 br, 3264, 1635, 1342, 1164	2.61(dd, J=9.4, 13.8 Hz, 1H), 2.78 (dd, J=6.0, 13.8 Hz, 1H), 3.78(m, 1H), 7.43(d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H).

 

TABLE 2
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
10			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			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—		R	178-179	3268, 1632, 1598, 1336, 1162	0.71(d, J=6.8 Hz, 3H), 0.74(d, J=5.4 Hz, 3H), 1.73(m, 1H), 1.73(m, 1H), 3.22(m, 1H), 3.82(s, 3H), 7.05(d, J=9.0 Hz, 2H), 7.69(d, J=9.0 Hz, 2H)
13			RS	184-185	3257, 1662, 1516, 1344, 1322, 1160	2.80(dd, J=10.0, 13.8 Hz, 1H), 2.92 (dd, J=5.0, 12.8 Hz, 1H), 3.90(dd, J= 5.4, 9.6 Hz, 1H)
14			RS	128-130	3258, 1669, 1509, 1322, 1157	2.62(dd, J=9.9, 13.5 Hz, 1H), 2.78 (dd, J=5.8, 13.0 Hz, 1H), 3.77(t, J= 6.2 Hz, 1H)
15			R	165-166	3278, 2920, 1632, 1337, 1161	0.50-1.62(m, 13H), 3.56(t, J= 7.4 Hz, 1H)
16			RS	172-173	3272, 1631, 1332, 1161	2.71(dd, J=7.9, 14.2 Hz, 1H), 2.94 (dd, J=6.9, 14.2 Hz, 1H), 3.57(s, 3H), 3.83(dd, J=7.0, 7.4 Hz, 1H)
17			RS	144-146	3404, 1670, 1320, 1159	2.25(s, 3H), 2.67(dd, J=7.5, 14.2 Hz, 1H), 2.95(dd, J=7.7, 14.6 Hz, 1H), 3.81(dd, J=6.2, 14.2 Hz, 1H)

 

TABLE 3
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
18			RS	—	3420, 1670, 1592, 1321, 1159	2.72(dd, J=8.0, 14.0 Hz, 1H), 2.90(dd, J=6.2, 14.2 Hz, 1H), 3.82(m, 1H)
19			RS	—	—	—
20			RS	154-158	3186, 1593, 1480, 1379	2.68(dd, J=9.8, 13.7 Hz, 1H), 2.79(dd, J=5.6, 12.8 Hz, 1H) , 3.85(t, J=7.0 Hz, 1H)
21			RS	111-115	3700-2400 br, 3252, 1668, 1328, 1160	3.22-3.38(m, 2H), 4.17-4.24(m, 2H), 7.80(d, J=8.0 Hz, 2H), 7.96(d, J=6.4 Hz, 2H)
22			RS	—	3455, 3362, 1672, 1398, 1162	3.86(d, J=3.6 Hz, 1H), 4.91 (d, J=3.6 Hz, 1H)
23			R	196-197	3404, 3315, 1669, 1594, 1316, 1162	4.88(d, J=9.4 Hz, 1H), 8.74(d, J=9.4 Hz, 1H), 8.98(s, 1H), 10.92(s, 1H)
24			R	197-199	3700-2400 (br), 3473, 1675, 1310, 1152	2.69(dd, J=7.6, 13.5 Hz, 1H), 2.93(dd, J=7.6, 13.5 Hz, 1H), 3.77(t, J=7.6 Hz, 1H), (CD3OD)
25			R	201-202	3700-2200 (br), 3278, 1706, 1645, 1322, 1162	2.74(dd, J=8.3, 13.5 Hz, 1H), 2.95(dd, J=6.5, 13.5 Hz, 1H), 3.87(dd, J=6.5, 8.3 Hz, 1H), (CD3OD)

 

TABLE 4
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
26			R	63-65	3700-2200 (br), 3362, 1670, 1590, 1336, 1152	2.60(dd, J=9.0, 13.8 Hz, 1H), 2.79(dd, J=9.3, 13.8 Hz, 1H), 3.76(m, 1H)
27			R	70-71	3700-2200 br, 3372, 1674, 1531, 1348, 1310, 1161	2.66(dd, J=9.5, 13.6 Hz, 1H), 2.79(dd, J=5.4, 13.6 Hz, 1H), 3.84(m, 1H), 7.73(A2B2q, J= 8.9 Hz, 2H), 8.20(A2B2q, J=8.9 Hz, 2H), 8.72(d, J=9.0 Hz, 1H), 8.88(s, 1H), 10.7(s, 1H)
28	HOOC—CH2—		R	—	—	—
29	HOOC—CH2—CH2—		R	—	—	—
30	HOCH2—		R	192-193	3700-2400 (br), 3392, 1667, 1320, 1161	3.29(dd, J=5.7, 10.7 Hz, 1H), 3.43(dd, J= 8.4, 10.7 Hz, 1H), 3.62(m, 1H), 7.85 (A2B2q, J=8.7 Hz, 2H), 7.88(A2B2q, J=8.7 Hz, 2H), 7.98(d, J=7.8 Hz, 1H), 10.61(s, 1H)
31			R	69-70	3700-2200 (br), 1871, 1329, 1163	2.69(dd, J=7.6, 13.5 Hz, 1H), 2.93(dd, J=7.8, 13.5 Hz, 1H) , 3.77(t, J=7.6 Hz, 1H), (CD3OD)
32			R	—	—	—
33			R	160-162	3401, 3260, 1673, 1316, 1165	2.66(dd, J=7.5, 13.4 Hz, 1H), 2.96(dd, J=7.6, 14.2 Hz, 1H), 3.81(m, 1H)

 

TABLE 5
Example				mp (decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
34			R	—	—	—
35			RS	141-145	3700-2400 (br), 1672, 1443, 1327, 1094	2.84-3.21(m, 2H), 4.29(m, 1H)

 

TABLE 6
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
2			RS	159-161	3276, 2503 br, 1897 br, 1724, 1344, 1170 (Nujol)	2.95(dd, J=9.0, 14.0 Hz, 1H), 3.12 (dd, J=5.4, 14.0 Hz, 1H), 4.13 (m, 1H), 7.29(d, J=2.0 Hz, 1H), 8.34(d, J=8.6 Hz, 1H), 8.88(d, J=2.0 Hz, 1H), 12.79(br, 1H)
3			R	227-229	3386, 3305, 1747, 1363, 1323, 1161, 1135 (Nujol)	2.88(dd, J=8.0, 14.0 Hz, 1H), 3.09(dd, J=6.0, 14.0 Hz, 1H), 3.91 (m, 1H), 8.23(m, 1H), 10.79(s, 1H), 12.70(br, 1H)
4			RS	181-189	2400-3700 (br), 1734, 1484, 1327, 1160	2.75-3.06(m, 2H), 3.69(s, 3H), 3.90(m, 1H)
5			RS	198-200	3446, 3065, 1594, 1397, 1303, 1154, 1094	3.17(dd, J=7.4, 13.8 Hz, 1H), 3.57 (dd, J=5.5, 13.9 Hz, 1H), 3.80(t, J=5.6 Hz, 1H), 8.11(d, J=7.4 Hz, 1H)
6			R	213-215	3184, 1723, 1337, 1317, 1156	2.77(dd, J=9.7, 13.7 Hz, 1H), 3.03(dd, J=4.9, 13.3 Hz, 1H), 3.93 (m, 1H), 8.38(d, J=8.8 Hz, 1H)
7	CF3CH2—		R	176-177	3276, 1706, 1344, 1260, 1165	2.40-2.90(m, 2H), 4.05(m, 1H), 8.51(d, J=9.0 Hz, 1H), 13.2(br, 1H)
8			RS	153-156	3289, 1739, 1326, 1159, 1089	1.83(m, 2H), 2.52(m, 2H), 3.70(m, 1H), 8.32(d, J=9.0 Hz, 1H)
11			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, 13.8 Hz, 1H), 4.15(m, 1H), 5.54(m, 1H)

 

TABLE 7
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
13			RS	212-213	3113, 1724 1520, 1345, 1158	2.86(dd, J=10.2, 13.2 Hz, 1H), 3.14(dd, J=4.5, 13.7 Hz, 1H), 4.02(m, 1H), 8.42(d, J=8.4 Hz, 1H)
14			RS	164-165	3426, 3114, 1715, 1509, 1224, 1159	2.71(dd, J=9.9, 13.7 Hz, 1H), 2.96 (dd, J=5.3, 13.5 Hz, 1H), 3.89(m, 1H), 8.34(d, J=9.0 Hz, 1H)
15			R	85-87	2919, 1688, 1448, 1335, 1326, 1169	0.52-1.72(m, 13 H), 3.68(m, 1H), 8.20(br. s, 1H)
16			RS	179-183	3432, 3294, 1713, 1482, 1341, 1159	2.80-3.12(m, 2H), 3.61(s, 3H), 3.94(m, 1H), 8.30(d, J=8.6 Hz, 1H)
17			RS	115-120	3419, 3397, 3291, 1736, 1482, 1336, 1321, 1165	2.28(s, 3H), 2.78-3.10(m, 2H), 3.91 (m, 1H), 8.29(d, J=8.3 Hz, 1H)
18			RS	208-211	3407, 3285 1751, 1735 1703, 1486, 1321, 1162	2.80-3.10(m, 2H), 3.92(m, 1H), 8.29(d, J=8.2 Hz, 1H)
20			RS	197-205	2600-3700 br, 1635, 1594, 1335, 1163, 1095	2.60-3.04(m, 2H), 3.98(m, 1H)
21			RS	196-199	2200-3700 br, 1713 br, 1345, 1125	3.24-3.56(m, 2H), 4.34(m, 1H)

 

TABLE 8
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
22			RS	141-143	3335, 3246, 1732, 1315, 1152	4.10(d, J=3.2 Hz, 1H), 5.13(d, J= 3.2 Hz, 1H)
23			R	211-214	3316, 1734, 1325, 1159 (Nujol)	4.94(d, J=9.4 Hz, 1H), 8.80(d, J= 9.4 Hz, 1H), 13.0(br. s, 1H)
28	HOOC—CH2—		R	171-173	3353, 1752, 1326, 1155, 1098	2.45(dd, J=6.2, 16.4 Hz, 1H), 2.63(dd, J=6.6, 16.4 Hz, 1H)
29	HOOC—CH2—CH2—		R	185-187	3270, 1709, 1336, 1159, 1093	1.68(dd, J=7.9, 14.1 Hz, 1H), 1.87(dd, J=6.0, 13.4 Hz, 1H), 2.22(t, J=7.2 Hz, 2H), 3.80(m, 1H)
30	HOCH2—		R	277-279	2200-3700 br, 3430, 3292, 1726, 1324, 1162	3.51(dd, J=6.0, 12.9 Hz, 1H), 3.55(dd, J=5.4, 12.9 Hz, 1H), 3.80(m, 1H), 8.06(d, J=8.7 Hz, 1H)
31			R	89-91	2200-3700 br, 3432, 3289, 1733, 1330, 1165	3.54(dd, J=4.8, 9.9 Hz, 1H), 3.60(dd, J=5.7, 9.9 Hz, 1H), 4.04(m, 1H), 4.39(s, 2H), 8.34(d, J=8.1 Hz, 1H)
32			R	>270	3319, 3052 1701, 1317, 1284, 1162	2.81 (dd, J=9.7, 13.7 Hz, 1H), 3.05(dd, J=4.8, 13.4 Hz, 1H), 3.96(m, 1H), 8.40(d, J=9.0 Hz, 1H), 12.88(br. s, 1H)

 

TABLE 9
				mp
Example				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
34			R	243-246	3420, 1588, 1402, 1324, 1151	3.06(dd, J=5.4, 14.4 Hz, 1H), 3.14(dd, J=5.1, 14.4 Hz, 1H), 3.65(t, J=5.4 Hz, 1H), 6.92(m, 1H), 10.72(s, 1H)
35			RS	151-156	2200-3700 br, 1734, 1334, 1161	3.17-3.50(m, 2H), 4.51(m, 1H)

 

TABLE 10
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
36			RS	>145	1726, 1354 1326, 1161	—
37			RS	—	1732, 1594 1404, 1155	—
38			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			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			R	149-152	1685, 1349 1166	—
41			R	104-107	1725, 1599 1372, 1173	—
42			R	167-169	1745, 1653 1391, 1147	—
43	(CH3)2CH—		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
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
44	(CH3)2CH—		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—		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:7.58
46	(CH3)2CH—		R	157-159	1670, 1375 1148	—
47	(CH3)2CH—		R	175-176	1717, 1694 1349, 1165	—
48	(CH3)2CH—		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—		R	183-186	1681, 1319 1162	—
50			R	183-184	1725, 1340 1159	—
51			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
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
52			R	157-160	1685, 1349 1166	—
53			R	111-112	1691, 1567 1390, 1159	—
54			R	194-195	1749, 1592 1323, 1164	—
55	(CH3)2CH—		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			R	108-110	1649, 1337 1165	—
57			R	187-190	1588, 1308 1141	—
58			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			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
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
60			R	foam	3700-2400 br, 3277, 1669, 1325, 1152	2.60(dd, J=8.7, 13.7 Hz, 1H), 2.79(dd, J=6.0, 13.7 Hz, 1H), 3.75(ddd, J=6.0, 8.7, 9.0, 1H), 6.94(d, J=8.9 Hz, 2H)
61			R	115-118	3302, 1667, 1324, 1153 (Nujol)	2.71 (dd, J=7.0, 14.4 Hz, 1H), 2.96(dd, J=7.0, 14.2 Hz, 1H), 3.78(t, J=7.6 Hz, 1H)
62			S	—	3406, 1670, 1582, 1325, 1153	2.71 (dd, J=7.9, 14.4 Hz, 1H), 2.96(dd, J=7.6, 14.4 Hz, 1H), 3.78(dd, J=7.2, 7.3 Hz, 1H)
63	(CH3)2CH—		R	149-151	3268, 1634, 1584, 1336, 1157	0.76(d, J=6.6 Hz, 6H), 1.77(m, 1H), 3.26(m, 1H)
64			RS	—	3314, 1669, 1582, 1420, 1328, 1154	2.71 (dd, J=7.9, 14.2 Hz, 1H), 2.93(dd, J=6.5, 14.3 Hz, 1H), 3.65(s, 3H), 3.78(dd, J=7.1, 7.2 Hz, 1H)
65			RS	—	3405, 1671, 1582, 1487, 1324, 1154	2.34(s, 3H), 2.65(dd, J=7.8, 14.1 Hz, 1H), 2.93(dd, J=7.6, 14.4 Hz, 1H), 3.75(dd, J=6.8, 7.7 Hz, 1H)
66			RS	—	3317, 1670 1582, 1488, 1323, 1153	2.71 (dd, J=8.9, 14.4 Hz, 1H), 2.89(dd, J=6.6, 14.4 Hz, 1H), 3.75(dd, J=6.5, 6.8 Hz, 1H)
67			RS	—	3421, 1702, 1676, 1582, 1354, 1328, 1153	2.54(s, 3H), 2.69-2.89(m, 2H), 3.87(m, 1H)

 

TABLE 14
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No	R1	R18	*	(° C.)	(KBr)	d6-DMSO
60			R	108-109	2400-3600 br, 3345, 3213, 1735, 1700, 1346, 1163	2.72(dd, J=8.7, 13.6 Hz, 1H), 2.94(dd, J=5.6, 13.6 Hz, 1H), 3.84(ddd, J=5.6, 8.7, 8.7 Hz, 1H), 8.23(d, J=8.7 Hz, 1H)
61			R	82-87	3410, 3276, 1724, 1582, 1488, 1331, 1152 (Nujol)	2.88(dd, J=7.4, 15.2 Hz, 1H), 3.07(dd, J=6.2, 14.4 Hz, 1H), 3.83(m, 1H), 8.08(m, 1H), 10.80(s, 1H), 12.70(br, 1H)
62			S	foam	3412, 1724, 1582, 1488, 1332, 1152	2.81-3.12(m, 2H), 3.88(m, 1H), 8.19(d, J=8.4 Hz, 1H)
63	(CH3)2CH—		R	137-138	3154, 1720, 1688, 1583, 1488, 1251	0.89(d, J=7.0 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 2.12(m, 2H), 3.80(dd, J= 4.7, 9.7 Hz, 1H), 5.17(d, J=9.6 Hz, 1H)
64			RS	—	3273, 1724, 1582, 1487, 1331, 1198, 1153	2.78-3.10(m, 2H), 3.67(s, 3H), 3.88(m, 1H)
65			RS	—	3409, 3281, 1725, 1582, 1331, 1197, 1153	2.34(s, 3H), 2.75-3.08(m, 2H), 3.86(m, 1H), 8.19(d, J=8.4 Hz, 1H)
66			RS	—	3415, 1725, 1582, 1488, 1329, 1196, 1174, 1152	2.78-3.08(m, 2H), 3.85(m, 1H), 8.18(d, J=8.6 Hz, 1H)
67			RS	236-237	3296, 1742, 1647, 1604, 1581, 1342, 1334, 1152	2.55(s, 3H), 2.79-3.11(m, 2H), 3.98(m, 1H)

 

TABLE 15
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
68			R	>240	1608, 1590 1507, 1232 1157	—
69			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			RS	—	1733, 1583 1150	—

 

TABLE 16
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
71			R	129-131	3700-2400 br, 3247, 1636, 1337, 1160	0.90(t, J=6.8 Hz, 3H), 1.22-1.40(m, 4H), 1.52-1.67(m, 2H), 2.62(t, J=7.7 Hz, 2H), 2.86(dd, J=8.4, 13.7 Hz, 1H), 3.02(dd, J=5.7, 13.7 Hz, 1H)(CDCl3)
72		CH3(CH2)7—	R	oil	3700-2400 br, 1663, 1320, 1145 (film)	0.87(t, J=6.3 Hz, 3H), 2.50(t, J=7.4 Hz, 2H), 2.76(dd, J=9.6, 14.0 Hz, 1H), 2.87 (dd, J=5.8, 14.0 Hz, 1H), 3.84(dd, J= 5.8, 9.6 Hz, 1H)
73		CH3(CH2)3—	R	oil	3600-2400 br, 3262, 1673, 1321, 1142 (CHCl3)	0.79(t, J=7.0 Hz, 3H), 2.32-2.56(m, 2H), 2.92(m, 1H), 3.26(m, 1H)
74			R	—	—	—
75			R	85-86	3700-2200 (br), 3262, 1839, 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 (A2B2q, J=7.5 Hz, 2H), 7.42 (A2B2q, J=7.5 Hz, 2H)(CDCl3)
76			R	—	—	—

 

TABLE 17
Exam-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
77			R	138-139	3700-2400(br), 3312, 1629, 1329, 1144	2.79(dd, J=8.5, 13.4 Hz, 1H), 2.89(dd, J=6.0, 13.4 Hz, 1H), 3.81(dd, J=6.0, 8.5 Hz, 1H), 6.55(d, J=15.5 Hz, 1H)
78			R	69-70	3700-2200(br), 1670 1318, 1152	2.78(dd, J=8.6, 13.4 Hz, 1H), 2.91(dd, J=6.0, 13.4 Hz, 1H), 3.92(ABq, J= 13.5 Hz, 1H), 3.90(m, 1H), 9.01(s, 1H), 10.78(s, 1H)
79			R	—	—	—

 

TABLE 18
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
71			R	121-122	2300-3700 br, 3426, 3318, 1713, 1330, 1159	0.89(t, J=6.7 Hz, 3H), 2.62(t, J=7.6 Hz, 2H), 2.96(dd, J=7.0, 13.9 Hz, 1H), 3.10 (dd, J=5.4, 13.9 Hz, 1H), 4.19(dt, J= 6.9, 8.2 Hz, 1H), 5.30(d, J=8.2 Hz, 1H)
72		CH3(CH2)7—	R	oil	2400-3600 br, 3340, 1736, 1334, 1142 (CHCl3)	0.88(t, J=6.9 Hz, 3H), 2.55-2.73(m, 2H), 2.97(dd, J=8.4, 13.8 Hz, 1H), 3.24(dd, J=4.8, 13.8 Hz, 1H), 4.35(m, 1H), 4.98(m, 1H) (CDCl3)
73		CH3(CH2)3—	R	89-90	2300-3700 br, 3240, 1725, 1341, 1144	0.84(t, J=7.1 Hz, 3H), 2.57-2.70(m, 2H), 2.97(dd, J=8.4, 13.9 Hz, 1H), 3.25(dd, J=4.8, 13.9 Hz, 1H), 4.35 (m, 1H), 4.96(d, J=9.6 Hz, 1H) (CDCl3)
74			R	>250	3421, 1580, 1333, 1421, 1153	2.41(s, 3H), 3.01(dd, J=6.0, 14.4 Hz, 1H), 3.12(dd, J=4.5, 14.4 Hz, 1H), 3.67(t, J= 5.4 Hz, 1H), 6.79(m, 1H), 6.89(m, 1H), 10.59(s, 1H)
76			R	foam	3413, 1594, 1458, 1416, 1157	3.03(dd, J=6.5, 15.1 Hz, 1H), 3.15 (dd, J=4.7, 14.1 Hz, 1H), 3.64(t, J=5.1 Hz, 1H), 10.86(s, 1H)
77			R	—	2400-3700 br, 3252, 1765, 1725, 1301, 1140	2.81(dd, J=9.2, 13.7 Hz, 1H), 3.03(dd, J= 5.4, 13.7 Hz, 1H), 3.94(dt, J=5.4, 9.2 Hz, 1H), 6.66(d, J=15.2 Hz, 1H), 7.16 (d, J=15.2 Hz, 1H), 8.01(d, J=9.2 Hz, 1H)
78			R	—	2200-3700 br, 3288, 1726, 1321, 1152 (film)	2.81 (dd, J=9.2, 13.7 Hz, 1H), 3.00(dd, J= 5.6, 13.7 Hz, 1H), 4.01(ABq, J=13.7 Hz, 2H), 4.01(m, 1H), 7.65(d, J=8.3 Hz, 1H)
79			R	—	3413, 2931, 1720 1585, 1455, 1421, 1313, 1144	0.90-1.68(m, 9H), 1.78(m, 1H), 2.74 (m, 1H), 3.00-3.20(m, 2H), 3.77(m, 1H), 6.45(br. s, 1H), 6.77(br. s, 1H)

 

TABLE 19
				mp
Example				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
80			R	153-155	1704, 1596 1349, 1164	—
81		n-C8H17—	R	>130	1576, 1356 1139	—
82			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			R	210-214	1745, 1590 1316, 1157	—
84			R	198-200	1594, 1456 1200, 1188	—

 

TABLE 20
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
85			R	157-160	3700-2400 br, 3273, 1633, 1338, 1166	2.65(dd, J=8.9, 13.6 Hz, 1H), 2.82(dd, J=6.6, 13.6 Hz, 1H), 3.86(m, 1H), 7.75(d, J=7.8 Hz, 2H), 7.87(d, J=8.7 Hz, 2H)
86			R	138-142	3700-2400 br, 2921, 1672, 1314, 1165	2.62(dd, J=8.6, 13.5 Hz, 1H), 2.81(dd, J=6.5, 13.6 Hz, 1H), 3.09(s, 6H), 3.83(m, 1H), 6.86 (d, J=9.0 Hz, 2H), 7.83(d, J=8.8 Hz, 2H)
87			S	206-207	3700-2400 (br), 3357, 1686, 1641, 1314, 1155	2.57(dd, J=8.3, 13.6 Hz, 1H), 2.79(dd, J=6.0, 13.6 Hz, 1H), 3.78(m, 1H), 8.02(d, J=8.7 Hz, 1H), 8.80(s, 1H), 8.85(d, J=1.7 Hz, 1H), 9.06(s, 1H), 10.59(d, J=1.7 Hz, 1H)

 

TABLE 21
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
85			R	172-174	2400-3600 br, 3426, 3296, 1698, 1350, 1167	2.75(dd, J=9.1, 13.7 Hz, 1H), 2.98(dd, J=5.5, 13.7 Hz, 1H), 3.96(ddd, J=5.5, 9.1, 9.1 Hz, 1H), 8.51 (d, J=9.1 Hz, 1H)
86			R	93-93	2200-3700 br, 3431, 1735, 1391, 1154	2.74(dd, J=9.1, 13.6 Hz, 1H), 2.96(dd, J=5.7, 13.6 Hz, 1H), 3.09(s, 6H), 3.93(dt, J=5.7, 9.1 Hz, 1H), 8.39(d, J=9.1 Hz, 1H)
87			S	203-204	2300-3700 br, 3358, 3262, 1718, 1686, 1660, 1313, 1159	2.71(dd, J=9.1, 13.7 Hz, 1H), 2.93(dd, J=5.6, 13.7 Hz, 1H), 3.84(dt, J=5.6, 9.1 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 8.78(s, 1H), 9.06(s, 1H)

 

TABLE 22
Example
No.	R1	R18	*
88			R
89	(CH3)2CH—		R
90	(CH3)2CH—		R
91			R
	Example	mp (decomp.)	IR (ν cm−1)	Elemental
	No.	(° C.)	(KBr)	analysis
	88	103-106	1719, 1390	—
			1229
	89	96-99	1734, 1461	C17H20N2O6S2.0.9Ethylether
			1327, 1158	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	110-112	1724, 1325	C16H21N3O6S2.0.8Ethylether
			1168	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	98-101	1735, 1598	C21H19BrN2O6S2.0.5CF3COOH
			1327, 1185	Calc. C:44.30 H:3.30 Br:13.40 N:4.70 S:10.75
				Foun. C:44.62 H:3.52 Br:13.07 N:4.64 S:10.85

 

EXAMPLE 92

(Method B)

 

Process 1

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

Yield 82%. 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 C₁₅H₂₁NO₅S₂.0.2H₂O; 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.

EXAMPLES 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
Example
No.	R1	R18	*
93			R
94			R
95			R
96			R
97			R
98			R
99			R
100			R
	Example	mp (decomp.)	IR (ν cm−1)	Elemental
	No.	(° C.)	(KBr)	analysis
	93	165-170	1590, 1316,	—
			1137
	94	223-226	1747, 1323	C26H22N2O5S
			1134	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	216-218	1724, 1325	—
			1135
	96	111-114	1739, 1336	—
			1163
	97	178-180	1710, 1511	—
			1329, 1161
	98	105-108	1725, 1618	—
			1373, 1163
	99	>250	1706, 1606	C26H20N2O6S.0.4H2O
			1350, 1164	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	176-177	1735, 1633	C25H21N3O4S.0.8H2O
			1321, 1173	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
Example
No.	R1	R18	*
101			R
102			R
103			R
104			R
105	(CH3)2CH—		R
106	(CH3)2CH—		R
107	(CH3)2CH—		R
108	(CH3)2CH—		R
	Example	mp (decomp.)	IR (ν cm−1)	Elemental
	No.	(° C.)	(KBr)	analysis
	101	227-229	1736, 1618	C26H22N2O4S.0.2H2O
			1398, 1168	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	230-233	1735, 1654	—
			1399, 1164
	103	234-236	1732, 1631	—
			1372, 1148
	104	>200	1600, 1558	—
		decomp.	1336, 1171
	105	146-149	1795, 1718	—
			1331, 1166
	106	231-232	1719, 1595	C19H18N2O6S.0.1H2O
			1344, 1167	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	166-169	1728, 1631	—
			1372, 1148
	108	163-165	1728, 1332	—
			1172

 

TABLE 25
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
109	(CH3)2CH—		R	187-189	1720, 1656 1319, 1165	—
110	(CH3)2CH—		R	111-114	1724, 1635 1366, 1158	—
111	(CH3)3C—		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—		R	157-159	1732, 1680 1329, 1167	—
113			R	133-136	1735, 1651 1348, 1165	—
114			R	183-185	1727, 1604 1335, 1182	—
115			R	166-168	1725, 1663 1399, 1197	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—		R	163-165	1728, 1332 1172	—

 

TABLE 26
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
117	(CH3)2CH—		R	187-189	1720, 1656 1319, 1165	—
118			R	111-114	1724, 1635 1366, 1158	—
119			R	167-169	1585, 1318 1153	—
120			R	—	1605, 1523 1340, 1151	—
121			R	—	1604, 1524 1336, 1173	—
122			R	103-106	1721, 1620 1339, 1163	—
123			R	180-182	1729, 1675 1340, 1168	—
124	(CH3)2CH—		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:15.98

 

TABLE 27
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
125	(CH3)2CH—		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—		R	154-156	1710, 1499 1358, 1165	—
127			R	149-150	1695, 1334 1184	C22H19NO5S20.2H2O 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			R	161-164	1710, 1329 1180	—
129			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			R	—	—	—
131			R	—	—	—
132			R	—	—	—

 

TABLE 28
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	Elemental
No.	R1	R18	*	(° C.)	(KBr)	analysis
133			R	—	—	—
134			R	—	—	—
135			R	—	—	—
136			R	—	—	—
137			R	—	—	—
138			R	—	—	—
139			R	—	—	—
140			R	—	—	—

 

TABLE 29
				mp
Example				(decomp.)	IR (ν cm−1)
No	R1	R18	*	(° C.)	(KBr)	Elemental analysis
141			R	—	—	—
142			R	—	—	—
143			R	—	—	—
144			R	—	—	—
145			R	—	—	—
146			R	—	—	—
147			R	—	—	—
148			R	—	—	—

 

TABLE 30
Example				mp (decomp.)	IR (ν cm−1)
No	R1	R18	*	(° C.)	(KBr)	Elemental analysis
149			R	—	—	—
150			R	—	—	—
151			R	—	—	—
152			R	—	—	—
153			R	—	—	—
154			R	—	—	—
155			R	—	—	—
156			R	—	—	—

 

EXAMPLES 157, 158

 

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^{31 1}): 3600-2300 br, 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.)

EXAMPLE 159

(Method C)

 

Process 1

To a solution of 500 mg (1.4 mmol) of compound(XVII-2) which was obtained Example 96 in 12 ml of dry tetrahydrofuran was added 387 mg (2×1.4 mmol) of powdery potassium carbonate, 319 mg (1.5×1.4 mmol) of 4-methoxyphenylboronic acid and 81 mg (0.05×1.4 mmol) of tetrakis(triphenylphosphine)palladium. The resulting mixture was stirred under argon atmosphere for 48 h at 75° C. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1N HCl, 5% 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; 6.52, N; 3.65, S; 16.72. Found: C; 53.26, H; 5.50, N; 3.69, S; 16.63.

[α]_D−21.7±0.6 (c=1.000 DMSO 25° C.)

IR (KBr, ν max cm⁻¹): 1735, 1605, 1505, 1350, 1167, 1136.

NMR (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.

EXAMPLES 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
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)
No.	R1	R18	*	(° C.)	(KBr)	Elemental analysis
160			R	93-96	1667, 1337 1180	—
161			R	157-159	1670, 1339 1194	—
162			R	168-171	1725, 1598 1371, 1185	—
163			R	226-230	1735, 1341 1159	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—		R	174-176	1735, 1503 1343, 1163	—
165	(CH3)2CH—		R	165-167	1713, 1353 1163	—
166	(CH3)2CH—		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—		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
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)
No.	R1	R18	*	(° C.)	(KBr)	Elemental analysis
168			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			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:15.88
170			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			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			R	—	—	—
173			R	—	—	—
174			R	—	—	—
175			R	—	—	—

 

EXAMPLE 176

(Method D)

 

Process 1

To a solution of 10 g (47.68 mmol) of D-valine tert-butyl ester hydrochloride (XV-3) in 100 ml of dichloromethane was added 15.7 ml (3×47.68 mmol) of N-methylmorpholine and 14.1 g (1.2×47.68 mmol) of 4-nitrobenzenesulfonyl chloride under ice-cooling. After being stirred for 5 h at room temperature the reaction mixture was washed with 2N HCl, 5% 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 C₁₅H₂₂N_2O6S; 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): 3430 br, 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_{20 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; 16.06

EXAMPLES 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
Example
No.	R1	R18	*
177			R
178			R
179			R
180			R
181			R
182			R
183			R
184			R
	Example	mp (decomp.)	IR (ν cm−1)
	No.	(° C.)	(KBr)	Elemental analysis
	177	215-217	1732, 1641	—
			1341, 1163
	178	233-234	1726, 1655	C25H23N3O6S.0.9H2O
			1323, 1177	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	216-218	1723, 1633	—
			1361, 1149
	180	211-213	1719, 1629	C24H20N4O7S.1.1H2O
			1340, 1156	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	236-238	1732, 1653	C26H26N4O5S.0.9H2O
			1399, 1199	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	240-244	1731, 1656	C25H23N3O5S.0.9H2O
			1591, 1327	Calc. C:60.82 H:5.06 N:8.51 S:6.49
			1160	Foun. C:60.83 H:5.19 N:8.66 S:6.66
	183	215-218	1727, 1668	C24H20BrN3O5S.0.6H2O
			1590, 1316	Calc. C:52.11 H:3.86 Br:14.44 N:7.60 S:5.80
			1154	Foun. C:52.13 H:4.04 Br:14.57 N:7.43 S:5.70
	184	244-249	1728, 1653	C25H23N3O5S2.0.7H2O
			1593, 1323	Calc. C:57.50 H:4.71 N:8.05 S:12.28
			1159	Foun. C:57.63 H:4.79 N:8.00 S:12.08

 

TABLE 34
Example
No.	R1	R18	*
185			R
186			R
187			R
188			R
189			R
190			R
191			R
192			R
	Example	(mp decomp.)	IR (ν cm−1)
	No.	(° C.)	(KBr)	Elemental analysis
	185	170-175	1730, 1651,	C24H20FN3O5S.0.6H2O
			1603, 1333	Calc. C:58.55 H:4.34 F:3.86 N:8.54 S:6.51
			1161	Foun. C:58.67 H:4.51 F:3.77 N:8.42 S:6.47
	186	237-239	1723, 1851	C23H22N2O6S
			1591, 1322	Calc. C:60.78 H:4.88 N:6.16 S:7.05
			1161	Foun. C:60.50 H:4.99 N:6.14 S:7.31
	187	235-239	1719, 1672	C22H19N3O7S
			1593, 1327	Calc. C:56.29 H:4.08 N:8.95 S:6.83
			1159	Foun. C:56.01 H:4.09 N:8.93 S:6.75
	188	114-115	1748, 1658	C22H20N2O5S.0.5CF3COOH
			1592, 1325	Calc. C:57.37 H:4.29 N:5.82 S:6.66
			1159	Foun. C:57.53 H:4.45 N:5.75 S:7.11
	189	242-243	1743, 1670	C22H19BrN2O5S.CF3COOH
			1591, 1335	Calc. C:46.69 H:3.27 Br:12.94 N:4.54 S:5.19
			1167	Foun. C:46.79 H:3.41 Br:12.86 N:4.57 S:5.37
	190	242-244	1752, 1726	C23H22N2O5S
			1656, 1591	Calc. C:63.00 H:5.06 N:6.39 S:7.31
			1324, 1160	Foun. C:62.70 H:5.13 N:6.36 S:7.36
	191	232-235	1742, 1667	C23H22N2O5S2.0.8CF3COOH
			1591, 1334	Calc. C:52.59 H:4.09 N:4.99 S:11.42
			1161	Foun. C:52.77 H:4.24 N:5.12 S:11.58
	192	218-220	1737, 1651	C22H19FN2O5S
			1598, 1324	Calc. C:59.72 H:4.33 F:4.29 N:6.33 S:7.25
			1160	Foun. C:59.59 H:4.42 F:4.30 N:6.37 S:7.24

 

TABLE 35
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)
No.	R1	R18	*	(° C.)	(KBr)	Elemental analysis
193			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			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—		R	254-256	1748, 1659 1590, 1324 1161	C24H24N2O5S.0.5H2O Calc. C:62.46 H:5.46 N:6.07 S:6.95 Foun. C:62.42 H:5.54 N:6.26 S:6.97
196	(CH3)2CH—		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—		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—		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—		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—		R	220-221	1696, 1654 1591, 1317 1255	C19H22N2O6S.0.2H2O Calc. C:55.65 H:5.51 N:6.83 S:7.82 Foun. C:55.63 H:5.48 N:7.03 S:7.75

 

TABLE 36
Example
No.	R1	R18	*
201	(CH3)2CH—		R
202	(CH3)2CH—		R
203	(CH3)3C—		R
204			R
205			R
206			R
207			R
208			R
	Example	mp (decomp.)	IR (ν cm−1)
	No.	(° C.)	(KBr)	Elemental analysis
	201	240-242	1726, 1688	C18H19N3O7S.0.4H2O
			1591, 1347	Calc. C:50.44 H:4.66 N:9.80 S:7.48
			1166	Foun. C:50.40 H:4.55 N:9.90 S:7.44
	202	229-230	1726, 1663	C18H19BrN2O5S.0.2Ethylether
			1592, 1318	Calc. C:48.03 H:4.50 Br:17.00 N:5.96 S:6.82
			1159	Foun. C:48.04 H:4.61 Br:16.83 N:5.96 S:6.86
	203	214-216	1659, 1591	C20H24N2O6S.0.4H2O
			1316, 1159	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	236-237	1723, 1679	C21H20N4O5S.0.25CF3COOH
			1590, 1337	Calc. C:55.06 H:4.35 N:11.95 S:6.84
			1162	Foun. C:54.80 H:4.90 N:12.16 S:7.10
	205	272-275	1719, 1672	C21H19N3O5S
			1594, 1339	Calc. C:59.28 H:4.50 N:9.88 S:7.54
			1165	Foun. C:58.84 H:4.56 N:9.71 S:7.36
	206	214-215	1733, 1685	C20H19N3O6S
			1594, 1319	Calc. C:55.94 H:4.46 N:9.78 S:7.47
			1154	Foun. C:55.50 H:4.47 N:9.74 S:7.31
	207	217-220	1732, 1679	—
			1592, 1312
			1155
	208	—	—	—

 

EXAMPLE 209

(Method E)

 

Process 1

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

Yield85%. mp. 118-120° C.

IR (KBr, ν max cm^{31 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 (CDCl_{3 67 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 collect 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^{31 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

EXAMPLES 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
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
210			R	—	—	—
211			R	194-195	3700-2200 (br), 3278, 1634, 1337, 1160	2.65(dd, J=9.3, 13.1 Hz, 1H), 2.82(dd, J=5.8, 13.1 Hz, 1H), 3.86(dt, J=5.8, 9.3 Hz, 1H), 7.72(A2B2q, J=8.1 Hz, 2H), 8.19(A2B2q, J=8.1 Hz, 2H), 8.49(d, J=9.3 Hz, 1H), 8.88(s, 1H), 10.69(s, 1H)

 

TABLE 38
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)	1H-NMR (δ ppm)
No.	R1	R18	*	(° C.)	(KBr)	d6-DMSO
210			R	—	—	—
211			R	215-216	2400-3700 br, 3422, 3337, 1733, 1698, 1347, 1170	2.75(dd, J=9.3, 13.7 Hz, 1H), 2.99(dd, J=5.3, 13.7 Hz, 1H), 3.96(dt, J=5.3, 9.3 Hz, 1H), 8.53(d, J=9.3 Hz, 1H)

 

TABLE 39
Example
No.	R1	R18	*
212			RS
213			RS
214	(CH3)2CHCH2—		R
215	(CH3)2CH—		R
216			RS
217			R
218			RS
219			R
	Example	mp (decomp.)	IR (ν cm−1)
	No.	(° C.)	(KBr)	Elemental analysis
	212	199-202	1734, 1337	C25H22N6O4S.0.5Ethylether
			1161	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	224-225	1728, 1338	C24H19FN6O4S.0.4Ethylether
			1166	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:5.68
	214	202-204	1720, 1595	C19H21N5O4S
			1338, 1170	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	221-222	1696, 1594	C18H19N5O4S
			1349, 1173	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	145-148	1727, 1337	—
			1163
	217	203-205	1735, 1495	C28H23N5O4S.0.6H2O
			1336, 1160	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	225-227	1721, 1418	C26H21N5O4S.0.2H2O
			1344, 1163	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	111-114	1727, 1703	C25H20N6O5S.H2O
			1459, 1332	Calc. C:56.17 H:4.15 N:15.72 S:6.00
			1165	Foun. C:56.20 H:4.18 N:15.68 S:6.10

 

TABLE 40
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)
No.	R1	R18	*	(° C.)	(KBr)	Elemental analysis
220			R	195-196	1749, 1719 1331, 1165	C25H22N6O5S Calc. C:57.91 H:4.28 N:16.21 S:6.18 Foun C:57.77 H:4.29 N:16.01 S:6.37
221	CH3CH2(CH3)CH—		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—		R	204-207	1729, 1693	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—		R	190 decomp.	1718, 1601 1385, 1162	—
224	(CH3)2CH—		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—		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—		R	204-207	1698, 1344 1168	—
227			R	203-205	1757, 1738 1331, 1163	—

 

TABLE 41
Ex-
am-				mp
ple				(decomp.)	IR (ν cm−1)
No.	R1	R18	*	(° C.)	(KBr)	Elemental analysis
228			R	197-199	1744, 1325 1154	—
229			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:10.69 N:13.66 S:6.31
230			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			R	205-207	1730, 1509 1236, 1165	C22H18FN5O4S.0.2H2O Calc. C:56.09 H:3.94 F:4.03 N:14.87 S:6.81 Foun. C:56.10 H:4.09 F:4.12 N:14.84 S:7.08
232			R	204-206	1730, 1493 1346, 1164	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			R	226-227	1732, 1697 1509, 1373 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			R	214-216	1732, 1697 1345, 1188	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			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
Example
No.	R1	R18	*
236			R
237			R
238			R
239			R
240			R
241			R
242	(CH3)2CH—		R
243	(CH3)2CH—		R
	Example	mp (decomp.)	IR (ν cm−1)
	No.	(° C.)	(KBr)	Elemental analysis
	236	224-226	1738, 1328	C26H27N5O4S
			1314, 1149	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	225-227	1739, 1512	C28H29N5O4S.0.3H2O
			1329, 1178	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	182-184	1587, 1506	—
			1242, 1159
	239	226-228	1713, 1514	—
			1341, 1159
	240	205-207	1744, 1716	C24H19BrN6O4S.1.7H2O
			1490, 1327	Calc. C:48.20 H:3.78 Br:13.36 N:14.05 S:5.36
			1159	Foun. C:48.27 H:3.75 Br:13.16 N:14.11 S:5.38
	241	199-201	1718, 1685	C25H22N6O4S.0.6H2O
			1334, 1170	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	206-207	1716, 1346	C19H21N5O4S.0.8H2O
			1165	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	208-209	1746, 1726	C18H18FN5O4S.0.2H2O
			1715, 1334	Calc. C:51.11 H:4.38 F:4.49 N:16.55 S:7.58
			1159	Foun. C:50.90 H:4.37 F:4.89 N:16.28 S:7.46

 

TABLE 43
Example
No.	R1	R18	*
244	(CH3)2CH—		R
245	(CH3)2CH—		R
246			R
247			R
248			R
249			R
250			R
251			R
	Example	mp (decomp.)	IR (ν cm−1)
	No.	(° C.)	(KBr)	Elemental analysis
	244	223-225	1696, 1348	—
			1171
	245	194-195	1720, 1343	C19H21N5O4S2.1.1H2O
			1166	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	222-224	1753, 1497	C23H21N5O4S2.0.2H2O
			1325, 1165	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	213-216	1718, 1677	C25H22N6O4S2.1.1H2O
			1495, 1333	Calc. C:54.16 H:4.40 N:15.16 S:11.57
			1170	Foun. C:54.20 H:4.66 N:15.09 S:11.62
	248	>220	1698, 1430	C18H16N6O4S.0.4H2O
			1327, 1163	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	—	—	—
	250	—	—	—
	251	—	—	—

 

EXAMPLES 252-266

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

TABLE 44
	(I)
Example
No.	R1	R18	R19	R20
252	(CH3)2CH—		—CH3	—COOH
253	(CH3)2CH—		—CH3	—CONHOH
254	(CH3)2CH—			—CONHOH
255	(CH3)2CH—		—(CH2)4NH2	—COOH
256	(CH3)2CH—		—CH3	—COOH
257	(CH3)2CHCH2—		—CH3	—COOH
258				—COOH
259	(CH3)2CH—		—CH3	—COOH
			mp	IR	1H-NMR
	Example		(decomp.)	(ν em−1)	(δ ppm)
	No.	*	(° C.)	(KBr)	d6-DMSO
	252	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	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	R	148-150	3344, 1684 1323, 1149	0.55(d, J=6.8Hz, 3H) 0.82(d, 6.6Hz, 3H) 3.74(s, 3H)
	255	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	R	206-207	3300-2400br 1711, 1336 1165	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	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	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	R	141-144	3284br, 1745 1714, 1323 1131	0.96(d, J=6.4Hz, 3H) 0.97(d, J=6.4Hz, 3H) 2.52(s, 3H), 2.93(s, 3H)

 

TABLE 45
	(I)
Example
No.	R1	R18	R19	R20
260	(CH3)2CH—			—COOH
261			—CH3	—COOH
262				—COOH
263			—(CH2)4NH2	—COOH
264			—CH3	—COOH
265				—COOH
266			—(CH2)4NH2	—COOH
			mp	IR	1H-NMR
	Example		(decomp.)	(ν em−1)	(δ ppm)
	No.	*	(° C.)	(KBr)	d6-DMSO
	260	R	—	3600-2400br 1718, 1344 1151	0.72(d, J=6.4Hz, 3H) 0.85(d, J=6.4Hz, 3H) 2.47(s, 3), 4.15(d, J=10.2Hz, 1H) 4.51(d, J=15.5Hz, 1H) 4.73(d, J=15.5Hz, 1H)
	261	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	R	—	—	—
	263	R	—	—	—
	264	R	—	—	—
	265	R	—	—	—
	266	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)
Ex-					mp	IR	1H-NMR
ample					(decomp.)	(ν em−1)	(δ ppm)
No.	R1	R18	R20	*	(° C.)	(KBr)	d6-DMSO
267			—CONHOH	R	156-158	3700-2400br, 3267, 2217, 1671, 1321, 1161	2.62(dd, J=8.4, 13.5Hz, 1H), 2.80(dd, J=6.0, 13.5Hz, 1H), 3.82(ddd, J=6.0, 6.4, 8.7Hz, 1H), 8.38(d, J=8.7(Hz, 1H)
267			—COOH	R	176-178	2200-3700br, 3430, 3292, 1728, 1324, 1162	2.73(dd, J=9.3, 13.6Hz, 1H), 2.96(dd, J=5.4, 13.5Hz, 1H), 3.92(dt, J=5.4, 9.3Hz, 1H), 8.42(d, J=9.3Hz, 1H)

 

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

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

Type IV collagenase (MMP-9) was purified according to the methods descrived in the following literature. Scott M. Wilhelm et al., J. Biol. Chem., 264, 17213-17221, (1989), SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV Collagenase Which Is Identical to That Secreted by Normal Human Macrophages; Yasunori Okada et al., J. Biol. Chem., 267, 21712-21719, (1992), Matrix Metalloproteinase 9 (92-kDa Gelatinase/Type IV Collagenase) from HT 1080 Human Fibrosarcoma Cells; Robin V. Ward et al., Biochem. J., (1991) 278, 179-187, The w 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-MMP9 (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 compound of the formula I;

2. A compound according to claim 1, wherein R5 is a phenyl group substituted with a halogen.

3. A compound according to claim 1, wherein R1 is an unsubstituted lower alkyl.

4. A compound according to claim 1, wherein R1 is isopropyl.

5. A compound according to claim 1, wherein Y is —OH.

6. A composition for inhibiting a metalloproteinase, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A method of inhibiting the activity of a metalloproteinase comprising administering an effective amount of a compound of the formula I:

8. A compound of the formula

9. A compound of the formula

10. A method for inhibiting a matrix metalloproteinase by administering a matrix metalloproteinase inhibiting amount of a compound of the formula

11. A method for inhibiting a matrix metalloproteinase by administering a matrix metalloproteinase inhibiting amount of a compound of the formula