MXPA00009744A

MXPA00009744A - Sulfonamide derivatives

Info

Publication number: MXPA00009744A
Application number: MXPA/A/2000/009744A
Authority: MX
Inventors: Tomio Kimura; Shigeru Ushiyama; Shoujiro Miyazaki; Keiji Ueda; Kazuhiko Tanzawa; Wataru Takasaki
Original assignee: Sankyo Company Limited
Priority date: 1998-04-03
Filing date: 2000-10-03
Publication date: 2001-12-13

Abstract

Compounds having a matrix metaloproteinase-13 inhibitory activity and an aggrecanase inhibitory activity. They are compounds represented by general formula (I) or pharmacologically acceptable salts, esters, or other derivatives thereof wherein R1 is H or NHOH;R2 is H, optionally substituted alkyl, cycloalkyl, or -AR6 (wherein A is O, -S(O)m-, or alkylene optionally interrupted by -N(R9)-;and R6 is a group represented by formula (II), (III), or (IV) [wherein X is O, S, -N(R10)-, or -C(R11)(R12)-;Y is O, CO, -S(O)n-, -N(R10)-, or -C(R11)(R12)-;R7 and R8 each is H, alkyl, COOH, optionally substituted alkyl, etc.;R9, R10, R11, and R12 each is H, alkyl, etc.;and m and n each is 0 to 2]);R3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl;R4 is optionally substituted (hetero)arylene;and R5 is optionally substituted alkyl or optionally substituted (hetero)aryl.

Description

DERIVATIVES OF SULFONAMIDE TECHNICAL FIELD The present invention relates to novel sulfonamide derivatives having excellent matrix metalloproteinase 13 inhibitory action, and aglycanase inhibitory action, and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION Conventionally, a non-steroidal anti-inflammatory drug (NSAID) is used for the treatment of osteoarthritis and chronic rheumatoid arthritis. However, such therapeutic methods are only symptomatic therapies, and there are still no drugs for etiotropic therapy that inhibit the progression of these diseases. In addition, in the field of drugs against tumors, since the drugs currently used in the clinical environment are usually associated with strong adverse side effects, there is a need for drugs that are effective, not only for the treatment of cancer, but also for the prevention of the disease and the prevention of relapses, and that cause, if at all, only slight adverse side effects.

Matrix metalloproteinase (hereinafter referred to as "MMP") is an enzyme that breaks down protein components of connective tissue. MMP-13 (collagenase 3), which is one of several subtypes of MMP, has strong decomposition activity against type II collagen, one of the main components of joint cartilage. MMP-13 is an enzyme found locally in joints, and it has been reported that its expression is elevated in the joints of patients with osteoarthritis and chronic rheumatoid arthritis, compared with that of the joints of healthy people (PG Mitchell et al. , Journal of Clinical Investigation, vol 97, 761-768, 1996, P. Reboul et al, Journal of Clinical Investigation, vol 97, 2011-2019, 1996, D. Wernicke et al., Journal of Rheumatology, vol 23 , 590-595, 1996) 11. Based on these reports, it is considered that MMP-13 plays an important role in the destruction of the cartilage matrix of the joint during the development of arthritis. In addition, it is reported that aglycan, another major component of joint cartilage, is broken down into osteoarthritis by an enzyme called aglycanase. Although the actual form of aglicanase has not been identified, it is known that this enzyme breaks down aglycan into a very characteristic sequence of Glu-373-Ala374 (JD Sandy et al., Journal of Biological Chemistry, vol 266, 8683-8685, 1990; JD Sandy et al., Journal of Biological Chemistry, vol.270, 2550-2556, 1995).

Thus, based on the above findings, it is considered that compounds that can strongly inhibit both MMP, particularly MMP-13, and aglycanase, are useful as therapeutic and preventive agents against osteoarthritis and other forms of arthritis. On the other hand, it is known that MMP-13 is expressed at a high level in breast carcinoma and in several other cancerous tissues, and it has been indicated that there is a strong possibility that it plays an important role in the growth and metastasis of these cancers (JMP Freije et al., Journal of Biological Chemistry, vol 269, 16766-16773, 1994). Thus, it is considered that the compounds that have inhibitory action against this enzyme, are useful inhibitors of metastasis, invasion and growth of several cancer cells. Compounds having MMP inhibitory activity, for example those shown below, are described in WO 07/27174. However, the inhibitory action of these compounds against MMP-13 is not described, and there is no description or suggestion of aglyngase inhibitory action.

EXAMPLE 235 As a result of a formal investigation into the synthesis and pharmacological action of compounds that strongly inhibit both MMP-13 and aglicanase, the inventors of the present invention found novel sulfonamide derivatives having potent MMP-13 inhibitory activity and inhibitory activity of aglicanase, thereby reaching the culmination of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to: (1) a compound of the following formula (I), or a pharmaceutically acceptable salt, ester or other derivative thereof: . { wherein: R1 represents a hydroxyl group or a hydroxyamino group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with at least one group selected from the group of substituents a, a cycloalkyl group having from 3 to 7 carbon atoms, or a group of the formula: -A-R6 [wherein A represents a lower alkylene group or a lower alkylene group interrupted by an oxygen atom, -S (0) m- or -N (R9) -; R6 represents a group of the following formula (II), (III) or (IV): 00 (lll) (IV) (wherein X represents an oxygen atom, a sulfur atom, -N (R10) -o -C (R11) (R12); Y represents an oxygen atom, a carbonyl group, -S (0) n-, - N (R10) - or -C (R11) (R12): R7 and R8 can be the same or different and each represents a hydrogen atom, a lower alkyl group, a carboxyl group, a group selected from the group of substituents a, a lower alkyl group substituted by at least one group selected from the group of substituents a, a lower alkoxy group substituted by at least one group selected from the group of substituents a, a lower alkylthio group substituted by at least one selected group from the group of substituents a, a lower alkylsulfinyl group substituted by at least one group selected from the group of substituents a, or a lower alkylsulfonyl group substituted by at least one group selected from the group of substituents a, or R7 and R8 can form, along with the atom or the carbon atoms to which are joined, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from the group of substituents and the group of substituents β, a non-aromatic heterocycle substituted at least a group selected from the group of substituents a and the group of substituents β, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from the group of substituents a and the group of substituents β, or a ring of heteroaryl substituted with at least one group selected from the group of substituents a and the group of substituents β; and R9, R10, R11 and R12 may be the same or different, and each represents a hydrogen atom or a lower alkyl group, and in addition R11 and R12 may form, together with the carbon atom or atoms to which they are attached. bonded, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from the group of substituents a and the group of substituents β, or a non-aromatic heterocycle substituted by at least one group selected from the group of substituents a and group of substituents β; with the proviso that, when R7 and R8 are attached to the same carbon atom, R7 and R8 do not form, together with the carbon atom to which they are attached, an aryl ring, a heteroaryl ring, a substituted aryl ring at least one group selected from the group of substituents a and the group of substituents β, or a heteroaryl ring substituted by at least one group selected from the group of substituents a and from the group of substituents β), and m and n may be the same or different and each represents 0, 1 or 2], R3 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group, an alkynyl group, a lower alkyl group substituted by at least one group selected from the group of substituents, a cycloalkyl group having from 3 to 7 carbon atoms substituted with at least one group selected from the group of substituents β and from the group of substituents a, alkenyl radical substituted by at least one group selected from the group of substituents a, or an alkynyl group substituted by at least one group selected from the group of substituents a; R 4 represents an arylene group, a heteroarylene group, an arylene group substituted by at least one group selected from the group of substituents a and from the group of substituents β, or a heteroarylene group substituted by at least one group selected from the group of substituents a and group of substituents β; and R5 represents a lower alkyl group, a lower alkyl group substituted by at least one group selected from the group of substituents, an aryl group, a heteroaryl group, an aryl group substituted by at least one group selected from the group of substituents and a group of substituents β, or a heteroaryl group substituted with at least one group selected from the group of substituents and the group of substituents β; with the proviso that, when R2 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with at least one group selected from the group of substituents a, or a cycloalkyl group having from 3 to 7 carbon atoms , R3 represents an alkynyl group or an alkynyl group substituted by at least one group selected from the group of substituents.

[Substituent group] halogen atoms, cycloalkyl groups having from 3 to 7 carbon atoms, lower alkoxy groups, lower halogenoalkoxy groups, lower alkanoyl groups, lower alkylthio groups, lower halogenoalkylthio groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups, groups amino, lower monoalkylamino groups, di (lower alkyl) amino groups, cyano groups, nitro groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, aryl groups substituted by at least one selected group from the group of substituents,, heteroaryl groups substituted by at least one group selected from the group of substituents,, aryloxy groups substituted by at least one group selected from the group of substituents,, heteroaryloxy groups substituted by at least one group selected from the group of substituents?, arylthio groups substituted with at least one group selected from group of substituents?, heteroarylthio groups substituted with at least one group selected from the group of substituents?, [Group of substituents β] lower alkyl groups, lower halogenoalkyl groups, [Substituent group?] Halogen atoms, lower alkyl groups, lower halogenoalkyl groups, lower alkoxy groups, lower halogenoalkoxy groups, lower alkylthio groups, lower halogenoalkylthio groups, nitro groups , cyano groups. Of these compounds, preferred are: (2) a compound in which R1 is a hydroxyamino group; (3) a compound in which R2 is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with at least one group selected from the group of substituents a; (4) a compound in which R2 is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with at least one group selected from the group of substituents a1 below; (5) a compound in which R2 is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with at least one group selected from the following group of substituents a2; (6) a compound in which R 2 is a methyl, ethyl, propyl, isopropyl, 2-methoxyethyl, 2-methylthiophenyl, 3,3,3-trifluoropropyl, benzyl, 2-phenylethyl, benzyloxymethyl, benzylthiomethyl or 2-thienylthiomethyl group; (7) a compound in which A is an alkylene group having 1 to 4 carbon atoms or a lower alkylene group interrupted by an oxygen atom or -S (0) m; (8) a compound in which A is a methylene, ethylene, 1, 1-dimethylethylene, trimethylene, tetramethylene, -CH20 (CH2) 2- or -CH2S (CH2) 2-; (9) a compound in which A is a methylene, ethylene or trimethylene group; (10) a compound in which R6 is: (11) a compound in which R3 is a hydrogen atom, a lower alkyl group, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group, an alkynyl group, a lower alkyl group substituted with an aryl group , a lower alkyl group substituted with a heteroaryl group, an alkenyl group substituted with an aryl group, an alkenyl group substituted with a heteroaryl group, an alkynyl group substituted with an aryl group or an alkynyl group substituted with a heteroaryl group (herein, the "aryl group" and "heteroaryl group" are unsubstituted or substituted by at least one group selected from the group of substituents a and the group of substituents β described above); (12) a compound in which R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group having from 3 to 6 carbon atoms, alkynyl group having from 3 to 6 carbon atoms, an alkyl group having from 1 to 3 carbon atoms substituted with a heteroaryl group, an alkenyl group having 3 carbon atoms substituted with an aryl group, an alkenyl group having 3 carbon atoms substituted with a heteroaryl group, an alkynyl group having 3 carbon atoms substituted with an aryl group, or an alkynyl group having 3 carbon atoms substituted with a heteroaryl group; (13) a compound in which R3 is a methyl, ethyl, propyl, cyclopropyl, allyl, 2-butenyl, propargyl, 2-butinyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3- (4-chlorophenyl) - propyl, 3-phenylpropargyl or 3- (4-chlorophenyl) propargyl; (14) a compound in which R 4 is a phenylene, naphthylene or thienylene group; (15) a compound in which R4 is a p-phenylene group; (16) a compound in which R5 is an alkyl group having from 1 to 6 carbon atoms, a halogenoalkyl group having from 1 to 4 carbon atoms, an aryl group, a heteroaryl group, an aryl group substituted by less with a group selected from the group of substituents a and the group of substituents β, or a heteroaryl group substituted by at least one group selected from the group of substituents a and from the group of substituents β; (17) a compound in which R5 is a methyl, ethyl, propyl, butyl, trifluoromethyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3- group methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 3-thienyl; (18) a compound in which R7 and R8 may be the same or different and each represents a hydrogen atom, a nitro group, an amino group, a lower monoalkylamino group, a di (lower alkyl) amino group, a group cyano, a carboxyl group, a halogen atom, an aryl group, a heteroaryl group, a lower alkyl group, a lower alkanoyl group, a lower alkyl group substituted with at least one group selected from the group of substituents ce, an alkoxy group lower substituted with at least one group selected from the group of substituents, a lower alkylthio group substituted by at least one group selected from the group of substituents a, a lower alkylsulfinyl group substituted by at least one group selected from the group of substituents a, or a lower alkylsulfonyl group substituted by at least one group selected from the group of substituents, or R7 and R8 form, together with the carbon atom or atoms to which they are attached. n linked, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from the group of substituents a and the group of substituents β, a non-aromatic heterocycle substituted by at least one group selected from the group of substituents a and the group of substituents β, or a heteroaryl ring substituted by at least one group selected from the group of substituents a and from the group of substituents β; (19) a compound in which R7 and R8 can be the same or different and each represents a hydrogen atom, a nitro group, a cyano group, a carboxyl group, a halogen atom, an aryl group, a heteroaryl group , a lower alkyl group, a lower alkanoyl group or a lower alkyl group substituted with at least one group selected from the group of substituents a, or R7 and R8 form, together with the carbon atom or atoms to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from the group of substituents a and group of substituents β, a non-aromatic heterocycle substituted by at least one group selected from the group of substituents a and of the group of substituents β, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from the group of substituents a and of the group of β-substituents, or a heteroaryl ring substituted with at least one group selected from the group of substituents a and of the group of substituents β, or a salt, ester or other pharmacologically acceptable derivative thereof.

[Group of substituents a1] halogen atoms, cycloalkyl groups having from 3 to 7 carbon atoms, lower alkoxy groups, lower alkylthio groups, amino groups, lower monoalkyl groups, di (lower alkyl) amino groups, cyano groups, aryl groups , heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups.

[Group of substituents a2] lower alkoxy groups, lower alkylthio groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups.

Of the above compounds, particularly preferred are: (20) a compound selected from the following compounds, or a salt, ester or other pharmacologically acceptable derivative thereof: (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- (2-ftal) Midoethyl) -glycinamide, (±) -N-hydroxy-N -methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl] glycinamide, (± ) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl) ethyl] glycinamide, (±) -2- [2- ( 5-fluoropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- (4-phenoxy-benzenesulfonyl) glycinamide, (±) -Nh-droxy-N- methy1- Na- (4-phenoxybenzenesulfonyl) -2- [2- (thieno [3,2-d] pyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (+ ) -N-hydroxy-Na-methyl-2- [2- (7-methylxanthin-1-yl) ethyl] -Na- (4-phenoxy-benzenesulfonyl) glycinamide, (±) -N-hydroxy-Na-methyl -Na- (4-phenoxybenzenesulfonyl) -2- [2-pteridin-2,4-dione-3-yl) ethyl] glycinamide, (±) -2- [2- (1,1-dioxo-1, 2- benzoisothiazol-3-one-2-yl) ethyl] -N-hydroxy-Na-methyl-N - (4-phenoxybenzenesulfonyl) glycinamide, (±) -N-hydroxy -Na-methyl-2- [2- (6-methylpyrimidin-2,4-dione-3-yl) ethyl] -Na- (4-phenoxybenzenesulfonyl) glycinamide, (±) -N-hydroxy-Na-methyl -Na- (4-phenoxybenzenesulfonyl) -2- [2- (5-trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethyl] glycinamide, N-hydroxy-Na-methyl-Na- ( 4-phenoxybenzenesulfonyl) -2 (R) - (2-phthalimidoethyl) -glycinamide, (±) -Na- [4- (4-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- (2-phthale) midoethyl) -glycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- (4-phenoxy-benzenesulfonyl) glycinamide, (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (6-trifluoro-methyl-pyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (±) -N-hydroxy-Na-methyl-Na- [4- (pyridin-4-yl) oxybenzenesulfonyl] -2- [2-t-ene [3,2-d] pyrimidine-2,4- di-3-yl) ethyl] glycinamide, (±) -2- [2- (6-chloro-1-methylpyrimidin-2,4-dione-3-yl) ethyl] -N -hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide, (±) -Na- [4- (4-chlorophenoxy) benzenesulfonyl] -2- [2- (6-chloropyrimidine-2,4 -dione-3-yl) -ethyl] -N-hydroxy-N-methylglycine ida, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl-Na- [4- (4-fluorophenoxy) benzenesulfonyl] -N-hydroxy- Na-methylglycinamide, (±) -Na- [4- (4-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (6-trifluoromethyl-pyrimidin-2,4-dione-3-yl ) ethyl] glycinamide, (±) -Na- [4- (4-fluorophenoxy) benzenesulfonyl] -Nh'droxy-Na-methyl-2- [2- (6-trifluoromethylpyrimidin-2,4-dione-3) -yl) ethyl] glycinamide, (±) -Na- [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (6-trifluoromethylpyrimidine-2,4-dione -3-yl) ethyl] glycinamide, (±) -Na- [4- (3-chlorophenoxy) benzenesulfonyl] -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) -ethyl ] -N-hydroxy-Na-methylglycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) etl] -Na-etlNNi droxi-N - (4-phenoxybenzenesulfonyl) glycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -Na- [4- (3-fluorophenoxy) - benzenesulfonyl] -N-hydroxy-N-methylglycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-N-methyl- Na- [4- (pyridin-4-yl) oxybenzenesulfonyl] glycinamide, ( ) -Na- [4- (3-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (6-trifluoromethylpyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (±) -N-hydroxy-Na-methyl-Na- [4- (pyridin-4-yl) oxy] -benzenesulfonyl] -2- [2- (6-trifluoromethylpyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (±) -Na-ethyl-N-hydroxy-N - (4-phenoxybenzenesulfonyl) -2- [2- (6-trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (± ) -N-hydroxy-Na-methyl-2- [2- (1-meth- l-6-trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethyl] -Na- (4-phenoxybenzenesulfonyl) glycine; da, (±) -2- [2- (5-chloropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide, Na- [4 - (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2-quinazolin-2,4-dione-3-yl) ethyl] glycinamide, Na- [4- (3-chlorophenoxy ) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (t-ene [3,2-d] pyrimidin-2,4-dione-3-yl) et!] glycinamide, and Na - [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- (2-phthalimidoethyl) glycinamide.

Another object of the present invention is to provide: (21) a medicament (particularly an inhibitor agent of MMP-13 and an aglicanase inhibiting agent) which contains as an active ingredient the compound described in any of the items (1) to (20) above, or a salt, ester or other pharmacologically acceptable derivative thereof; more specifically, (22) the medicament mentioned in (21) for the prevention or treatment of arthritis (particularly osteoarthritis), or (23) the medicament mentioned in (21) to inhibit metastasis, invasion or development of cancer (particularly breast cancer) ).

In addition, the present invention also provides: (24) a method for preventing or treating arthritis (particularly osteoarthritis) or a method for inhibiting cancer metastasis, invasion or growth (particularly breast cancer), which comprises administering the compound described in any of points (1) to (20) above, or a pharmaceutically acceptable salt, ester or other derivative thereof, and (25) a use of the compound mentioned above in (1) to (20), or a salt, a ester or other pharmacologically acceptable derivative thereof, for manufacturing a medicament for the prevention or treatment of arthritis (particularly osteoarthritis) or a medicament for inhibiting cancer metastasis, invasion or growth (particularly breast cancer).

In the above formula (I): the "lower alkyl group" in the definition of R2, R3, R5, R7, R8, R9, R10, R11, R12, "group of substituents ß" and "group of substituents?"; the "lower alkyl group" of the "lower alkyl group substituted with at least one group selected from the group of substituents a" in the definition of R2, R3, R5, R7 and R8; the "lower alkyl" portion of the "lower alkoxy group substituted by at least one group selected from the group of substituents a", the "lower alkylthio group substituted by at least one group selected from the group of substituents a", the "alkylsulfinyl group" lower substituted with at least one group selected from the group of substituents a "and the" lower alkylsulfonyl group substituted by at least one group selected from the group of substituents a "in the definition of R7 and R8; the "lower alkyl" portion of the "lower alkoxy group", the "lower halogenoalkoxy group", the "lower alkylthio group", the "lower halogenoalkylthio group", the "lower alkylsulfinyl group", the "lower alkylsulfonyl group", lower mono-alkylamino group "and the" di- (lower alkyl) amino "group in the definition of the" substituent group a "; the "lower alkyl" portion of the "lower halogenoalkyl group" in the definition of the "substituent group β"; and the "lower alkyl" portion of the "lower halogenoalkyl group", the "lower alkoxy group", the "lower halogenoalkoxy group", the "lower alkylthio group" and the "lower halogenoalkylthio group" in the definition of "group of substituents? ", represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 2- groups pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1-trimethylpropyl and 1, 2,2-trimethylpropyl, preferably a straight or branched chain alkyl group having from 1 to 4 carbon atoms, preferably a methyl, ethyl, propyl, isopropyl or butyl group.

The "cycloalkyl group having from 3 to 7 carbon atoms" in the definition of R2, R3 and the "group of substituents a"; and the "cycloalkyl group having from 3 to 7 carbon atoms" of the "cycloalkyl group having from 3 to 7 carbon atoms substituted with a group selected from the group of substituents a and from the group of substituents β" in the definition of R3, includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. The "lower alkylene group" in the definition of A represents a straight or branched alkylene group having from 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, 1,1-dimethylethylene, 1, 1-dimethyltrimethylene and 1,1-dimethyltetramethylene, preferably a straight or branched alkylene group having from 1 to 4 carbon atoms, preferably a straight alkylene group having from 1 to 4 carbon atoms, prefer a methylene, ethylene or trimethylene group. The "lower alkylene group interrupted by an oxygen atom, -S (0) m- or -N (R9) -" in the definition of A, represents a group in which an oxygen atom is present, S (0) m- or -N (R9) - between two carbon atoms of the "lower alkylene group" defined above, and preferred examples of such a group include -CH20CH2-, -CH2SCH2-, -CH2NHCH2-, -CH2N (CH3) CH2-, -CH2OCH2CH2-, -CH2SCH2CH2-, -CH2NHCH2CH2-, -CH2N (CH3) CH2CH2-, -CH2SOCH2CH2- and -CH2S02CH2CH2-. The "lower alkoxy group" in the definition of the "substituent group a" and the "substituent group", and the "lower alkoxy group" of the "lower alkoxy group substituted with at least one group selected from the group of substituents a "in the definition of R7 and R8, represents a group in which an oxygen atom is attached to the group" lower alkyl "defined above, prefer a straight or branched alkoxy group having from 1 to 4 carbon atoms, prefer a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, most prefer a methoxy, ethoxy or propoxy group. The term "lower alkylthio group" in the definition of "group of substituents a" and "group of substituents?"; and the group "lower alkylthio" of the group "lower alkylthio substituted with at least one group selected from the group of substituents a" in the definition of R7 and R8, represents a group in which a sulfur atom is attached to the group "alkyl" "lower" defined above, preferably a straight or branched alkylthio group having from 1 to 4 carbon atoms, preferably a methylthio, ethylthio, propylthio, isopropylthio or butylthio group, most preferably a methylthio, ethylthio or propylthio group. The "lower alkylsulfinyl group" in the definition of "group of substituents a", and the "lower alkylsulfinyl group" of the group "lower alkylsufinyl substituted with at least one group selected from the group of substituents a" in the definition of R7 and R8 represents a group in which a sulphinyl moiety (-SO-) is attached to the "lower alkyl group" defined above, preferably a straight or branched alkylsulfinyl group having from 1 to 4 carbon atoms, preferably a methylisulfinyl, ethylisulfinyl group, propylsulfinyl, isopropylsulfinyl or butylsulfinyl, most preferably a methylisulfinyl, ethylisulfinyl or propylsulfinyl group.

The "lower alkylsulfonyl group" in the definition of "group of substituents a", and the "lower alkylsulfonyl group" of the group "lower alkylsulfonyl substituted with at least one group selected from the group of substituents a" in the definition of R7 and R8 , represents a group in which a sulfonyl moiety (-S02-) is attached to the "lower alkyl group" defined above, preferably a straight or branched alkylsulfonyl group having from 1 to 4 carbon atoms, preferably a methylsulfonyl, ethylsulfonyl group , propylsulfonyl, isopropylsulfonyl or butylsulfoniium. most preferably a methylsulfonyl, ethylsulfonyl or propylsulfonyl group. The "non-aromatic hydrocarbon ring" formed by R7 and R8 together with the carbon atom or atoms to which they are attached, the "non-aromatic hydrocarbon ring" of the "non-aromatic hydrocarbon ring substituted with at least one selected group of the group of substituents a and of the group of substituents β ", which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, the" non-aromatic hydrocarbon ring "which is formed by R11 and R12 together with the carbon atom or atoms to which they are attached, and the "non-aromatic hydrocarbon ring" of the "non-aromatic hydrocarbon ring substituted with at least one group selected from the group of substituents a and substituent group β", which is formed by R11 and R12 together with the carbon atom or atoms to which they are attached, represent a saturated hydrocarbon ring having from 3 to 7 carbon atoms, such as for example cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring and cycloheptane ring, or an unsaturated hydrocarbon ring having from 3 to 7 carbon atoms, such as a ring of cyclopropene, cyclobutene, cyclopentene, cyclohexene and cycloheptene, preferably a saturated hydrocarbon ring having 5 or 6 carbon atoms, or an unsaturated hydrocarbon ring having 5 or 6 carbon atoms, preferably an unsaturated hydrocarbon ring having 5 or 6 carbon atoms. In formulas (II) and (III) above, as there is a double bond between the carbon atom to which R7 is attached and the carbon atom to which R8, R7 and R8 are attached, together with the carbon atom to which they are joined, they do not form a saturated hydrocarbon ring. The "non-aromatic heterocycle" formed by R7 and R8 together with the carbon atom or atoms to which they are attached, the "non-aromatic heterocycle" of the "non-aromatic heterocycle" substituted with at least one group selected from the group of substituents a of the group of substituents a ". which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, and the "non-aromatic heterocycle" of the "non-aromatic heterocyclic substituted with at least one group selected from the group of substituents a and the group of Substituents ß ", which is formed by R11 and R12 together with the carbon atom or atoms to which they are attached, represent a saturated or partially saturated 5- to 7-membered heterocycle containing from 1 to 3 sulfur, oxygen and hydrogen atoms. / or of nitrogen, preferably a saturated or partially saturated 5- or 6-membered heterocycle containing one or two sulfur, oxygen and / or nitrogen atoms, and examples of this ring include for example a dithiolane ring, a ring of dioxane and a pyrrolidine ring. The "aryl ring" which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, and the "aryl ring" of the "aryl ring substituted with at least one group selected from the group of substituents a and the group of substituents ß ", which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, represent an aromatic hydrocarbon ring having from 6 to 10 carbon atoms, such as a benzene ring and a naphthalene ring, preferably a benzene ring or a naphthalene ring, particularly preferably the benzene ring. The above-mentioned "aryl ring" may be fused with a cycloalkyl group having from 3 to 10 carbon atoms, and such fused rings include an indane ring. The "heteroaryl ring" which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, and the "heteroaryl ring" of the "heteroaryl ring substituted with at least one group selected from the group of substituents a and the group of substituents ß ", formed by R7 and R8 together with the carbon atom or atoms to which they are attached, represent a 5- to 7-membered aromatic heterocycle containing from 1 to 3 sulfur, oxygen and and / or nitrogen, and examples of such rings include a furan ring, a thiophene ring, a pyrrole ring, an azepine ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring , a thiazole ring, an isothiazole ring, a 1,2-oxadiazole ring, a triazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring and a ring of pyrazine, preferably an aromatic heterocycle of 5 or 6 members containing one or two sulfur, oxygen and / or nitrogen atoms, preferably a thiophene ring, a imidazole ring, a pyridine ring and a pyrazine ring. The "heteroaryl ring" mentioned above can be fused with another cyclic group, and examples of said fused ring include an indole ring, a benzofuran ring, a benzothiophene ring, an isoquinoline ring and a quinoline ring. Specific examples of the group of "formula (II), (III) or (IV)" in the definition of R6, preferably include: The "alkenyl group" and the "alkenyl group" of the "alkenyl group substituted with at least one group selected from the group of substituents" in the definition of R3 represents a straight or branched alkenyl group having from 3 to 10 carbon atoms, preferably a straight or branched alkenyl group having from 3 to 6 carbon atoms, such as the allyl, 2-butenyl, 3-butenyl, 2-methylallyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 5-pentenyl groups , 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl, preferably a straight or branched alkenyl group having 3 or 4 carbon atoms, preferably an allyl or 2-butenyl group. The "alkynyl group" and the "alkynyl group" of the "alkynyl group substituted by at least one group selected from the group of substituents a" in the definition of R3, represents a straight or branched alkynyl group having from 3 to 10 carbon atoms. carbon, preferably a straight or branched alkynyl group having from 3 to 6 carbon atoms, such as the groups propargyl, 2-butinyl, 3-butinyl, 2-methyl-3-butinyl, 2-pentynyl, 3-pentynyl, -pentinyl, 5-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, preferably a straight or branched alkynyl group having 3 or 4 carbon atoms, preferably a propargyl or 2-butynyl group. The "arylene group" and the "arylene group" of the "arylene group substituted with at least one group selected from the group of substituents a and the group of substituents β" in the definition of R4 represents a divalent aromatic hydrocarbon ring having 6 to 10 carbon atoms, such as the phenylene and naphthylene groups, preferably a phenylene group, particularly preferably a p-phenylene group. The above-mentioned "arylene group" can be fused with a cycloalkyl group having from 3 to 10 carbon atoms, and examples of said group include an indane-4,7-diyl group. The "heteroarylene group" and the "heteroarylene group" of the "heteroarylene group substituted with at least one group selected from the group of substituents a and the group of substituents β" in the definition of R 4 represents a divalent aromatic heterocyclic ring of 5 to 7. members, containing 1 to 3 sulfur, oxygen and / or nitrogen atoms, and examples thereof include the groups furanylene, thienylene, pyrrolylene, azepinylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, 1, 2,3-oxadiazolylene, triazolylene, thiadiazolylene, pyridylene, pyridazinylene, pyrimidinylene and pyrazinylene. Preferably, it represents a 5- or 6-membered aromatic heterocycle containing one or two sulfur, oxygen and / or nitrogen atoms, preferably the thienylene, imidazolylene, pyridylene or pyrazinylene group, particularly preferably a thienylene group. The "heteroarylene group" mentioned above may be fused with other cyclic groups, and examples of such a fused ring include indole-4,7-diyl and benzothiophene-4,7-diyl. The "aryl group" in the definition of R5 and the "group of substituents a", the "aryl group" of the "aryl group substituted by at least one group selected from the group of substituents a and group of substituents β" in the definition of R5, and the "aryl group" of the "aryl group substituted by at least one group selected from the group of substituents?" in the definition of "group of substituents a", represents a monovalent aromatic hydrocarbon ring having from 6 to 10 carbon atoms, such as a phenyl and naphthyl group, preferably a phenyl group.

The "aryl group" mentioned above can be fused with a cycloalkyl group having from 3 to 10 carbon atoms, and an example of this group includes 5-indanyl. The "heteroaryl group" in the definition of R5 and the "group of substituents a", the "heteroaryl group" of the "heteroaryl group substituted with at least one group selected from the group of substituents a and the group of substituents β" in the definition of R5, and the "heteroaryl group" of the "heteroaryl group substituted by at least one group selected from the group of substituents?" in the definition of "group of substituents a", represents a 5-7 membered monovalent aromatic heterocyclic group containing from 1 to 3 sulfur, oxygen and / or nitrogen atoms, and includes furanyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazoyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Preferably, it represents a 5- or 6-membered monovalent aromatic heterocyclic group containing one or two sulfur, oxygen and / or nitrogen atoms, preferably a thienyl, imidazolyl, pyridyl or pyrazinyl group, and a thienyl group is particularly preferred. pyridyl. The heteroaryl group mentioned above may be fused with another cyclic group, and examples of such fused rings include the indolyl, benzofuranyl, benzothienyl, isoquinolyl and quinolyl groups.

The "halogen atom" in the definition of the "substituent group a" and the "substituent group?" it includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The "lower halogenoalkoxy group" in the definition of the "substituent group a" and the "substituent group", represents a group in which a "lower halogenalkyl group" described below, is attached to a oxygen, and a dilfuoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy group is particularly preferred. The "lower alkanoyl group" in the definition of "substituent group a" represents a formyl group or a group in which a carbonyl group is attached to the "lower alkyl group" mentioned above. Preferably, it is a straight or branched alkanoyl group having from 1 to 4 carbon atoms, preferably a formyl, acetyl, propionyl, butyryl or isobutyryl group; most preferably a formyl, acetyl or propionyl group, and a formyl or acetyl group is particularly preferred. The "lower halogenoalkylthio group" in the definition of the "substituent group a" and the "substituent group", represents a group in which a "lower halogenoalkyl group", described below, is attached to a sulfur. Particularly preferred is a difluoromethylthio group, trifluoromethylthio or 2,2,2-trifluoroethylthio. The "lower monoalkylamino group" in the definition of "group of substituents a" represents a group in which a hydrogen atom of a group -NH 2 is substituted with the "lower alkyl group" mentioned above.

Preferably, it is a straight or branched monoalkylamino group having from 1 to 4 carbon atoms, preferably a methylamino, ethylamino, propylamino, isopropylamino or butylamino group, and a methylamino, ethylamino or propylamino group is particularly preferred. The "di (lower alkyl) amino" group in the definition of "substituent group a" represents a group in which the two hydrogen atoms of a -NH2 group are substituted with the "lower alkyl group" mentioned above, which can be to be the same or different Preferably, it is a dialkylamino group wherein either of the two alkyl groups is a straight or branched alkyl group having from 1 to 4 carbon atoms, most preferably a dimethylamino, ethylmethylamino, methylpropylamino, isopropylmethylamino, butylmethylamino, diethylamino or diisopropylamino group, and a dimethylamino, ethylmethylamino or diethylamino group is particularly preferred. The "aryloxy group" and the "aryloxy group" of the "aryloxy group substituted with at least one group selected from the group of substituents?" in the definition of the "group of substituents a", represents a group in which the "aryl group" mentioned above is linked to an oxygen atom. The "heteroaryloxy group" and the "heteroaryloxy group" of the "heteroaryloxy group substituted with at least one group selected from the group of substituents?" in the definition of "group of substituents a", represents a group in which the "heteroaryl group" mentioned above is linked to an oxygen atom.

The "arylthio group" and the "arylthio group" of the "arylthio group substituted by at least one group selected from the group of substituents?" in the definition of "group of substituents a", represents a group in which the "aryl group" mentioned above is attached to a sulfur atom. The "heteroarylthio group" and the "heteroarylthio group" of the "heteroarylthio group substituted with at least one group selected from the group of substituents and" in the definition of "group of substituents a", represents a group in which the "heteroaryl group" "Above mentioned is attached to a sulfur atom. The "lower halogenoalkyl group" in the definition of the "group of substituents β" and the "group of substituents y", represents a group in which two or more hydrogen atoms of the "lower alkyl group" mentioned above are substituted with the " halogen atom "mentioned above. Preferably, Is a lower halogenoalkyl group having 1 to 4 carbon atoms, preferably a trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2- bromoethyl, 2-chloroatyl, 2-fluoroethyl or 2,2-dibromoethyl, and a trifluoromethyl, trichloromethyl, difluoromethyl or fluoromethyl group is particularly preferred. Since the compound (I) of the present invention can be converted to an ester, the "ester" means said ester and includes an "ester of a hydroxyl group" and an "ester of a carboxyl group", and includes an ester in a which each ester residue is a "general protective group" or a "protective group removable by a biological process such as hydrolysis in vivo". The "general protecting group" means a removable protective group according to a chemical method such as hydrogenolysis, hydrolysis, electrolysis and photolysis. Preferred examples of the "general protecting group" for the "ester of the hydroxyl group" include "aliphatic acyl groups", for example groups alkylcarbonyl as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, isovaleryl, octanoyl, nonylcarbonyl, I decylcarbonyl , 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethylctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl , octadecilcarbonilo, 1-metilheptadecilcarbonilo, nonadecylcarbonyl, eicosilcarbonilo and heneicosilcarbonilo, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl, alkoxyalkylcarbonyl groups such as methoxyacetyl lower groups, and unsaturated alkylcarbonyl groups such as acryloyl , propionyl, methacryloyl, crotonyl, isocrotonyl and (E) -2-methyl-2-butenoyl (of which a lower aliphatic acyl group having from 1 to 6 carbon atoms is preferred); "aromatic acyl groups", for example arylcarbonyl groups such as benzoyl, naphthyl and naphthyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and 4-toluyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, nitro-arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, arylcarbonyl lower alkoxycarbonyl groups such as 2- (methoxycarbonyl) benzoyl, and arylated arylcarbonyl groups such as 4-phenylbenzoyl; "alkoxycarbonyl groups" such as lower alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups, and lower alkoxycarbonyl groups substituted with halogen atoms, or a tri (lower alkyl) group silyl, for example the 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups; the "general protective group" for a hydroxyl group also includes ethers that include "tetrahydropyranyl or tetrahydrothiopyranyl groups" such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2 groups ilo and 4-methoxytetrahydrothiopyran-4-yl; "tetrahydrofuranyl or tetrahydrothiofuranyl groups" such as the tetrahydrofuran-2-yl and tetrahydrothiophan-2-yl groups; "silyl groups", for example, tri (lower alkyl) silyl groups such as the trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl and triisopropylsilyl groups, and tri (lower alkyl) silyl groups in which 1 or 2 alkyl groups are substituted with 1 or 2 aryl groups, such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl; "alkoxymethyl groups", for example, lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl and lower halogenoalkoxymethyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; "substituted ethyl groups", for example, lower alkoxylated ethyl groups such as 1-ethoxyethyl and 1- (isopropoxy) ethyl and halogenated ethyl groups such as 2,2,2-trichloroethyl; "aralkyl groups", for example, lower alkyl groups substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl, and lower alkyl groups substituted with to 3 aryl groups, each having an aryl ring substituted with a lower alkyl, lower alkoxy, nitro, halogen or cyano group, for example, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl , 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; "alkenyloxycarbonyl groups" such as vinyloxycarbonyl and allyloxycarbonyl groups; and "aralkyloxycarbonyl groups" having an aryl ring which may be substituted with one or two lower alkoxy or nitro groups, such as the benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxy-benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups . Preferred examples of the "general protecting group" with respect to an "ester of a carboxyl group" include the "lower alkyl groups" mentioned above; lower alkenyl groups such as the ethenyl groups, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, -ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-buteniio, 3-butenyl , 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3 -pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl , 4-hexenyl and 5-hexenyl; lower alkynyl groups such as the ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3 groups -butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl , 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl; the "lower halogenalkyl" groups mentioned above; "lower alkyl groups" hydroxy such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl; "lower ayliphatic acyl groups" - "lower alkyl groups" such as acetylmethyl; the "aralkyl groups" mentioned above and the "silyl groups" mentioned above. The "protective group removable by a biological process such as hydrolysis in vivo" means a group that is removable by means of a biological process such as hydrolysis in the human body, to give a free acid compound or a salt thereof. Whether a compound is such a derivative or not can be determined in the following manner: the compound is administered intravenously to an experimental animal such as a rat or mouse, and then the body fluid of the animal is studied. If the original compound or its pharmacologically acceptable salt can be detected in the body fluid, the compound studied is considered as a derivative. Preferred examples of the "protective group removable by a biological process such as in vivo hydrolysis" for a hydroxyl group include "carbonyloxyalkyl groups" such as the groups 1- (acyloxy) "lower alkyl", including 1 - ("lower aliphatic acyl") oxy) "lower alkyl", for example the formyloxymethyl, acetoxy methyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1- propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxy xyl, groups "1 - (" cycloalkyl "carbonyloxy)" lower alkyl ", for example the cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl groups; groups 1 - ("aromatic acyl" -oxi) "lower alkyl", for example the benzoyloxymethyl groups; (lower alkoxycarbonyloxy), for example the methoxycarbonyloxymethyl group, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxicarboniloximetilo, pentyloxycarbonyloxymethyl, hexiloxicarboniloximetilo, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, (methoxycarbonyloxy) ethyl, 1 - (ethoxycarbonyloxy) ethyl, 1 - (propoxycarbonyloxy ) ethyl, (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, (isobutoxycarbonyloxy) ethyl, 1- (tert-butoxycarbonyloxy) ethyl, (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbon) Lox) propyl, (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonoxy) butyl, (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, (ethoxycarbonyloxy) propyl, 2- (methoxycarbonyloxy) ethyl, 2- (ethoxycarbonyloxyethoxycarbonyloxy) ethyl, 2- (propoxycarbonyloxy) etyl, 2- (isopropoxycarbonyloxy) ethyl, 2- (Butoxycarbonyloxy) ethyl, 2- (isobutoxycarbonyloxy) -ethyl, 2- (pentyloxycarbonyloxy) ethyl, 2- (hexyloxycarbonyloxy) ethyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, l- (Propoxycarbonyloxy) -propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl , l- (ethoxycarbonyloxy) -butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) -pentyl, 1- (ethoxycarbonyloxy) ) pentyl, 1- (methoxycarbonyloxy) hexyl and 1- (ethoxycarbonyloxy); oxy-oxyxolenylmethyl groups, for example the groups (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl ] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] ] methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-dioxolen-4-yl) methyl, (5-methyl- 2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1, 3- dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; and the like; "phthalidyl groups", for example the phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl groups; the "lower aliphatic acyl groups" mentioned above; the "lower aromatic acyl groups" mentioned above; "semi-ester succinic acid salt residues", "phosphate ester salt residues", "ester-forming residues of an amino acid or the like"; carbamoyl groups; carbamoyl groups substituted with 1 or 2 lower alkyl groups; and "1- (acyloxy) alkyloxycarbonyl groups", for example pivaloyloxymethyloxycarbonyl. Preferred examples of the "protective group removable by a biological process such as in vivo hydrolysis" for a carboxyl group, include "lower alkoxy alkyl groups" such as the lower alkoxy lower alkyl groups, for example the methoxyethyl groups, ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isoproxymethyl, n-butoxymethyl or tert-butoxymethyl , the groups (lower alkoxy-lower alkoxy) alkyl such as 2-methoxyethoxymethyl; groups (lower alkoxy) lower alkoxylated alkyl (with lower alkoxy group), for example methoxyethoxymethyl, groups "aryl" oxy "-lower alkyl", for example phenoxymethyl, and lower (halogenoalkoxy) lower alkyl groups, for example 2,2,2 -trichloroethoxymethyl and bis (2-chloroethoxy) methyl; "lower alkoxycarbonyl-lower alkyl" groups, for example the methoxycarbonyl groups; "cyano-lower alkyl groups" for example cyanomethyl or 2-cyanomethyl; "lower alkyl-thiomethyl" groups, for example methylthiomethyl or ethylthiomethyl; "arylthiomethyl groups", for example phenylthiomethyl or naphthythiomethyl; "groups (" lower alkyl ") sulfonyl-lower alkyl optionally substituted with halogen atoms", for example 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; "arylsulfonyl-lower alkyl groups", for example 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; the "1 - (acyloxy) lower alkyl" groups mentioned above; the "phthalidyl groups" mentioned above; the "aryl groups" mentioned above; the "lower alkyl groups" mentioned above; "carboxyalkyl groups" for example carboxymethyl groups; and "amino acid-forming residues of an amino acid", for example phenylalanine groups. Since the compound (I) of the present invention can be converted into another derivative apart from the "pharmaceutically acceptable salt" mentioned above and the "ester" mentioned above, when it has an amino group and / or a carboxyl group, the "other derivative "means such a derivative. Examples of said derivatives include the amide derivatives. In the case in which the compound (I) of the present invention has a basic group such as an amino group, the compound can be converted into a salt by reacting it with an acid, and in the case in which the compound (I ) has an acidic group such as a carboxyl group, as the compound can be converted to the salt by reacting it with a base, the "pharmacologically acceptable salt thereof" means said salt. Preferred examples of the salt based on the basic group include salts of inorganic acids such as salts of hydrohalogenated acids, for example hydrofluoride, hydrochloride, bromohydrate and iodohydrate, nitrates, perchlorates, sulfates and phosphates; salts of inorganic acids such as lower alkane sulphonate, for example salts of methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, arylsulfonate, for example benzenesulfonate and p-toluenesulfonate, acetates, maleates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates and maleates; and salts of amino acids such as glycine salts, lysine, arginases, ornithine salts, glutamates and aspartates. Preferred examples of the salt based on the acid group include metal salts such as an alkali metal salt, for example sodium, potassium and lithium salts, an alkaline earth metal salt, for example calcium and magnesium salts, salts of aluminum and iron salts; amine salts such as inorganic salts, for example ammonium salts and organic salts, for example t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N salts. -methylglucamine, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and salts of tris (hydroxymethyl) aminomethane; and amino acid salts such as glycine salts, lysine salts, arginases, ornithine salts, glutamates and aspartates. The compounds of formula (I) of the present invention sometimes absorb moisture when allowed to stand in the atmosphere, or crystallize, so that they carry water adsorbed and are therefore hydrated.

Said hydrates are also included in the present invention. Since the compound of formula (I) has an asymmetric carbon atom in its molecule, it has several isomers. In the compound of the present invention, these isomers and mixtures of these isomers are shown by means of a single formula, that is, formula (I).

Accordingly, the present invention includes all these isomers and mixtures of these isomers. Specific examples of the compounds of formula (I) of the present invention include the compounds described in the following tables 1-9.

TABLE 1 TABLE 2 TABLE 3 TABLE 4 03 YES I heard s ¿QZ I 01 9L TABLE 5 TABLE 6 TABLE 7 03 St 01 8 or i heard 03 SI 01 68 03 SI 01 06 03 I 01 16 TABLE 8 03 SI 01 86 TABLE 9 In the above tables, "Me" means methyl, "Et" means ethyl, "Pr" means propyl, "i-Pr" means isopropyl, "c-Pr" means cyclopropyl, "Bu" means butyl, "s-Bu" means s-butyl, "i-Bu" means isobutyl, "t-Bu" means t-butyl, "c-Pn" means cyclopentyl, "c-Hx" means cyclohexyl, "Ph" means phenyl, "Py" means pyridyl. , "Thie" means tieniio, and "Bn" means benzyl. In addition, "sus.1" to "sus.51" in Table 5 above mean the following substituents, respectively: sus.23: -N M sus.24: -N or sus.51: - N, "-CH > or Y In the previous tables, the compounds of formula are illustrated (I) in which R1 is a hydroxyamino group. However, the present invention also encompasses hydroxy derivatives [which are compounds of formula (I) wherein R1 is a hydroxy group], which correspond to the above compounds as specific examples. In the tables, the preferred compounds are compounds numbers: 1-1 to 1-4, 1-8 to 1-11, 1-24 to 1-27, 1-40 to 1-43, 1-56 to 1- 59, 1-68 to 1-75, 1-88 to 1-91, 1-104 to 1-107, 1-121, 1-137, 1-153, 1-180 to 1-189; 2-1 to 2-4, 2-8 to 2-11, 2-24 to 2-27, 2-40 to 2-43, 2-56 to 2-59, 2-68 to 2-75, 2- 88 to 2-91, 2-104 to 2-107, 2-121, 2-137, 2-153, 2-180 to 2-189; 3-1 to 3-5, 3-7 to 3-12, 3-25 to 3-28, 3-41 to 3-44, 3-57 to 3-60, 3-69 to 3-76, 3- 89 to 3-92, 3-105 to 3-108, 3-122, 3-136, 3-138, 3-154, 3-169, 3-171, 3-172, 3-181 to 3-192; 4-1 to 4-4, 4-8 to 4-11, 4-24 to 4-27, 4-40 to 4-43, 4-56 to 4-59, 4-68 to 4-75, 4- 88 to 4-91, 4-104 to 4-107, 4-121, 4-137, 4-153, 4-180 to 4-189; 5-1 to 5-91, 5-98, 5-99; 6-4, 6-10 to 6-12, 6-22 to 6-27; 7-9 to 7-12, 7-14, 7-16, 7-25 to 7-28, 7-30, 7-32, 7-41 to 7-44, 7-46, 7-48, 7- 57 to 7-60, 7-62, 7-64, 7-69 to 7-76, 7-89 to 7-92, 7-94, 7-96, 7-105 to 7-108, 7-121 a 7-123, 7-136 to 7-139, 7-153 to 7-155, 7-172, 7-181 to 7-183, 7-185 to 7-187, 7-190, 7-194 to 7- 197, 7-206 to 7-208, 7-211 to 7-214, 7-217 to 7-221; 8-9 to 8-12, 8-14, 8-16, 8-25 to 8-28, 8-30, 8-32, 8-41 to 8-44, 8-46, 8-48, 8- 57 to 8-60, 8-62, 8-64, 8-69 to 8-76, 8-89 to 8-92, 8-94, 8-96, 8-105 to 8-108, 8-121 to 8-123, 8-136 to 8-139, 8-153 to 8-155, 8-172, 8-181 to 8-183, 8-185 to 8-187, 8-190, 8-194 to 8- 197, 8-206 to 8-208, 8-211 to 8-214, 8-217 to 8-221; 9-3, 9-9, 9-11 to 9-19, 9-22, 9-28, 9-30 to 9-38, 9-41, 9-47, 9-49 to 9-57, 9- 60, 9-66, 9-68 to 9-76, 9-79, 9-85, 9-87 to 9-95, 9-98, 9-104, 9-106 to 9-114, 9-117, 9-123, 9-125 to 9-133, 9-136, 9-142 and 9-144 to 9-152; the most preferred compounds are compounds numbers 1-2, 1-9, 1-10, 1-25, 1-26, 1-41, 1-42, 1-57, 1-58, 1-69, 1- 70, 1-73, 1-74, 1-89, 1-90, 1-105, 1-137, 1-153, 1-180 to 1-189; 2-2, 2-9, 2-25, 2-26, 2-41, 2-57, 2-69, 2-73, 2-89, 2-105, 2-137, 2-153, 2- 180, 2-181, 2-185, 2-186; 3-2, 3-7, 3-10, 3-11, 3-25 to 3-27, 3-42, 3-43, 3-58, 3-59, 3-70, 3-71, 3- 74, 3-75, 3-90, 3-91, 3-106, 3-107, 3-122, 3-136, 3-138, 3-154, 3-169, 3-171, 3-172, 3-181 to 3-192; 4-2, 4-9, 4-10, 4-25, 4-26, 4-41, 4-42, 4-57, 4-58, 4-69, 4-70, 4-73, 4- 74, 4-89, 4-90, 4-105, 4-137, 4-153, 4-180 to 4-189; 5-1, 5-2, 5-9, 5-10, 5-15 to 5-35, 5-37 to 5-40, 5-43 to 5-45, 5-68 to 5-71, 5- 74 a -79, 5-98, 5-99; 7-25 to 7-27, 7-32, 7-41 to 7-43, 7-57 to 7-59, 7-64, 7-70, 7-73 to 7-75, 7-89 to 7- 91, 7-96, 7-106, 7-122, 7-138, 7-154, 7-172, 7-181, 7-182, 7-185, 7-186, 7-194 to 7-197, 7-206 to 7-208, 7-211 to 7-214, 7-217 to 7-221; 8-25 to 8-27, 8-32, 8-41 to 8-43, 8-57 to 8-59, 8-64, 8-70, 8-73 to 8-75, 8-89 to 8- 91, 8-96, 8-106, 8-122, 8-138, 8-154, 8-172, 8-181, 8-182, 8-185, 8-186, 8-194 to 8-197, 8-206 to 8-208, 8-211 to 8-214, 8-217 to 8-221; 9-12, 9-13, 9-15, 9-16, 9-18, 9-19, 9-31, 9-32, 9-34, 9-35, 9-37, 9-38, 9- 50, 9-51, 9-53, 9-54, 9-56, 9-57, 9-69, 9-70, 9-72, 9-73, 9-75, 9-76, 9-88, 9-89, 9-91, 9-92, 9-94, 9-95, 9-107, 9-108, 9-110, 9-111, 9-113, 9-114, 9-126, 9-127, 9-129, 9- 130, 9-132, 9-133, 9-145, 9-146, 9-148, 9-149, 9-151 and 9-152; and compounds numbers 1-9, 1-25, 1-41, 1-57, 1-69, 1-73, 1-89, 1-180 to 1-182, 1-185, 1-186 are highly preferred.; 2-25, 2-89; 3-10, 3-26, 3-42, 3-58, 3-70, 3-74, 3-90, 3-106, 3-181 to 183, 3-186, 3-187; 4-9, 4-25, 4-41, 4-57, 4-69, 4-73, 4-89, 4-180, 4-181, 4-185, 4-186; 5-15, 5-17, 5-18, 5-21 to 5-27, 5-29 to 5-35, 5-37 to 5-40, 5-44, 5-45, 5-68 to 5- 71, 5-74 to 5-77, 5-84 to 5-91, 5-98, 5-99; 7-26, 7-42, 7-58, 7-74, 7-90, 7-181, 7-182, 7-194, 7-196, 7-212, 7-213, 7-217 a 7-221; 8-26, 8-42, 8-58, 8-74, 8-90, 8-181, 8-182, 8-194, 8-196, 8-212, 8-213 and 8-217 through 8- 221. The following can be exemplified as the particularly preferred compounds: (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine-mide (Compound No. 3-26), (±) -N-hydroxy-N -met L-Na- (4-phenoxybenzenesulfonyl) -2- [2- (t-azolidin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 5-44), (±) -N -hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 1-25), (±) -2 - [2- (5-fluoropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- (4-phenoxy-benzenesulfonyl) glycinamide (Compound No. 5-31 ), (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (thieno [3,2-d] pyrimidin-2,4-dione-3-yl) ) ethyl] glycinamide (Compound No. 5-23), (±) -N-hydroxy-Na-methyl-2- [2- (7-methylxanten-1-yl) etl] -Na- (4) -phenoxy-benzenesulfonyl) glycinamide (Compound No. 5-25), (±) -N-hydroxy-N -methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2-pteridine-2,4-dione] -3-yl) ethyl] glycinamide (Compound No. 5-21), (±) -2- [2- (1,1-dioxo-1,2-benzisothiazol-3-one-2-yl) etl. ] -N-hydroxy-Na-methyl-N - (4-phenoxybenzenesulfonyl) glycinamide (Compound No. 2-25), (±) -Nh / droxy-Na-methyl-2- [2- (6-methylpyrimidin-2,4-dione-3-yl) ethyl] -Na- (4 -phenoxybenzenesulfonyl) glycinamide (Compound No. 5-39), (+) - N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (5-trifluoromethylpyrimidin -2,4-dione-3-yl) ethyl] glycinamide (Compound No. 5-37), N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2 (R) - (2-phthalimidoethyl) glycinamide (Compound No. 3-26), (±) -Na- [4- (4-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- (2-phthalimidoethyl) glycinamide (Compound No. 3-182), (±) -2- [2- (6-chloropyrimidine-2,4-dione-3-) il) etl] -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide (Compound No. 5-84), (±) -N-hydroxy-Na-methyl-Na- (4) -phenoxybenzenesulfonyl) -2- [2- (6-trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 5-88), (±) -N-hydroxy-N-methyl -Na- [4- (pyridin-4-yl) oxybenzenesulfonyl] -2- [2-thieno [3,2-d] pyrimidin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 5- 98), (+) - 2- [2- (6-chloro-1-methyl-pyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- ( 4-phenoxybenzenesulfonyl) glycinamide (Compound No. 7-212), (±) -Na- [4- (4-chlorophenoxy) benzenesuifonyl] -2- [2- (6-chloropyrimidine-2,4-dione-3 -yl) -ethyl] -N-hydroxy-Na-methylglycinamide (Compound No. 7-181), (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl) -Na- [4- (4-fluorophenoxy) -be ncenosulfoniI] -N-hydroxy-Na-methylglycinamide (Compound No. 7-182), (±) -Na- [4- (4-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- ( 6-trifluoromethyipyrimidin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 8-181), (±) -Na- [4- (4-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl -2- [2- (6-trifluoromethylpyrimidin-2), 4-dione-3-yl) etl] glycanamide (Compound No. 8-182), (±) -Na- [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl -2- [2- (6-Trifluoromethyl-2,4-dione-3-yl) ethyl] glycineamide (Compound No. 8-194), (+) - Na- [4- (3 -chlorophenoxy) benzenesulfonyl] -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) -eti] N-hydroxy-Na-methylglycinamide (Compound No. 7-194), (± ) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -N-ethyl-N-hydroxy-Na- (4-phenoxybenzenesulfonyl) glycinamide (Compound No. 7-42), (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -Na- [4- (3-fluorophenoxy) -benzenesulfonyl] -N-hydroxy-Na-methyl-glucinamide (Compound No. 7-196), (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-N -methyl-Na- [4- ( pyridin-4-yl) oxybenzenesulfonyl] glycinamide (Compound No. 7-26), (±) -Na- [4- (3-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (6 -trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 8-196), (±) -N-hydroxy-Na-methyl-Na- (4- (pyridine-4-) il) oxybenzenesulfonyl] -2- [2- (6-trifluorome tilpyrimidin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 8-26), (±) -Na-ethyl-N-hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- [2- ( 6-trifluoromethylpyrimidin-2,4-dione-3-yl) etl] glycinamide (Compound No. 8-42), (±) -N-hydroxy-Na-methyl-2- [2- (1-methyl-6-trifluoromethylpyrimidin-2,4-dione-3-yl) ethyl] -Na- (4-phenoxybenzenesulfonyl) glycinamide (Compound No. 8-212), (±) -2- [2- (5 chloropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide (Compound No. 5-35), Na- [4- (3 chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2-quinazolin-2,4-dione-3-yl) ethyl] glycinamide (Compound No. 1 -182), Na- [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (thieno [3,2-d] pyrimidin-2,4-dione-3-yl) ethyl] glycinamide (Compound No 5-99), and N - [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- (2-phthalimidoyl) glycinamide (Compound No. 3-183).

PREFERRED MODALITIES OF THE INVENTION The compound of formula (I) of the present invention can be prepared according to the following A-F methods.

METHOD A Step 6 Hydroxyamidation In the above formulas, R2, R4 and R5 have the same meanings defined above; R3a represents a group of the definition of R3 different from a hydrogen atom; G1 represents a carboxyl protecting group; L represents a hydroxyl group or a leaving group; and Q represents a "halogen atom" mentioned above (preferably a bromine atom or a chlorine atom, preferably a chlorine atom). The "leaving group" in the definition of L denotes a group that normally comes out as a nucleophilic residue, and examples of such a group include halogen atoms such as chlorine, bromine and iodine; trihalogenomethyloxy groups such as trichloromethyloxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; lower halogenoalkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy, of which halogen atoms and lower alkanesulfonyloxy groups are preferred. The "carboxyl protecting group" in the definition of G1 means a protecting group that can be removed by chemical methods such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and examples of such group include groups similar to those described as the "group". general protector "referred to an" ester group of a carboxyl group ". Preferably, it is a "lower alkyl group", a "lower alkenyl group", an "aryl group" or an "aralkyl group", and is preferably a "lower alkyl group", a "lower alkenyl group" or a "lower alkyl group" aralkyl. " Step 1 is a process for preparing the compound of formula (3) by reacting the amino group of the compound of formula (1) with the sulfonylhalogenide compound of formula (2), and is carried out in a solvent in the presence or absence of one base. Examples of the solvent to be used herein include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; and aliphatic hydrocarbons such as pentane, hexane and heptane. Examples of the base to be employed herein include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] -7-undequene. The reaction can be carried out at a temperature of -20 ° C to 150 ° C, preferably at a temperature of 0 ° C to 100 ° C.

Although the reaction time varies mainly depending on the reaction temperature, the solvent used, etc., is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.

Step 2 is a process for preparing the compound of formula (la) of the present invention, removing the group G1 of the compound of formula (3), and removing the protecting group, which may vary depending on the type thereof, which can be carried performed, according to methods generally known in the art, as follows: In the case where a lower alkyl group or an aryl group is used as the carboxyl protecting group, it can be removed by treatment with a acid or a base. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and the base is not particularly limited, as long as it does not affect other parts of the compound, and preferred examples include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or a solution of concentrated ammonia and methanol. Incidentally, isomerization may occur in hydrolysis with a base. The solvent to be used here is not particularly limited, as long as it is usual in hydrolysis reactions and does not inhibit the reaction; preferred examples include water or mixtures of water and an organic solvent such as an alcohol, for example methanol, ethanol or n-propanol, or an ether, for example tetrahydrofuran or dioxane. Although the temperature and the reaction time vary depending on the starting material, the solvent, the reagent used, etc., are not particularly limited, the reaction is usually carried out at a temperature of 0 ° C to 150 ° C for a period of time. period from 1 to 10 hours to control any secondary reaction. In the case where the carboxyl protecting group is a methyl group substituted with diaryl, such as diphenylmethyl, this can usually be removed by treatment with an acid in a solvent. The solvent that can be employed herein is, preferably, an aromatic hydrocarbon such as anisole, and a fluorinated organic acid such as trifluoroacetic acid can be used herein as the acid. Although the temperature and the reaction time vary depending on the starting material, the solvent, the acid used, etc., the reaction is usually carried out at room temperature for a period of 30 minutes to 10 hours. In the case where the carboxyl protecting group is an aralkyl group or a lower halogenalkyl group, this can usually be removed by reduction in a solvent. In the case where the carboxyl protecting group is a lower halogenoalkyl group, the reduction method is preferably a chemical reduction process such as with zinc-acetic acid, and in the case where it is an aralkyl group, it can be carried out by a catalytic reduction with a catalyst such as palladium on carbon, palladium hydroxide or platinum, or by chemical reduction with an alkali metal sulfide such as potassium sulfide or sodium sulfide. The solvent for use herein is not particularly limited, so long as it does not affect the present reaction, and preferred examples of solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; aliphatic acids such as acetic acid, or mixtures of these organic solvents and water. Although the temperature and the reaction time vary depending on the starting material, the solvent, the reduction method, etc., the reaction is usually carried out at a temperature of 0 ° C at room temperature, for a period of 5 minutes. 12 hours. In the case in which the carboxyl protecting group is an alkoxymethyl group, this can usually be removed by treatment with an acid in a solvent. The acid that can be employed herein is not particularly limited, as long as it is commonly used as a Bpansted acid, and preferred examples include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and paratoluenesulfonic acid.The solvent employed herein is not particularly limited, as long as it does not affect the present reaction, and preferred examples include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or mixtures of these organic solvents and water. Although the temperature and the reaction time vary depending on the starting material, the solvent, the type of acid used, etc., the reaction is usually carried out at a temperature of 0 ° C to 100 ° C, over a period of time. 10 minutes to 18 hours. When the removal of the carboxyl protecting group is carried out by treatment with ammonia, according to a conventional method, amidation can be carried out. If desired, alkali metal salts can be prepared according to a conventional method, by dissolving the above-mentioned carboxylic acid thus produced, in a mixture of water and an organic solvent immiscible with water, such as ethyl acetate, by adding to this solution an aqueous solution of alkali metal carbonate or bicarbonate, such as an aqueous solution of sodium acid carbonate or an aqueous solution of potassium carbonate, at a temperature of 0 ° C to room temperature, then adjusting the pH of the mixture to approximately 7, and collecting the separated precipitates by filtration. In addition, the esters protected with a carboxyl protecting group, which can be hydrolysed easily hydrolyzed in vivo, can be prepared by reacting the salt thus prepared or the carboxylic acid mentioned above, with 2 equivalents of base (preferably an organic base such as triethylamine or dicyclohexylamine, a hydrogenated alkali metal salt such as sodium hydride or an alkali metal carbonate or bicarbonate such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate) in a solvent (preferably an ether such as tetrahydrofuran or a polar solvent) such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and triethyl phosphate) and reacting an aliphatic acyloxymethyl halide such as acetoxymethyl chloride or propionyloxymethyl bromide, a halide of 1-lower alkoxycarbonyl alcohol; such as 1-methoxycarbonyloxyethyl chloride or 1-ethoxycarbonyloxyethyl iodide, a halide of phthalidiyl or a halide of (2-oxo-5-methyl-1,3-dioxolen-4-yl) methyl, with the reaction mixture. Although the temperature and reaction time vary depending on the starting material, the solvent and the types of reagents, the reaction is usually carried out at a temperature of 0 ° C to 100 ° C, for a period of 0.5 to 10 hours. .

Step 3 is a process for hydroxyamidation of the compound of formula (Ia) of the present invention. The compound of formula (Ib) of the present invention is produced by reacting the compound of formula (Ia) of the present invention, or a reactive derivative thereof, with hydroxylamine.

In the case in which the compound per se is subjected to hydroxyamidation in the present step, the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) ) carbodiimide or N, N'-carbonyldiimidazole. Examples of the solvent that can be used herein include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol and t-butanol; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; and water, or a mixture thereof. The reaction can be carried out at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. The reaction time is usually a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours. In the case where the compound of formula (la) is first converted into a reactive derivative and then subjected to hydroxyamidation, examples of the reactive derivatives include acid halides, mixed acid anhydrides and activated esters. Acid halides can be prepared by reacting the compound of formula (la) with a halogenating agent such as thionyl chloride or oxalyl chloride; mixed acid anhydrides can be prepared by reacting the compound of formula (la) with an acid halide such as methyl chlorocarbonate or ethyl chlorocarbonate; and the activated esters can be prepared by reacting the compound of formula (la) with a hydroxy compound such as N-hydroxysuccinimide or N-hydroxyphthalimide, in the presence of one of the condensation agents mentioned above, and in each case reaction usually employed in conventional organic synthesis chemistry. It is possible to prepare the compound of formula (Ib) by preparing a protected hydroxyamide using a protected hydroxylamine such as O-benzylhydroxylamine or O- (t-butyldimethylsilyl) hydroxylamine in place of the hydroxylamine according to the present step and, after , deprotecting it according to the method described in step 2. Step 4 is a process for preparing the compound of formula (5) by modifying the N atom in the sulfonamide portion of the compound of formula (3). (a) In this step, if L of the compound of formula (4) is a hydroxyl group, the Mitsunobu reaction [D.L. Hughes, Org. React., 42, 335 (1992)]. The reagent that can be used in the Mitsunobu reaction is not particularly limited, as long as it is usual in the Mitsunobu reaction, and preferred examples include the combination of an azo compound such as a di-lower alkyl azodicarboxylate, for example, diethyl azodicarboxylate or diisopropyl azodicarboxylate, or an azodicarbonyl, for example 1,1 '- (azodicarbonyl) dipiperidine such as a triarylphosphine, for example triphenylphosphine, or a tri-lower alkylphosphine such as tri-n-butylphosphine; the combination of the di-lower alkyl azodicarboxylate and the triarylphosphine is preferable, and the combination of diethyl azodicarboxylate and triphenylphosphine is very preferred. The solvent that can be employed herein is not particularly limited, as long as it does not inhibit the reaction and dissolves the starting material to a certain degree, and preferred examples include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide and sulphones such as sulfolane, of which aromatic hydrocarbons and ethers are preferred. The reaction can be carried out at a temperature of -20 ° C to 150 ° C, preferably from 0 ° C to 100 ° C. Although the reaction time varies mainly depending on the reaction temperature, the starting material, the reagent or the type of solvent used, it is usually for a period of 10 minutes to 3 days, preferably 30 minutes to 12 hours. (b) In the case in which the group L of the compound of formula (4) is a leaving group, the reaction is carried out in a solvent in the presence or absence of a base. Examples of the solvent that can be employed herein include alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; and aliphatic hydrocarbons such as pentane, hexane and heptane. Examples of the bases that may be employed herein include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] -7-undequene. Step 5 is a process for preparing the compound of formula (le) of the present invention, removing the G1 group from the compound of formula (5), and carried out in a manner similar to the procedure described in step 2. Step 6 is a process for preparing the compound of formula (Id) of the present invention by means of hydroxyamidation of the compound of formula (le) of the present invention, and is carried out in a manner similar to the procedure described in step 3.

METHOD B Method B is a process for preparing the compound of formula (1 '), which is a compound of formula (1) in which R2 is a group of formula -A-R6 (in the formulas, A and R6 have the same meanings defined above), which is a starting material in method A. (6) (8) (11) In the formulas, R6, A, G1 and L have the same meanings defined above; and G2 represents an amino protecting group. The "amino protecting group" in the definition of G2 means a protecting group that can be removed by a chemical process such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and examples include the "aliphatic acyl groups" mentioned above, the "groups aromatic acyl "mentioned above, the" alkoxycarbonyl groups "mentioned above, the alkenyloxycarbonyl groups" mentioned above, the "aralkyloxycarbonyl groups" mentioned above, the "silyl groups" mentioned above and the "aralkyl groups" mentioned above, of which are preferred the "alkoxycarbonyl groups", the "alkenyloxycarbonyl groups" and the "aralkyloxycarbonyl groups", the t-butoxycarbonyl, allyloxycarbonyl and benzyloxycarbonyl groups being most preferred Step 7 is a process for preparing the compound of formula (8) by reacting the compound of formula (6) with the compound of formula (7), and is carried out in a manner similar to the processes of written in (a) or (b) of step 4 above. Step 8 is a process for preparing the compound of formula (1 ') by removing the group G2 from the compound of formula (8). The removal of the G2 group, which may vary depending on its type, can be carried out according to the methods generally known in the art, which are described below: In the case where G2 is a silyl group, it is it can be conventionally removed by treatment with a compound capable of producing a fluoride anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited, as long as it does not inhibit the reaction, and preferred examples include ethers such as tetrahydrofuran and dioxane.

The temperature and the reaction time are not particularly limited, and the reaction is usually carried out at room temperature for a period of 10 to 18 hours. In the case where G2 is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, this can be removed by treatment with an acid or a base in the presence of an aqueous solvent. The acid used here is not particularly limited, so long as it is conventionally used and does not inhibit the reaction, and preferred examples include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, organic acids such as trifluoroacetic acid or Lewis acids such as bromocatecolborane (Lewis acids are most preferred and B-bromocatechylborane is preferred). The base employed herein is not particularly limited, as long as it does not affect other parts of the compounds, and preferred examples include metal alkoxides such as sodium methoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and ammonia compounds such as aqueous ammonia and concentrated ammonia-methanol. Incidentally, isomerization may occur in hydrolysis with a base. The solvent employed herein is not particularly limited, as is usual in hydrolysis reactions, and preferred examples include water; organic solvents such as alcohols, for example methanol, ethanol and n-propanol; and ethers such as for example tetrahydrofuran and dioxane; and mixtures of these organic solvents and water. Although the temperature and the reaction time vary depending on the starting material, the solvent, the acid or base used, etc., and are not particularly limited, the reaction is usually carried out at a temperature of 0 ° C to 150 ° C. ° C for a period of 1 to 10 hours, to control any secondary reaction. In the case where G2 is an aralkyl group or an aralkyloxycarbonyl group, the G2 removal method is preferably carried out by placing a compound in contact with a reducing agent in a solvent (preferably a catalytic reduction at a normal temperature in the presence of a catalyst) or using an oxidizing agent. The solvent that is employed in the removal by catalytic reduction is not particularly limited, as long as it does not affect the present reaction, and preferred examples include alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene, benzene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; esters such as ethyl acetate and propyl acetate; aliphatic acids such as acetic acid; and mixtures of these organic solvents and water. The catalyst employed herein is not particularly limited, so long as it is conventionally used in catalytic reduction reactions, and preferred examples include palladium on carbon, palladium hydroxide, Raney nickel, platinum oxide, platinum black, rhodium oxide. -aluminum, triphenylphosphine-rhodium chloride and palladium-barium sulfate. The pressure is not particularly limited and the reaction is usually carried out at a pressure of 1 to 10 atm. Although the temperature and the reaction time vary depending on the starting material, the solvent and the type of catalyst employed, the reaction is usually carried out at a temperature of 0 to 100 ° C for a period of 5 minutes to 24 hours. The solvent that is used in the oxidation removal is not particularly limited, as long as it does not affect the present reaction, and an hydrated organic solvent is preferred. Preferred examples of said organic solvent include ketones such as acetone, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, nitriles such as acetonitrile, ethers such as diethyl ether, tetrahydrofuran and dioxane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide, and sulfoxides such as dimethyl sulfoxide. The oxidizing agent employed herein is not particularly limited, as long as it is used in oxidation, and preferred examples include potassium persulfate, sodium persulfate, cerium ammonium nitrate (CAN) and 2,3-dichloro-5,6 -dic-p-benzoquinone (DDQ).

Although the temperature and the reaction time vary depending on the starting material, the type of solvent and the catalyst, the reaction is usually carried out at a temperature of 0 ° C to 150 ° C for a period of 10 minutes to 24 hours. . In the case where G2 is an alkenyloxycarbonyl group, the removal can usually be performed using conditions similar to those of the removal reaction in the case where the amino protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. In the case where G2 is an allyloxycarbonyl group, particularly, the removal can be carried out easily using palladium and triphenylphosphine or nickel tetracarbonyl, with fewer side reactions. Although the G1 group can be removed in this step, the carboxyl group can be protected again according to the following methods: Method 1 Method 1 is to react the resulting carboxylic acid derivative with a compound of formula G1-L '(wherein G1 has the same meaning as defined above and L' represents a leaving group) in a solvent (the solvent that is employed herein is not particularly limited, as long as it does not inhibit the reaction and dissolves the starting material to a certain degree, and preferred examples include aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone, nitriles such as acetonitrile and isobutyronitrile, and amides such as rmamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide) in the presence of a base [the base used here is not particularly limited, as long as it is used as a base in conventional reactions, and preferred examples include inorganic bases such as alkali metal carbonates, for example sodium carbonate, potassium carbonate and lithium carbonate; alkali metal acid carbonates, for example sodium hydrogen carbonate, potassium hydrogen carbonate and lithium acid carbonate; alkali metal hydrides, for example lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal fluorides, for example sodium fluoride and potassium fluoride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; alkaline metal mercaptans such as sodium methyl mercaptan and sodium ethyl mercaptan; organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) ) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane (DABCO) ) and 1, 8-diazabicyclo [5.4.0] -7-undequene (DBU), and organic metal bases such as butyllithium, lithium diisopropylamide and lithium bis (trimethylsilyl) amide], usually at a temperature of -20 ° C at 150 ° C (preferably 0 to 100 ° C) for a period of 0.5 to 10 hours.

Method 2 Method 2 is to react the resulting carboxylic acid derivatives with a compound of formula G1-OH (wherein G1 has the same meaning as defined above) in a solvent, in the presence or absence of a base, with the "agent of condensation "next. Examples of the condensing agent that are employed in the present reaction include: (1) a combination of a phosphoric ester such as diphenylphosphorylazide or diethyl cyanophosphate, and a base of which are mentioned below; (2) a carbodiimide such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; a combination of the carbodiimide and an N-hydroxy compound such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxyimide; (3) a combination of a disulfide such as 2,2'-dipyridyl disulfide or 2,2'-dibenzothiazolyl disulfide, and a phosphine such as triphenylphosphine or tributylphosphine; (4) a carbonate such as N.N'-disuccinimidyl carbonate, di-2-pyridyl carbonate or S, S'-b.s (1-phenyl-1 H-tetrazol-5-yl) dithiocarbonate; (5) a phosphinic chloride such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; (6) an oxalate such as N.N'-disuccinimidyl oxalate, N.N'-diftalimide oxalate, N, N'-bis (5-norbornene-2,3-dicarboximide) oxalate, oxalate of 1 , 1'-bis (benzotriazolyl), 1,1'-bis (6-chlorobenzotriazolyl) oxalate or l, 1'-bis-trifluoromethyl-benzotriazolyl oxalate): (7) a combination of the phosphine and an acid ester azodicarboxylic acid or an azodicarboxyamide such as diethylazodicarboxylate ol.l'-iazodicarboni -dipiperidine; a combination of the phosphines and a base of those mentioned below; (8) an N- (lower alkyl) -5-arylisoxazole-3'-sulfonate such as N-ethyl-5-phenylisoxazolium-3'-sulfonate; (9) a diheteroaryldiselenide such as di-2-pyridyldiselenide; (10) an arylsulfonyltriazolide such as p-nitrobenzenesulfonyltriazolide; (11) a halide of 2-halo-1 - (lower alkyl) pyridinium such as 2-chloro-1-methylpyridinium iodide; (12) an imidazole such as 1,1'-oxalyldiimidazole or N, N'-carbonyl-diimidazole; (13) a 3- (lower alkyl) -2-halogeno-benzothiazolium fluoroborate, such as 3-ethyl-2-chloro-benzothiazolium fluoroborate; (14) a 3- (lower alkyl) -benzothiazole-2-selone, such as 3-methylbenzothiazole-2-selone; (15) a phosphate, such as phenyldichlorophosphate or polyphosphate; (16) a halo-sulfonyl socianate such as chlorosulfonyl socianate; (17) a halosilane such as trimethylsilyl chloride or triethylsilyl chloride; (18) a combination of a lower alkanesulfonyl halide such as methanesulfonyl chloride, and a base of those mentioned below; (19) a N, N, N ', N'-tetra- (lower alkyl) haloformamide chloride such as N, N, N \ N'-tetra- (methyl) chloroformamide chloride. Of these, carbodiimides or a combination of a phosphine and an azodicarboxylic ester or azodicarboxyamide are preferred. The solvent employed herein is not particularly limited, as long as it does not inhibit the reaction and dissolves the starting material to a certain degree, and preferred examples include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; and amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide. The base employed herein is not particularly limited, so long as it is used as a base in conventional reactions, and preferred examples include organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine. , picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline and N, N-diethylaniline. Incidentally, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be used in a catalytic amount, by combining them with other bases and in addition a dehydrating agent such as molecular sieves, quaternary ammonium salts can also be added as benzyltriethylammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and an acid scavenger such as 3,4-dihydro-2H-pyrido [1,2-a] pyrimidin-2-one, to perform the reaction effectively.

The reaction is usually carried out at a temperature of -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C. The reaction time varies mainly depending on the reaction temperature, the starting material, the reagent and the type of solvent used, and usually it is for a period of 10 minutes to 3 days, preferably 30 minutes to 1 day.

Method 3 In the case where the protecting group is a lower alkyl group, method 3 is a method for reacting the resulting carboxylic acid derivatives with a corresponding alcohol such as methanol, ethanol, propanol or butanol, in a solvent ( the solvent employed herein is not particularly limited, as long as it does not inhibit the reaction and dissolves the starting material to a certain degree, and preferred examples include alcohols identical to the reactant, aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene , toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, sophorone and cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; and amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide, of which alcohols identical to the reagent are preferred) in the presence of an acid catalyst (The catalyst employed herein is not particularly limited, so long as it is used as an acid catalyst in conventional reactions, and preferred examples include Bpzmsted acids such as inorganic acids, for example hydrogen chloride, hydrobromic acid, sulfuric acid, acid perchloric and phosphoric acid, and organic acids for example acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid, and Lewis acids, for example boron trichloride, boron trifluoride and boron tribromide, and acid ion exchange resins), at a temperature of 0 ° C to 150 ° C (preferably 50 C to 100 ° C) for a period of 10 minutes to 24 hours (preferably 30 minutes to 10 hours).

METHOD C In the formulas, R4, R5, R7, R8, A, G1, G2 and Q have the same meanings defined above; and G3 represents an amide protecting group. The "amide protecting group" in the definition of G3 means a protecting group that can be removed by a chemical process such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and preferred examples include lower alkoxy-lower alkyl groups such as the groups " lower alkoxymethyl "mentioned above; aralkyloxymethyl groups such as benzyloxymethyl; and 2- [tri (lower alkyl) silyl] ethoxy-lower alkyl groups such as 2- (tri-methylsilyl) ethoxymethyl, of which methoxymethyl, benzyloxymethyl and 2- (tri-methylsilyl) ethoxymethyl are preferred. Steps 9, 10, 11 and 13 of method C are carried out in a manner similar to the procedures described in steps 4, 8, 1 and 3, respectively. Step 12 is a process for preparing the compound of formula (1e) of the present invention, removing the two protecting groups (groups G1 and G2) of the compound of formula (12), and carried out in a manner similar to the process described in steps 2 or 8. In the present invention, although the compound of formula (13) or (14), which is a compound of formula (12) in which one of the protecting groups is removed, can be produced, it can convert into a compound of formula (le) by additionally carrying out a deprotection reaction in a manner similar to the procedure described above (steps 12a and 12b). METHOD D fifteen In the above formulas, R3a, R4, R5, R7, R8, A, G \ G3 and L have the same meanings defined above. Steps 14 and 16 of method D are carried out in a manner similar to the procedures described in steps 4 and 3 of method A, respectively, and step 15 (15a and 15b) is carried out in a manner similar to the procedures described in step 12 (12a and 12b).

METHOD E In the formulas, R3a, R4, R5, R6, G1, L and Q have the same meanings defined above; and p is an integer from 1 to 6, preferably from 2 to 4. Steps 17, 18, 21a, 21 b, 22 and 23 of method E are carried out in a manner similar to the procedures described in steps 1, 4, 4-a), 4-b), 2 and 3, respectively. Step 19 is a process for preparing an ester derivative of formula (22) by hydrolyzing the lactone compound of formula (20), followed by reaction of the resulting compound with a halide compound of formula (21). (1) Although the above hydrolysis reaction can be carried out by a method generally used in organic synthesis chemistry, the method of treating the lactone compound of formula (20) with a base in a solvent is preferred. The base employed herein is not limited, as long as it does not affect other parts of the compound, and preferred examples include metal alkoxides such as sodium methoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, and ammonia products such as aqueous ammonia and concentrated ammonia-methanol. The solvent employed herein is not limited, as long as it is usual in hydrolysis reactions, and preferred examples include water; organic solvents such as alcohols, for example methanol, ethanol and n-propanol; and ethers such as for example tetrahydrofuran and dioxane; and mixtures of these organic solvents and water. Although the temperature and the reaction time may vary depending on the starting material, the solvent, the base used, etc., and are not particularly limited, the reaction is usually carried out at a temperature of 0 ° C to 150 ° C. for a period of 1 to 10 hours, to control any secondary reaction. (2) The above protection reaction of the carboxyl group can be carried out in a manner similar to that described in step 8. Preferably, it is carried out according to the method 1 described in step 8. Step 20 is a process for preparing the compound of formula (23), converting the hydroxyl group of the compound of formula (22) to a halogen atom and, for example, a fluorination reaction with diethylamino sulfurotrifluoride (DAST); a chlorination reaction with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or triphenylphosphine / carbon tetrachloride; a bromination reaction with hydrobromic acid, thionyl bromide, phosphorus tribromide or triphenylphosphine / carbon tetrabromide; or an iodination reaction is carried out with hydroiodic acid or phosphorus triiodide, according to the method described in "W.J. Middleton [J. Org. Chem., 40, p 574 (1975)]".

METHOD F In the formulas, R3a, R4, R5, R6, L and Q have the same meanings defined above; and G4 represents a hydroxyl protecting group.

The "hydroxyl protecting group" in the definition of G4 means a protecting group that can be removed by a chemical process such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and preferred examples include the "silyl groups" mentioned above, of which The above-mentioned "tri (lower alkyl) silyl groups" are preferred, with trimethylsilyl, triethylsilyl, isopropyldimethylsilyl and t-butyldimethylsilyl groups being particularly preferred. Step 24 is a process for preparing a compound of formula (26) by reacting the amino group of serinol (25) with the sulfonyl halide compound of formula (2), and carried out in a manner similar to the procedure described in step 1. Step 25 is a process for preparing a compound of formula (27) by modifying the N atom in the sulfonamide portion of the compound of formula (26), and carried out in a manner similar to the procedure described in step 4. Step 26 is a process for preparing a compound of formula (29), protecting one of the two hydroxyl groups of the diol compound of formula (27), and is carried out, for example, by reacting it with a halogenide compound of tri (lower alkyl) silyl of formula (28). The reaction is carried out, for example, according to the procedures for the synthesis of silyl ethers described in "Protective Groups in Organic Synthesis", John Wiley &Sons, New York, 1991. " Step 27 is a process for preparing a compound of formula (30), by reacting the compound of formula (29) with the compound of formula (7), and carried out in a manner similar to the procedure described in step 4- to). Step 28 is a process for preparing a compound of formula (31), by removing the hydroxyl protecting group of compound (30), and is carried out, for example, according to the silyl ether decomposition process described in "Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991." Step 29 is a process for preparing an aldehyde compound of formula (32) by oxidizing the hydroxyl group of the compound of formula (31), and is carried out, for example, using chromic acid, manganese dioxide, dimethyl sulfoxide, etc. ., according to the procedures described in "K. Omura, AK Sharma and D. Swern [J. Org. Chem., 4 .957 (1976)] and SL Huang, K. Omura and D. Swern [Tetrahedron , 34, p.1651 (1978)] ". Step 30 is a process for preparing a compound of formula (Ik) of the present invention, by oxidizing the aldehyde compound of formula (32), and is carried out using permanganic acids, chromic acid, peroxides, oxygen, halogen, hypohalogenic acids , halogenic acids, halogen acids, nitric acid, etc., according to the procedures described in "T. Kageyama, Y. Ueno and M. Okawara [Synthesis, p.815 (1983)] and CD Hurd, JW Garrett and IN Osborne [J. Am. Chem. Soc, 55, p.1082 (1933)] ". Step 31 is a process for preparing a compound of formula (II) of the present invention, by hydroxyamidation of the compound of formula (Ik) of the present invention, and carried out in a manner similar to the procedure described in step 3. The starting materials, particularly the compounds (1), (6), (18) and (25), and the secondary starting materials, particularly the compounds (2), (4), (7), (9), (21) and (28), are known per se. , or can be obtained from known compounds by means of treatments according to known methods.

After finishing each of the reactions described above, the desired compound is isolated from the reaction mixture in the conventional manner. For example, it is obtained by neutralizing the reaction mixture as necessary, removing the insoluble materials by filtration, if any.; adding organic solvents that are not miscible with each other, such as water and ethyl acetate; washing with water or similar; separating the organic layer containing the desired compound, drying it over anhydrous magnesium sulfate or the like, and then separating the solvent by distillation. If necessary, the desired compound thus obtained can be isolated and purified using a conventional method such as recrystallization or reprecipitation, and chromatography, which is a method ordinarily employed for the isolation and purification of an organic compound in combination, as required, and eluting with an appropriate eluent. Examples of the chromatography include column adsorption chromatography using a carrier such as silica gel, alumina or magnesium-silica gel of the Florisil type; chromatography using a synthetic adsorbent, eg, column partition chromatography using a carrier such as Sephadex LH-20 (product of Pharmacia), Amberlite XAD-11 (product of Rhom &Haas) or Diaion HP-20 (product of Mitsubishi Chemical ), ion exchange chromatography or normal reverse phase column chromatography (high performance liquid chromatography) using a silica gel or alkylated silica gel. As the compounds of formula (I) of the present invention or their salts, esters or other pharmacologically acceptable derivatives thereof, exhibit excellent inhibitory action of MMP-13 and an excellent aglyngase inhibitory activity, they are effective as medicaments (particularly, as agents for the prevention or treatment of arthritis such as osteoarthritis and chronic rheumatism, or as medicaments for inhibiting metastasis, invasion or development of cancer), and examples of the route of administration include oral administration in the form of tablets, capsules, granules, powders or syrups, and parenteral administration in the form of injections or suppositories. Said formulations can be prepared in the known manner using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrigents or diluents.

Examples of the excipients include organic excipients, for example sugar derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose and internally interlaced sodium carboxymethylcellulose; gum arabic; dextran and pullulan; and inorganic excipients such as for example silicate derivatives such as soft silicic acid anhydride, synthetic aluminum silicate and magnesium aluminometasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate. Examples of the lubricant include stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talcum powder; colloidal silica; waxes such as bees glue and whale sperm; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of an aliphatic acid; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid derivatives such as silicic acid anhydride and hydrated silicic acid; and starch derivatives, above exemplified as excipients. Examples of binders include polyvinyl pyrrolidone, Macrogol and similar compounds to those exemplified above as excipients. Examples of the disintegrant include compounds similar to those above exemplified as excipients, and chemically modified starch or cellulose derivatives, such as croscarmellose sodium, carboxymethylstarch sodium and crosslinked polyvinylpyrrolidone. Examples of the stabilizer include esters of paraoxybenzoate such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol and cresol; thimerosal; dehydroacetic acid and sorbic acid. Examples of the proofreader include ordinary sweeteners, acidifiers and flavorings.

The dose of the compound (I) or its pharmacologically acceptable salt, ester or derivative according to the present invention will vary depending on the condition, age of the patient or route of administration. Orally administered to an adult in an amount of 0.1 mg (preferably 1 mg) daily as the lower limit and 1000 mg (preferably 100 mg) daily as the upper limit. It is convenient to administer it in one or more portions, depending on the patient's condition. Intravenously, an adult is administered in an amount of 0.01 mg (preferably 0.1 mg) daily as the lower limit, and 100 mg (preferably 10 mg) daily as the upper limit. It is convenient to administer it in one or several portions a day, depending on the patient's condition.

PREFERRED MODALITIES OF THE INVENTION In the following, the present invention will be described more specifically by examples, formulation examples and test examples. However, the present invention is not limited to such examples.

EXAMPLES EXAMPLE 1 (±) -N-Met.l-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidodoxy) kinin (Compound No. 3-179) (1) (±) -N- (tert-butoxycarbonyl) -2- (phthalimidoethyl) glycine allyl ester Diethyl azodicarboxylate (5.7 ml, 36.2 mmol, abbreviated DEAD hereinafter) was added dropwise to a mixture allyl ester of (±) -N- (tert-butoxycarbonyl) homoserine (7.79 g, 30.0 mmol), phthalimide (4.41 g, 30 mmol), triphenylphosphine (9.45 g, 36.0 mmol) and tetrahydrofuran (75 mL), at room temperature environment and with agitation. This mixture was stirred for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 4/1 as eluent to produce the desired compound (8.46 g, 73% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.86-7.83 (2H, m), 7.74-7.70 (2H), m), 5.92-5.77 (1H, m), 5.31-5.19 (3H, m), 4.51-4.39 (3H, m), 3.80 (2H, t, J = 7Hz), 2.30-2.07 (2H, m), 1.44 (9H, s). (2) Allyl ester of (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine (a) Trifluoroacetic acid (14 ml) was added to an allylester solution of (±) - N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine (5.60 g, 14.4 mmol), the product of (1) above, in dichloromethane (30 ml) with ice-cooling. This mixture was stirred at room temperature for 2 hours. The solvent in the reaction mixture was evaporated under reduced pressure. Hydrochloric acid (6N) was added to the residue and the mixture was extracted with diethyl ether. The water layer was made basic with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue and the mixture was filtered to yield a white powder (3.77 g, 91% yield, de-tert-butoxycarbonyl product). (b) Triethylamine (4.5 ml, 32.4 mmol) was added to a solution of the white powder (3.71 g, 12.9 mmol), product of (a) above, in dichloromethane (40 ml). A solution of 4-phenoxybenzenesulfonyl chloride (3.64 g, 13.5 mmol) in dichloromethane (10 ml) was added dropwise to the solution, with cooling with ice. This mixture was stirred at room temperature for 6 hours. The solvent in the reaction mixture was evaporated under reduced pressure. Hydrochloric acid (1N) was added to the residue to make it acidic. This residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diiodopropyl ether was added to the residue and the mixture was filtered to yield the desired product (6.30 g, 94% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.86-7.70 (6H, m), 7.40 (2H, t, J = 7Hz), 7.22 (1H, t, J = 7Hz), 7.07-6.98 (4H, m), 5.77-5.60 (1 H, m), 5.49 (1 H, d, J = 9Hz), 5.20-5.13 (2H, m), 4.36-4.22 (2H, m), 4.13-4.05 ( 1 H, m), 3.97-3.86 (1 H, m), 3.79-3.68 (1 H, m), 2.20-2.13 (2H, m). (3) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine allyl ester Methyl iodide (0.83 g, 5.8 mmol) and potassium carbonate (5.34 g, 38.4 mmol) to a solution of (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine (2.00 g, 3.8 mmol) allylester, the product of (2) above, in N , N-dimethylformamide (20 ml). This mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 3/1 as eluent to produce the desired compound (1.90 g, 93% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.87-7.70 (6H, m), 7.40 (2H, t, 7Hz), 7.22 (1H, t, J = 7Hz), 7.08-6.98 (4H , m), 5.80-5.66 (1 H, m), 5.28-5.19 (2H, m), 4.78 (1 H, dd, J = 9Hz, 5Hz), 4.49-4.37 (2H, m), 3.88-3.70 ( 2H, m), 2.93 (3H, s), 2.36-2.23 (1H, m), 2.10-1.96 (1H, m). (4) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine Water (1.75 ml), tetrakis (triphenylphosphine) palladium (0) (8.2 mg, 0.007 mmol) were successively added. ) and pyrrolidine (0.45 ml, 5.3 mmol), to a solution of (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine allyl ester (1.88 g, 3.5 mmol), the product of (3) above, in dioxane (33 ml); The mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was washed with diethyl ether to give the title compound (1.64 g, 94% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDC-DMSO-dβ) d ppm: 7.86-7.71 (6H, m), 7.44-7.36 (2H, m), 7.24-7.17 (1H, m), 7.80-6.97 ( 4H, m), 4. 70 (1 H, dd, J = 10Hz, 6Hz), 3.88-3.71 (2H, m), 2.94 (3H, s), 2.38-2.24 (1 H, m), 2.07-1.93 (1H, m).

EXAMPLE 2 (±) -N-Hydroxy-Na-methyl-Na-tf4-phenoxybenzenesulfonyl) -2-f2-phthalimidoetiDalicinamide (Compound No. 3-26) N.N'-carbonyldiimidazole (0.60 g, 3.7 mmol) was added to a solution of (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine (1.50 g, 3.0 mmol) , the product of example 1, in a mixture of dichloromethane (15 ml) and tetrahydrofuran (7.5 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was added dropwise to a mixture of aqueous hydroxylamine [50% (p), 1.86 ml, 30.3 mmol], tetrahydrofuran (8 ml) and tert-butanol (4 ml), with ice-cooling and stirring, and this was stirred for 3 hours. The reaction mixture was acidified with hydrochloric acid (1 N) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as eluent, to give the title compound (0.95 g, 61% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 9.38 (1H, br.s), 7.85-7.80 (2H, m), 7.77-7.71 (2H, m), 7.62-7.59 (2H, m) , 7.45-7.40 (2H, m), 7.29-7.17 (2H, m). 7.09-7.06 (2H, m), 6.84-6.81 (2H, m), 4.33 (1H, dd, J = 9Hz, 5Hz), 3.67-3.61 (1H, m), 3.50-3.43 (1H, M) , 2.93 (3H, s), 2.38-2.27 (1H.m), 1.61-1.53 (1H, m).

EXAMPLE 3 (±) -N-Met.l-N- (4-phenoxybenzenesulfonyl) -2-f2- (thiazolidin-2,4-dione-3-yl) ethyl) glycine (1) (±) -N- (tert-butoxycarbonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl] glycine allyl ester A reaction was carried out in a manner similar to that which is described in Example 1 (1), using thiazolidin-2,4-dione in place of phthalimide, to give the desired compound (68% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 5.98-5.84 (1 H, m), 5.38-5.23 (3H, m), 4.63 (1 H, dt, J = 5Hz, 1 Hz), 4.43 -4.34 (1 H, m), 3.94 (2H, s), 3.75 (2H, t, J = 7Hz), 2.24-1.98 (2H, m), 1.46 (9H, s). (2) (±) -N- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl] glycine allyl ester Reactions were carried out in a manner similar to the procedures which are described in example 1 (2) (a) and (b), using (±) -N- (tert-butoxycarbonyl) -2- [2- (thiazolidin-2,4-dione-3- allyl ester il) ethyl] glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to produce the desired compound (43% of yield) as a pale yellow oil Nuclear Magnetic Resonance Spectrum 1H (270 MHz, CDCl 3) d ppm: 7.82-7.77 (2H, m), 7.41 (2H, t, J = 7Hz), 7.23 (1H, t, J = 7Hz), 7.08-6.99 (4H, m), 5.82-5.67 (1H, m), 5.44 (1H, d, J = 10Hz), 5.27-5.21 (2H, m), 4.43 (2H , d, J = 5Hz), 4.08-4.00 (1 H, m), 3.95-3.82 (3H, m), 3.73-3.63 (1 H, m), 2.14-2.06 (2H, m). (3) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl] glycine allyl ester A reaction of similarly to that described in example 1 (3), using (±) -N- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl allyl ester ] glycine, the product of (2) above, in place of the (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to produce the desired compound (88% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.78-7.73 (2H, m), 7.42 (2H, t, J = 8Hz), 7.23 (1H, t, J = 8Hz), 7.08-6.99 (4H, m), . 78-5.64 (1 H, m), 5.37-5.19 (2H, m), 4.70 (1 H, dd, J = 10Hz, 6Hz), 4.48-4.36 (2H, m), 3.98 (2H, s), 3.83-3.67 (2H, m) 2.87 (3H, s), 2.29-2.17 (1 H, m), 2.07- 1.92 (1 H, m). (4) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl] glycine A reaction was carried out in a similar manner to the one described in example 1 (4), using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl] glycine allyl ester, the product of (3) above instead of the (±) -N-metH-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to give the title compound (quantitative yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.78-7.73 (2H, m), 7.45-7.37 (2H, m), 7.25-7.19 (1H, m), 7.08-6.99 (4H, m ), 4.22 (1 H, dd, J = 10Hz, 6Hz), 3.96 (2H, s), 3.80-3.62 (2H, m). 2.86 (3H, s), 2.32-2.18 (1H, m), 2.03-1.88 (1 H, m).

EXAMPLE 4 f ±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonip-2-r2-ftiazolidin-2,4-dione-3-yl) ethyl) allicinamide (Compound No. 5-44 A reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione- 3-yl) ethyl] glycine, product of Example 3 above, in place of (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoetyl) glycine, to give the title compound (60% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.17 (1 H, br.s), 7.78-7.20 (2H, m), 7.48-7.39 (2H, m), 7.30-7.04 (6H, m ), 4.33 (1H, dd, J = 8Hz, 6Hz), 3.96 (1H, d, J = 18Hz), 3.94 (1H, d, J = 18Hz), 3.58-3.51 (1 H, m), 3.45-3.38 (1H, m), 2.86 (3H, s), 2.30-2.21 (1 H, m), 1.67-1.53 (1 H, m).

EXAMPLE 5 (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2-r2- (quinazolin-2,4-dione-3-yl) ethyl) glycine (Compound No. 1-178) (1) (±) -2- [2- (1-Benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine allyl ester A reaction was carried out in a similar manner to that described in Example 1 (1), using 1-benzyloxymethylquinazolin-2,4-dione in place of phthalimide, to produce the desired compound (76% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 8.18 (1 H, dd, J = 8 Hz, 1 Hz), 7.67 (1 H, dt, J = 8 Hz, 1 Hz), 7.48 (1 H, br.d, J = 8Hz), 7.31-7.25 (6H, m), 5.88-5.66 (3H, m), 5.53 (1H, br.d, J = 9Hz), 5.24 (1H, br D, J = 17Hz), 5.16 (1H, br.d, J = 10Hz), 4.71 (2H, s), 4.49-4.42 (3H, m), 4.28-4.10 (2H, m), 2.24-2.17 (2H, m). (2) (±) -2- [2- (1-Benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine ester. Reactions were carried out in a similar manner to the procedures described in example 1 (2) (a) and (b), using (±) -2- [2- (1-benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl allyl ester] -N- (tert-butoxycarbonyl) glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to produce the desired compound (88% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.15 (1 H, dd, J = 8Hz, 1Hz), 7.82-7.77 (2H, m), 7.67 (1 H, dt, J = 8Hz, 1Hz ), 7.48 (1 H, br.d, J = 8Hz), 7.43-7.35 (2H, m), 7.32-7.18 (7H, m), 7.05-6.94 (4H, m), . 90 (1 H, d, J = 9Hz), 5.68-5.54 (3H, m), 5.15-5.08 (2H, m), 4.71 (2H, s), 4.35-4.03 (5H, m), 2.37-2.23 ( 1 H, m), 2.18-2.05 (1 H, m). (3) (±) -2- [2- (1-Benzyloxymethyl-1-quinazolin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine ester carried out a reaction in a manner similar to that described in Example 1 (3), using (±) -2- [2- (1-benzyloxymethylquinazolin-2,4-dione-3-yl allyl ester ) etl] -N- (4-phenoxybenzenesulfonyl) glycine, the product of (2) above, in place of (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) allyl ester glycine, to produce the desired compound (quantitative yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 8.16 (1 H, dd, J = 8Hz, 1 Hz), 7.80-7.74 (2H, m), 7.67 (1 H, dt, J = 8Hz, 1 Hz), 7.48 (1 H, br.d, J = 8Hz), 7.43-7.36 (2H, m), 7.31-7.18 (7H, m), 7.08-6.97 (4H, m), 5.82-5.67 (3H , m), 5.28-5.18 (2H, m), 4.83 (1H, dd, J = 11Hz, 6Hz), 4.70 (2H, s), 4.50-4.37 (2H, m), 4.22-4.04 (2H, m), 2.98 (3H, s), 2.33-2.20 (1 H, m), 2.13-1.98 (1 H, m). (4) (±) -2- [2- (1-Benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine A reaction was carried out in a manner similar to that described in example 1 (4), using (±) -2- [2- (1-benzyloxymethylquinazoln-2,4-dione-3-yl) ethyl allyl ester] -N-methyl-N- (4-phenoxy-benzenesulfonyl) glycine, the product of (3) above, in place of the (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- allyl ester ( 2-phthalimidoethyl) glycine, to produce the desired compound (99% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) ppm: 8.15 (1 H, dd, J = 8Hz, 1 Hz), 7.78-7.72 (2H, m), 7.67 (1 H, dt, J = 8Hz, 1 Hz), 7.47 (1 H, br.d, J = 8Hz), 7.40-7.23 (8H, m), 7.16 (1 H, br.t, J = 8Hz), 7.04-6.95 (4H, m), . 69 (2H, br.s), 4.82 (1H, dd, J = 10Hz, 6Hz), 4.68 (2H, s), 4.18-3.99 (2H, m), 3. 70 (2H, s), 2.96 (3H, s), 2.35-2.22 (1 H, m), 2.09-1.95 (1 H, m). (5) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl) ethyl] glycine (a) A solution of (±) was added. ) -2- [2- (1-benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxy-benzenesulfonyl) glycine (1.89 g, 3.0 mmol), the product from (4) above, in tetrahydrofuran (30 ml), to a suspension of palladium hydroxide (20%, containing 50% water, 0.42 g, 0.30 mmol) in methanol (30 ml). The mixture was stirred vigorously under a hydrogen atmosphere at 50 ° C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield (±) -2- [2- (1-hydroxymethylquinazolin-2,4-dione-3-yl) ethyl] -N-methyl-N- ( 4-phenoxybenzenesulfonyl) glycine (1.62 g) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.15 (1 H, dd, J = 8Hz, 1 Hz), 7.75-7.65 (3H, m), 7.45 (1 H, br.d, J = 8Hz), 7.42-7.33 (2H, m), 7.29-7.16 (2H, m), 7.06-6.94 (4H, m), 5.68 (1 H, d, J = 11 Hz), 5.58 (1 H, d, J = 11 Hz), 4.79 (1 H, dd, J = 10Hz, 6Hz), 4.19-4.03 (2H, m), 2.91 (3H, s), 2.35-2.21 (1 H, m), 2.07-1.92 ( 1 H, m). (b) After the addition of an aqueous solution of sodium hydroxide (1 N, 15 ml) to a solution of the 1-hydroxymethyl compound, product of (a) above, in tetrahydrofuran (30 ml), the mixture was stirred for 1 hour. The reaction mixture was neutralized with hydrochloric acid (6N) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was washed with diethyl ether to give the title compound (1.33 g, 87% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb-DMSO-dβ) d ppm: 10.60 (1 H, br.s), 8.06 (1 H, br.d, J = 8Hz), 7.83-7.77 (2H, m ), 7.55 (1 H, dt, J = 8Hz, 1 Hz), 7.43-7.35 (2H, m), 7.23-7.14 (3H, m), 7.08-6.97 (4H, m), 4.76 (1H, dd) , J = 11Hz, 6Hz), 4.18-4.00 (2H, m), 2.98 (3H, s), 2.38-2.24 (1H, m), 2.12-1.96 (1H, m).

EXAMPLE 6 (±) -N-Hydroxy-N -methyl-Na- (4-phenoxybenzenesulfonyl) -2-r2- (quinazolin-2,4-dione-3-yl) ethyl) qylinamide (Compound No. 1-25) A reaction was carried out in a manner similar to that described in Example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (quinazoline-2,4-dione- 3-yl) ethyl] glycine, the product of Example 5, in place of (±) -N-methyl-N- (4-phenoxybenzenesui onyl) -2- (2-phthalimidoethyl) glycine I to give the title compound (93 % yield) as a white powder. Melting point: 126-128 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 11.45 (1 H, s), 10.76 (1 H, d, J = 1 Hz), 8.95-8.94 (1H, m), 7.91 (1 H, d, J = 7Hz), 7.79-7.76 (2H, m), 7.68-7.64 (1 H, m), 7.47-7.41 (2H, m), 7.26-7.05 (7H, m), 4.32 (1 H , dd, J = 9Hz, 6Hz), 3.80-3.68 (2H, m), 2.95 (3H, s), 1.94-1.75 (2H, m).

EXAMPLE 7 (±) -N- (4-Phenoxybenzenesulfonyl) -2-r2- (quinazolin-2,4-dione-3-yl) etinalicin (Compound No. 1-177) (1) (+) - 2- [2- (1-Benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl] -N- (4-phenoxy-benzenesulfonyl) glycine A de-allylation reaction was carried out in a manner similar to that described in Example 1 (4), using (±) -2- [2- (1-benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl] -N- ( 4-phenoxybenzenesulfonyl) glycine, product of example 5 (2), to produce the desired compound (quantitative yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.14 (1H, dd, J = 8Hz, 1Hz), 7.80-7.74 (2H, m), 7.38 (1H, dt, J = 8Hz, 1Hz), 7.48 (1 H, br.d, J = 8Hz), 7.42-7.34 (2H, m), 7.31-7.17 (7H, m), 7.05-7.01 (2H, m), 6.98-6.93 (2H, m), 5.92 (1 H, br.d, J = 9Hz), 5.68 (2H, br. S), 4.68 (2H, s), 4.24-4.02 (3H, m), 2.35-2.22 (1 H, m), 2.16 -2.04 (1 H, m). (2) (±) -N- (4-Phenoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl) ethyl] glycine A des-benzyloxymethylation reaction was conducted in a similar manner to The procedures described in Example 5 (5) (a) and (b), using (±) -2- [2- (1-benzyloxymethylquinazolin-2,4-dione-3-yl) ethyl] -N- (4-phenoxy-benzenesulfonyl) glycine, the product of (1) above, for give the title compound (89% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-d6) d ppm: 11.43 (1 H, s), 8.19 (1 H, br.d, J = 9Hz), 7.91 (1 H, br.d, J = 7Hz), 7.80-7.75 (2H, m), 7.66 (1 H, dt, J = 7Hz, 1Hz), 7.49-7.42 (2H, m), 7.27-7.03 (7H, m), 4.02-3.77 (3H, m), 2.02-1.72 (2H, m).

EXAMPLE 8 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -2-r2- (2-quinazolin-2,4-dione-3-Detinalicinamide (Compound No. 1-9) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N- (4-phenoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl) ethyl] glycine, to give the title compound (73% yield) as a white powder. Melting point: 184-185 ° C (with decomposition). Nuclear magnetic resonance spectrum 1 H (400 MHz, DMSO-dβ) d ppm: 11.42 (1 H, s), 10.58 (1 H, d, J = 2 Hz), 8.90 (1 H, d, J = 2 Hz), 8.10 (1 H, d, J = 9Hz), 7.92-7.90 (1 H, m), 7.80-7.75 (2H, m), 7.67-7.63 (1H.m), 7.47-7.40 (2H, m), 7.25- 7.16 (3H, m), 7.11-7.04 (4H, m), 3.89-3.82 (1H, m), 3.78-3.67 (2H, m), 1.86-1.76 (1H, m), 1.69-1.60 (1H , m).

EXAMPLE 9 (±) -N- (4-Methoxy-benzenesulfonyl) -2-r2- (pyrimidin-2,4-dione-3-yl) etinqlicine (1) (±) -2- [2- (1-Benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine allyl ester A reaction was carried out in a similar manner to that described in example 1 (1), using 1-benzyloxymethyl? irimidin-2,4-dione in place of phthalimide, to produce the desired compound (78% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.36-7.30 (5H, m), 7.24 (1H, d, J = 8Hz), 5.96-5.82 (1H, m), 5.74 (1H, d, J = 8Hz), 5.50 (1 H, br.d, J = 9Hz), 5.35-5.21 (4H, m), 4.64 (2H, s), 4.57 (2H, s), 4.57 (2H, br. d, J = 6Hz), 4.48-4.37 (1 H, m), 4.12-3.95 (2H, m), 2.17-2.09 (2H, m). (2) (±) -2- [2- (1-Benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl] -N- (4-methoxybenzenesulfonyl) glycol ester Reactions were carried out in a manner similar to the procedures described in example 1 (2) (a) and (b), using (±) -2- [2- (1-benzyloxymethylpyrimidin-2 allyl ester , 4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) allyl ester l) -2- (2-phthalimidoethyl) glycine, and using 4-methoxybenzenesulfonyl chloride in place of 4-phenoxybenzenesulfonyl chloride, to produce the desired compound (93% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.81-7.76 (2H, m), 7.36-7.30 (5H, m), 7.24 (1H, d, J = 8Hz), 6.95-6.89 (2H , m), 5.80-5.62 (3H, m), 5.23-5.14 (4H, m), 4.64 (2H, s), 4.39-4.27 (2H, m), 4.20-4.04 (2H, m), 3.97-3.87 (1 H, m), 3.84 (3H, s), 2.25-1.98 (2H, m). (3) (±) -2- [2- (1-Benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl] -N- (4-methoxy-benzenesulfonyl) glycine A de-allylation reaction was carried out in a manner similar to that described in example 1 (4), using (±) -2- [2- (1-benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl] -N allyl ester - (4-methoxybenzenesulfonyl) glycine, product of (2) above, to produce the desired compound (25% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.81-7.76 (2H, m), 7.35-7.27 (6H, m), 6.96-6.91 (2H, m), 5.90 (1H, br.d , J = 9Hz), 5.76 (1H, d, J = 8Hz), 5.23 (2H, s), 4.63 (2H, s), 4.10-3.88 (3H, m), 3.84 (3H, s), 2.38- 2.15 (1H, m), 2.08-1.97 (1 H, m). (4) (±) -N- (4-Methoxybenzenesulfonyl) -2- [2- (pyrimidin-2,4-dione-3-yl) etl] glycine Reactions were carried out similarly to, the procedures described in example 5 (5) (a) and (b), using (±) -2- [2- (1-benzyloxymethyl-pyrimidin-2,4-dione-3-yl) ethyl] - N- (4-methoxybenzenesulfonyl) -glycine, the product of (3) above, to give the title compound (89% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb-DMSO-dβ) d ppm: 10.47 (1H, br.d, J = 6Hz), 7.83-7.77 (2H, m), 7.13 (1H, dd, J = 8Hz , 6Hz), 6.97-6.92 (2H, m), 6.05 (1 H, br.d, J = 9Hz), 6.64 (1 H, dd, J = 8Hz, 1 Hz), 4.14-3.88 (3H, m), 3.85 (3H, s), 2.23-1.97 (2H, m).

EXAMPLE 10 (±) -N-Hydroxy-Na- (4-methoxybenzenesulfonyl) -2-r2- (pyrimidine-2,4-dione-3- iDetillqlicinamide (Compound No. 5-43) A hydroxy-amidation reaction was carried out in a manner similar to that described in example 2, using (±) -N- (4-methoxybenzenesulfonyl) -2- [2- (pyrimidin-2,4-dione-3-yl) ethyl] glycine, to give the title compound (59% yield) as a pale pink powder.

Melting point: 112 - 115 ° C (with decomposition).

Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 11. 09 (1 H, br.d, J = 6Hz), 10.53 (1 H, br.s), 8.87 (1 H, br.s), 7.93 (1 H, d, J = 9Hz), 7. 73-7.66 (2H, m), 7.40 (1 H, dd, J = 8Hz, 6Hz), 7.06-7.01 (2H, m), 5.55 (1 H, dd, J = 8Hz, 1 Hz), 3.82 (3H , s), 3.75-3.54 (3H, m), 1.77-1.68 (1 H, m), 1.58-1.49 (1 H, m) EXAMPLE 11 (±) -N- (4-Methoxybenzenesulfonyl) -2-f2- (quinazolin-2,4-dione-3-yl) ethynyl (Compound No. 1-168) (1) Benzyl ester of (±) -N- (tert-butoxycarbonyl) -2- [2- [1- (2-trimethylsilyl) ethoxymethylquinazolin-2,4-dione-3-yl] ethyl] glycine Was carried out a reaction similar to that described in Example 1 (1), using (±) -N- (tert-butoxycarbonyl) homoserine benzyl ester in place of the (±) -N- (tert-butoxycarbonyl) allyl ester ) homoserin, and 1- (2-trimethylsilyl) ethoxymethyl-quinazoline-2,4-dione in place of phthalimide, to produce the desired compound (79% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1 H (270 MHz, CDCb) d ppm: 8.17 (1 H, dd, J = 8 Hz, 1 Hz), 7.66 (1 H, dt, J = 8 Hz, 1 Hz), 7.43 (1 H, br.d, J = 8Hz), 7.39-7.25 (6H, m), 5.55-5.51 (3H, m), 5.02 (1 H, br.d, J = 13Hz), 4.96 (1 H, br. J = 13Hz), 4.53-4.45 (1H, m), 4.30-4.12 (2H, m), 3.75-3.68 (2H, m), 2.26-2.17 (2H, m), 1.44 (9H, s), 0.98 -0.91 (2H, m), -0.02 (9H, s). (2) Benzyl ester of (±) -N- (4-methoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl] ethyl] glycine Reactions were carried out in a manner similar to the procedures described in example 1 (2) (a) and (b), using (±) -N- (tert-butoxycarbonyl) -2- [2- [1- (2-trimethylsilyl) ethoxymethylquinazolin-2,4-benzyl ester -dione-3-yl] ethyl] glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine, allyl ester, and using 4-methoxybenzenesulfonyl in place of 4-phenoxybenzenesulfonyl chloride, to produce the desired compound (27% yield) as a pale yellow powder 1H nuclear magnetic resonance spectrum (270 MHz, CDCb) d ppm: 9.57 (1H, br s), 8.07 (1 H, br.d, J = 8Hz), 7.79-7.74 (2H, m), 7.61 (1 H, dt, J = 8Hz, 1 Hz), 7.29-7.09 (7H, m) , 6.88-6.83 (2H, m), 6.24 (1H, br.d, J = 9Hz), 4.85 (1H, d, J = 13Hz), 4.76 (1H, d, J = 13Hz), 4.32-4.02 (3H, m), 3.82 (3H, s), 2. 46-2.05 (2H, m). (3) (+) - N- (4-Methoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl] ethyl] glycine A de-benzylation reaction was carried out in a similar manner to which is described in example 5 (5) (a), using benzyl ester of (±) -N- (4-methoxybenzenesulfonyl) -2- [2- (quinazolin-2,4-dione-3-yl) ethyl] glycine, the product of (2) above, to give the title compound (85 % yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 12.69 (1 H, br s), 11.42 (1 H, s), 8.05 (1 H, br.d, J = 9Hz), 7.91 (1 H, d, J = 8Hz), 7.72-7.63 (3H, m), 7.22-7.16 (2H.m), 7.05-7.01 (2H, m), 4.00-3.93 (1H, m), 3.87-3.74 (5H, m), 1.98-1.89 (1 H, m), 1.82-1.73 (1 H, m).

EXAMPLE 12 (±) -N-Hydroxy-Na- (4-methoxy-benzenesulfonyl) -2-r2- (quinazolin-2,4-dione-3-petipqlicinamide (Compound No. 1-2) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N- (4-methoxybenzenesulfonyl) -2- [2- (quinazoline-2,4-dione-3-) il] ethyl] glycine, the product of example 11, to give the title compound (83% yield) as a white powder Melting point: 173-174 ° C (with decomposition).

Nuclear magnetic resonance spectrum 1 H (400 MHz, DMSO-dβ) d ppm: 11.41 (1 H, br s), 10.56 (1 H, br s), 8.87 (1 H, br s), 7.96-7.90 ( 2H, m), 7.73-7.63 (3H, m), 7.22-7.15 (2H, m), 7.04-7.00 (2H, m), 3.90-3.65 (6H, m), 1.89-1.75 (1H, m), 1.68-1.59 (1 H, m).

EXAMPLE 13 (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2-r2- (pyrimidine-2,4-dione-3-Detinqlicine (1) (±) -2- [2- (1-Benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine benzyl ester A reaction of similar to that described in example 1 (1), using (±) -N- (tert-butoxycarbonyl) homoserine benzyl ester in place of the (±) -N- (tert-butoxycarbonyl) homoserine allyl ester, and using 1-benzyloxymethylpyrimidine-2,4-dione in place of phthalimide, to produce the desired compound (74% yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.47-7.30 (10H, m), 7.21 (1H, d, J = 8Hz), 5.70 (1H, d, J = 8Hz), 5.54 (1 H, d, J = 9Hz), 5.19 (2H, s), 5.10 (2H, s), 4.63 (2H, s), 4.50-4.42 (1 H, m), 4.08-3.97 (2H, m), 2.18-2.10 (2H, m), 1.44 (9H, s). (2) Benzyl ester of (±) -2- [2- (1-benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine. Reactions were carried out in a manner similar to the procedures described in Example 1 (2) (a) and (b), using (±) -2- [2- (1-benzyloxymethylpyrimidin-2,4-dione-3-yl) benzyl ester) ethyl] -N- (tert-butoxycarbonyl) -glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to produce the desired compound (79% yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.79-7.73 (2H, m), 7.42-7.28 (10H, m), 7.24-7.17 (4H, m), 7.04-6.99 (2H, m) , 6.94-6.89 (2H, m), 5.91 (1 H, d, J = 9Hz), 5.69 (1 H, d, J = 8Hz), 5.19 (2H, s), 4.93 (1 H, d, J = 12Hz), 4.84 (1 H, d, J = 12Hz), 4.63 (2H, s), 4.21-4.08 (2H, m), 3.98-3.89 (1 H, m), 2.32-2.19 (1 H, m) , 2.12-2.00 (1 H, m). (3) Benzyl ester of (±) -2- [2- (1-benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine Was carried performed a methylation reaction in a manner similar to that described in Example 1 (3), using (±) -2- [2- (1-benzyloxymethylpyrimidin-2,4-dione-3-yl) ethyl benzyl ester ] -N- (4-phenoxybenzenesulfonyl) glycine, the product of (2) above, to produce the desired compound (92% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.74-7.68 (2H, m), 7.44-7.36 (2H, m), 7.35-7.28 (8H, m), 7.25-7.19 (4H, m) , 7.06-7.01 (2H, m), 6.93-6.87 (2H, m), 5.74 (1H, d, J = 8Hz), 5.23 (2H, s), 5.02 (1H, d, J = 12Hz), 4.93 (1 H, d, J = 12Hz), 4.82 (1 H, dd, J = 10Hz, 5Hz), 4.62 (2H, s), 4.16-3.96 (2H, m), 2.89 (3H, s), 2.28 -2.15 (1 H, m), 2.08-1.93 (1 H, m). (4) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (pyrimidin-2,4-dione-3-yl) ethyl] glycine De-benzylation reactions were carried out and dehydroxymethylation in a manner similar to the procedures described in Example 5 (5) (a) and (b), using (±) -2- [2- (1-benzyloxymethylpyrimidine-2,4-dione) benzyl ester -3-yl) ethyl] -N-methylN- (4-phenoxybenzenesulfonyl) -glycine, the product of (3) above, to give the title compound (85% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 9.90-9.88 (1 H, m), 7.77-7.12 (2H, m), 7.45-7.34 (2H, m), 7.23-7.17 (2H, m ), 7. 06-6.99 (4H, m), 5.76 (1 H, d, J = 8Hz), 4.76 (1H, t, J = 7Hz), 3.96 (2H, t, J = 7Hz), 2.86 (3H, s), 2.34-2.09 (1 H, m), 1.97-1.84 (1 H, m).

EXAMPLE 14 (+) - N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-r2- (pyrimidin-2,4-dione-3-yl) ethyglycinamide (Compound No. 5-29) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (pyrimidin-) 2,4-dione-3-yl) ethyl] glycine, product of example 13, to give the title compound (87% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 10.05 (1 H, s), 10.04 (1H, s), 8.53 (1H, s), 7.70 (2H, d, J = 9Hz), 7.42- 7.38 (2H, m), 7.25-7.19 (2H, m), 7.07-6.98 (4H, m), 5.73 (1H, d, J = 10Hz), 4.12 (1H, dd, J = 14Hz, 7Hz) , 3.80 (2H, t, J = 6Hz), 2.84 (3H, s), 2.30-2.22 (1H, m), 1.58-1.53 (1H, m).

EXAMPLE 15 (±) -2-r2- (5-Met.lpyrimidin-2,4-dione-3-yl) ethylen-N-methyl-N- (4-phenoxybenzenesulfonium D-glycine) (1) Benzyl ester of (±) -2- [2- (1-benzyloxymethyl-5-methylpyrimidin-2,4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine Was carried performed a reaction in a manner similar to that described in example 1 (1), using (±) -N- (tert-butoxycarbonyl) homoserine benzyl ester, instead of (±) -N- allyl ester (tert-butoxycarbonyl) homoserine, and using 1-benzyloxymethyl-5-methyl-pyridin-2,4-dione, in place of phthalimide, to produce the desired compound (51% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.34-7.28 (10H, m), 7.06 (1 H, s), 5.71 (1 H, d, J = 8Hz), 5.20 (2H, s) , 5.13 (1H, d, J = 12Hz), 5.08 (1H, d, J = 12Hz), 4.60 (2H, s), 4.18-4.07 (3H, m), 3.58-3.47 (1H, m), 2.19-2.09 (1 H, m), 1.98-1.82 (4H, m), 1.55 (9H, s). (2) Benzyl ester of (±) -2- [2- (1-benzyloxymethyl-5-methyl-pyrimidin-2,4-dione-3-yl) etl] -N- (4-phenoxybenzenesulfonyl) glyc Reactions were carried out in a manner similar to the procedures described in example 1 (2) (a) and (b), using (±) -2- [2- (1-benzyloxymethyl) benzyl ester. 5-methylpyrimidin-2,4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine, the product of (1) above, in place of (±) -N- (tert-butoxycarbonyl) allyl ester ) -2- (2-phthalimidoethyl) glycine, to produce the desired compound (64% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.77 (2H, d, J = 9Hz), 7.39 (2H, t, J = 8Hz), 7.35-7.27 (8H, m), 7.22-7.15 ( 2H, m), 7.06-7.00 (3H, m), 6.92 (2H, dt, J = 9Hz, 3Hz), 5.95 (1H, d, J = 9Hz), 5.18 (2H, s), 4.90 (1H, d, J = 12Hz), 4.84 (1H, d, J = 12Hz), 4.61 (2H, s), 4.22-4.08 (2H, m), 4.00-3.90 (1H, m), 2.32-2.20 (1 H, m), 2.12-1.99 (1 H, m), 1.86 (3H, s). (3) Benzyl ester of (±) -2- [2- (1-benzyloxymethyl-5-methyl-pyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine A methylation reaction was carried out in a manner similar to that described in example 1 (3), using (±) -2- [2- (1-benzyloxymethyl-5-methylpyrimidin-2-benzyl ester. , 4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) -glycine, the product of (2) above, to produce the desired compound (94% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.71 (2H, d, J = 5Hz), 7.43-7.24 (11H, m), 7.22-7.17 (2H, m), 7.06-7.02 (3H , m), 6.90 (2H, d, J = 5Hz), 5.23 (2H, s), 5.01 (1H, d, J = 12Hz), 4.96 (1H, d, J = 12Hz), 4.86-4.78 (1 H, m), 4.61 (2H, s), 4.08-3.96 (2H, m), 2.86 (3H, s), 2.34-2.18 (1 H, m), 2.12-2.00 (1 H, m), 1.58 ( 3H, s). (4) (±) -2- [2- (5-Methylpyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine. de-benzylation and de-hydroxymethylation in a manner similar to the procedures described in Example 5 (5) (a) and (b), using (±) -2- [2- (1-benzyloxymethyl-5-benzyl ester -methylpyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine, the product of (3) above, to give the title compound (39% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 9.79 (1 H, d, J = 3Hz), 7.74 (2H, d, J = 5Hz), 7.38 (2H, t, J = 3Hz), 7.31 -7.22 (1 H, m), 7.08-6.95 (5H, m), 4.78 (1 H, t, J = 9Hz), 3.99 (2H, t, J = 3Hz), 3.82 (3H, s), 2.30- 2.18 (1H, m), 2.10-1.95 (1 H, m), 1.57 (3H, s).

EXAMPLE 16 (±) -N-Hydroxy-2-r2- (5-methyl-pyrimidin-2,4-dione-3-yl) -etin-N -methyl-Na- (4-phenoxybenzenesulfoni) D-glycinamide (Compound No. 5-33) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -2- [2- (5-methylpyrimidin-2,4-dione-3-yl) ethyl] -N -methyl-N- (4-phenoxybenzenesulfonyl) glycine, the product of example 15, to give the title compound (65% yield) as a white powder. Melting point: 166-167 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 10.93 (1H, s), 10.73 (1H, s), 8.94 (1H, s), 7.77 (2H, d, J = 9Hz), 7.45 (2H, t, J = 8Hz), 7.30 (1H, d, J = 5Hz), 7.25 (1H, t, J = 7Hz), 7.14-7.06 (4H, m). 4.27 (1 H, dd, J = 9Hz, 6Hz), 3.65-3.53 (2H, m), 2.92 (3H, s), 1.76-1.66 (5H, m).

EXAMPLE 17 (±) -2-r2- (5,6-Dimethylpyrimidin-2,4-dione-3-yl) etin-N-methyl-N- (4-phenoxybenzenesulfonyl) glycine (Compound No. 4-178) (1) Benzyl ester of (±) -2- [2- (1-benzyloxymethyl-5,6-d, methylpyrimidin-2,4-dione-3-yl) ethyl] -N- (ter- butoxycarbonyl) glycine A reaction was carried out in a manner similar to that described in example 1 (1), using (±) -N- (tert-butoxycarbonyl) homoserine benzyl ester, instead of allyl ester of (±) -N- (tert-butoxycarbonyl) homoserine, and using 1-benzyloxymethyl-5-methyl-pyrimidine-2,4-dione in place of phthalimide, to produce the desired compound (69% of yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.73-7.26 (10H, m), 5.56 (1 H, d, J = 9Hz), 5.42 (2H, s), 5.08 (2H, s), 4.65 (2H, s), 4.48-4.41 (1 H, m), 4.10-4.01 (2H, m), 2.31 (3H, s), 2.17-2.07 (2H, m), 1.91 (3H, s), 1.44 (9H, s). (2) (±) -2- [2- (1-Benzyloxymethyl-5,6-dimethylpyrimidin-2,4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine benzyl ester performed reactions similarly to the procedures described in example 1 (2) (a) and (b), using benzyl ester of (± ^ - ^ - yl-benzyloxymethyl-d.β-dimethylpyrimidine ^ -dione-Si eti ^ -N-ether-butoxycarbonyl) glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to produce the desired compound (28% yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.79-7.74 (2H, m), 7.42-7.15 (13H, m), 7.04-6.99 (2H, m), 6.94-6.88 (2H, m) , 6.02 (1 H, d, J = 10 Hz), 5.40 (2 H, s), 4.91 (1 H, d, J = 12 Hz), 4.81 (1 H, d, 12 Hz), 4.65 (2 H, s), 4.19 -4.08 (2H, m), 3.99-3.89 (1H, m), 2.33-2.14 (4H, m), 2.11-1.99 (1 H, m), 1.90 (3H, s). (3) (+) - 2- [2- (1-Benzyloxymethyl-5,6-dimethylpyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-) benzyl ester phenoxybenzenesulfonyl) glycine A methylation reaction was carried out in a manner similar to that described in Example 1 (3), using (±) -2- [2- (1-benzyloxymethyl-5,6-d) benzyl ester Methylpyrimidin-2,4-dione-3-yl) ethyl] -N- (4-phenoxy-benzenesulfonyl) glycine, the product of (2) above, to produce the desired compound (quantitative yield) as a pale yellow oil . Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.78-7.68 (2H, m), 7.43-7.19 (13H, m), 7.05-7.01 (2H, m), 6.93-6.87 (2H, m) , 5.45 (2H, s), 5.01 (1H, d, J = 12Hz), 4.93 (1H, d, J = 12Hz), 4.82 (1H, dd, J = 10Hz, 5Hz), 4.64 (2H, s), 4.14-3.93 (2H, m), 2.91 (3H, s), 2.33 (3H, s), 2.26-2.13 (1H, m), 2.07-1.94 (4H, m). (4) (±) -2- [2- (5,6-Dimethyl-pyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxy-benzenesulfonyl) glycine performed de-benzylation and de-hydroxymethylation reactions in a manner similar to the procedures described in example 5 (5) (a) and (b), using (±) -2- [2- (1) benzyl ester -benzyloxymethyl-5,6-di-methyl-pyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) -glycine, the product of (3) above, to give the title compound (62% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-dβ) d ppm: 10.96 (1 H, s), 7.81-7.76 (2H, m), 7.49-7.43 (2H, m), 7.28-7.22 (1 H, m), 7.16-7.07 (4H, m), 4.46 (1H, dd, J = 10Hz, 6Hz), 3.69 (2H, t, J = 8Hz), 2.82 (3H, s), 2.10-1.98 (4H, m), 1.76-1.66 (4H, m).

EXAMPLE 18 (±) -2-r2- (5,6-D-methylpyridin-2,4-dione-3-yl) ethyn-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide (Compound No 4-25) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -2- [2- (5,6-dimethylpyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine, the product of Example 17, to give the title compound (81% yield) as a white powder. Melting point: 179-180 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 10.94 (1 H, s), 10.73 (1 H, d, J = 1 Hz), 8.94 (1H, d, J = 2Hz), 7.78 -7.75 (2H, m), 7.47-7.42 (2H, m), 7.25 (1H, t, J = 7Hz), 7.14-7.08 (4H, m), 4.27 (1H, dd, J = 9Hz, 7Hz) , 3.64-3.52 (2H, m), 2.93 (3H, s), 2.05 (3H, s), 1.84-1.65 (5H, m).

EXAMPLE 19 (±) -2- (2-Phthalimidoethyl) -N-r4- (pyridin-4-yl) oxybenzenesulfonipglycine (1) Benzyl ester of (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine A reaction was carried out in a manner similar to that described in example 1 (1), using ester benzyl of (±) -N- (tert-butoxycarbonyl) homoserine in place of (±) -N- (tert-butoxycarbonyl) homoserine allyl ester, to produce the desired compound (58% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.89-7.78 (2H, m), 7.74-7.68 (2H, m), 7.40-7.28 (5H, m), 5.31 (1H, d, J = 9Hz), . 07 (1 H, d, J = 12 Hz), 5.01 (1 H, d, J = 12 Hz), 4.51-4.33 (1 H, br s), 3.78 (2 H, t, J = 9Hz), 2.30-2.18 (2H, m), 1.43 (9H, s). (2) Benzyl ester of (±) -2- (2-phthalimidoethyl) -N- [4- (pyridin-4-yl) oxybenzenesulfonyl] glycine Reactions were carried out in a manner similar to the procedures described in the example 1 (2) (a) and (b), using (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine benzyl ester in place of (±) -N- (ter) allyl ester -butoxycarbonyl) -2- (2-phthalimidoethyl) glycine, and using 4- (pyridin-4-yl) oxybenzenesulfonyl chloride in place of 4-phenoxybenzenesulfonyl chloride, to produce the desired compound (13% of yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.52 (1H, d, J = 4Hz), 7.87-7.76 (4H, m), 7.74-7.65 (4H, m), 7.39-7.23 (5H, m), 7.23-7.14 (1 H, m), 7.08 (1 H, d, J = 5 Hz), 6.88 (1 H, d, J = 3 Hz), 5.51 (1 H, d, J = 9 Hz), 4.84 (1 H, d, J = 12Hz), 4.77 (1 H, d, J012Hz), 3.98-3.82 (1 H, m), 3.80-3.65 (1 H, m), 2.25-2.10 (2H, m). (3) (±) -2- (2-Ftalmidoethyl) -N- [4- (pyridin-4-yl) oxybenzenesulfonyl] glycine A de-benzylation reaction was carried out in a manner similar to that described in Example 5 (5) (a), using benzyl ester of (±) -2- (2-phthalimidoethyl) -N- [4- (pyridin-4-yl) oxybenzenesulfonyl] glycine, the product of (2) ) above, to give the title compound (76% yield) as a brown amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.53 (1 H, d, J = 4Hz), 7.87-7.75 (4H, m), 7.74-7.64 (4H, m), 7.22-7.11 (1 H, m), 7.10 (1 H, d, J = 5 Hz), 6.90 (1 H, d, J = 4 Hz), 5.62 (1 H, d, J = 9 Hz), 4.15-4.04 (1 H, m) , 3.90-3.67 (2H, m), 2.26-2.13 (2H, m).

EXAMPLE 20 (±) -N-Hydroxy-2- (2-phthalimidoethyl) -Na-r4- (pyridin-4-yl) oxybenzenesulfonin-alicinamide (Compound No. 3-185) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -2- (2-phthalimidoethyl) -N- [4- (pyridin-4-yl) oxybenzenesulfonyl] glycine, the product of Example 19, to give the title compound (6% yield) as a yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.55 (1 H, d, J = 4Hz), 7.87-7.77 (4H, m), 7.73-7.60 (4H, m), 7.20-7.15 (1 H, m), 7.04 (1 H, d, J = 5 Hz), 6.91 (1 H, d, J = 4 Hz), 5.55 (1 H, d, J = 9 Hz), 4.12-4.05 (1 H, m), 3.89-3.72 (2H, m), 2.20-2.15 (2H, m).

EXAMPLE 21 (±) -N- (4-Methoxy-benzenesulfonyl) -2- (2-phthalimidoethyl) -choline (Compound No. 3-169) (1) Benzyl ester of (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine Reactions were carried out in a manner similar to the procedures described in example 1 (2) (a) and (b), using (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine benzyl ester, the product of example 19 (1), in place of the (±) -N allyl ester - (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine, and using 4-methoxybenzenesulfonyl chloride in place of 4-phenoxybenzenesulfonyl chloride, to produce the desired compound (61% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.83-7.77 (2H, m), 7.73-7.67 (4H, m), 7.33-7.31 (3H, m), 7.16-7.13 (2H, m) , 6.87 (2H, d, J = 9Hz), 5.51 (1H, d, J = 9Hz), 4.83 (1H, d, J = 12Hz), 4.76 (1H, d, J = 12Hz), 4.16- 4.04 (1 H, m), 3.96-3.83 (4H, m), 3.77-3.67 (1 H, m), 2.15 (2H, dd, J = 12Hz, 8Hz). (2) (±) -N- (4-Methoxy-benzenesulfonyl) -2- (2-phthalimidoethyl) glycine A de-benzylation reaction was carried out in a manner similar to that described in example 5 (5) (a) ), using (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine benzyl ester, the product of (1) above, to give the title compound (75% yield) as a white powder . Melting point: 189-190 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.84-7.82 (2H, m), 7.79 (2H, d, J = 9Hz), 7.73-7.69 (2H, m), 6.93 (2H, d, J = 9Hz), 5.56 (1H, d, J = 8Hz), 4.05-3.97 (1H, m), 3.93-3.68 (5H, m), 2.15 (2H, dd, J = 12Hz, 8Hz).

EXAMPLE 22 (±) -N-Hydroxy-Na- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) qycininamide (Compound No. 3-2) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoetyl) glycine, the product of Example 21 , to give the title compound (34% yield) as a white powder. Melting point: 185-187 ° C (with decomposition). Nuclear magnetic resonance spectrum 1 H (270 MHz, DMSO-dβ) d ppm: 10.57 (1 H, s), 8.88 (1 H, s), 8.00 (1 H, d, J = 9 Hz), 7.84 (4 H, m ), 7.70 (2H, d, J = 9Hz), 7.02 (2H, d, J = 9Hz), 3.82 (3H, s), 3.68-3.65 (1H, m). 3.54-3.43 (2H, m), 1.92-1.80 (1 H, m), 1.79-1.62 (1 H, m).

EXAMPLE 23 (±) -2- (2-Phthalimidoethyl) -N- (4-trifluoromethoxybenzenesulfonyl) qycine (1) Benzyl ester of (±) -2- (2-phthalimidoethyl) -N- (4-trifluoromethoxy-benzenesulfonyl) glycine Reactions were carried out in a manner similar to the procedures described in example 1 (2) ( a) and (b), using (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine benzyl ester, the product of example 19 (1), instead of the (±) allyl ester -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine, and using 4-trifluoromethoxybenzenesulfonyl chloride in place of 4-phenoxybenzenesulfonyl chloride, to produce the desired compound (52% yield) as a yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.88 (1 H, s), 7.84 (1 H, s), 7.83-7.81 (2H, m), 7.73-7.69 (2H, m), 7.43 -7.31 (3H, m), 7.22 (1H, s), 7.19 (1H, s), 7.15 (2H, dd, J = 7Hz, 4Hz), 5.65 (1H, d, J = 9Hz), 4.79 ( 1 H, d, J = 12Hz), 4.72 (1 H, d, J = 12Hz), 4.16-4.12 (1 H, m), 3.93-3.85 (1 H, m), 3.78-3.75 (1 H, m ), 2.25-2.16 (2H, m). (2) (±) -2- (2-Ftataldodoethyl) -4- (4-trifluoromethoxybenzenesulfonyl) glycine A de-benzylation reaction was carried out in a manner similar to that described in example 5 (5) (a), using (±) -2- (2-phthalimidoethyl) -4- (4-trifluoromethoxybenzenesulfonyl) glycine benzyl ester, the product of example 23 (1), to give the title compound (69). % yield) as a yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.87 (1H, s), 7.84 (1H, s), 7.83-7.80 (2H, m), 7.74-7.69 (2H, m), 7.18- 7.11 (2H, m), 5.65 (1H, d, J = 9Hz), 4.00 (1H, d, J = 9Hz), 3.93-3.80 (1H, m), 3.78-3.65 (1H, m) , 2.50 (2H, dd, J = 12Hz, 7Hz).

EXAMPLE 24 (±) -N-Hydroxy-2- (2-phthalimidoetyl) -Na- (4-trifluoromethoxybenzenesulfonyl) -qlicinamide (Compound No. 3-172) A hydroxylation reaction was performed in a manner similar to that described in example 2, using (±) -2- (2-phthalimidoethyl) -N- (4-trifluoromethoxybenzenesulfonyl) glycine, the product of example 23, to give the compound of the title (63% yield) as a white powder. Melting point: 153-155 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-d6) d ppm: 10.62 (1 H, s), 8.99-8.75 (1 H, br s), 8.43 (1 H, d, J = 9Hz), 7.95 -7.70 (6H, m), 7.52 (2H, d, J = 9Hz), 3.76 (1H, dd, J = 10Hz, 3Hz). 3.60-3.42 (2H, m), 1.94-1.81 (1H, m), 1.75-1.66 (1H, m).

EXAMPLE 25 (±) -N- (4-Phenoxy-benzenesulfonyl) -2- (2-phthalimidoetyl) allicin (Compound No. 3-178) (1) Benzyl ester of (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine Reactions were carried out in a manner similar to the procedures described in Example 1 (2) (a) and (b), using (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine benzyl ester, the product of example 19 (1), in place of the (±) -N allyl ester - (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine, to produce the desired compound (54% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.88-7.67 (6H, m), 7.42-7.10 (8H, m), 7.02 (2H, d, J = 6Hz), 6.91 (2H, d, J = 6Hz), 5.52 (1H, d, J = 9Hz), 4.85 (1H, d, J = 12Hz), 4.80 (1H, d, J = 12Hz), 4.19-4.03 (1H, m) , 3.99-3.81 (1 H, m), 3.79-3.64 (1 H, m), 2.25-2.10 (2H, m). (2) (±) -N- (4-Phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine A de-benzylation reaction was carried out in a manner similar to that described in example 5 (5) (a) ), using benzyl ester of (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, the product of (1) above, to give the title compound (67% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.95-7.69 (6H, m), 7.50 (2H, t, J = 4Hz), 7.20 (1 H, t, J = 3Hz), 7.13-6.98 (4H, m), . 62 (1 H, d, J = 9Hz), 4.15-4.02 (1 H, m), 3.91-3.68 (2H, m), 2.19 (2H, dt, J = 12Hz, 8Hz).

EXAMPLE 26 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) qycinamide (Compound No. 3-10) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, the product of example 25, to give the title compound (10% yield) as a white powder. Melting point: 91-96 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSOdβ) d ppm: 7. 84 (4H, s), 7.76 (2H, d, J = 9Hz), 7.44 (2H, t, J = 8Hz), 7.23 (1H, t, J = 8Hz), 7.13 (2H, d, J = 9Hz ), 7.05 (2H, d, J = 9Hz), 3.68 (1H.t, J = 7Hz), 3.53-3.38 (2H, m), 1.89-1.83 (1H, m), 1.75-1.69 (1H, m).

EXAMPLE 27 (±) -N- (4-Phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N-propargylglycine (Compound No. 3-180) (1) (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N-propargylglycine allyl ester A reaction was carried out in a manner similar to that described in example 1 (3) , using propargyl bromide in place of methyl iodide, to produce the desired compound (88% yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.86-7.81 (4H, m), 7.74-7.70 (2H, m), 7.44-7.37 (2H, m), 7.25-7.20 (1 H, m ), 7.09-7.05 (2H, m), 7.01-6.97 (2H, m), 5.85-5.70 (1 H, m), 5.30-5.20 (2H, m), 4.67 (1 H, dd, J = 9Hz, 6Hz), 4.52-4.45 (2H, m), 4.24-4.08 (2H, m), 3.94-3.72 (2H, m), 2.46-2.14 (3H, m). (2) (±) -N- (4-Phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N-proparglylicin A reaction was carried out in a manner similar to that described in Example 1 (4). ), using (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N-propargylglycine allyl ester, the product of (1) above, to give the title compound (90% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.86-7.81 (4H, m), 7.74-7.71 (2H, m), 7.45-7.36 (2H, m), 7.23-7.18 (1H, m ), 7.07-7.01 (2H, m), 6.99-6.94 (2H, m), 4.65 (1H, t, J = 7Hz), 4.32 (1H, dd, J = 19Hz, 2Hz), 4.01 (1H , dd, J = 19Hz, 2Hz), 3.90-3.67 (2H, m), 2.51-2.39 (1H, m), 2.29 (1H, t, J = 2Hz), 2.25-2.12 (1H, m) .

EXAMPLE 28 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoetyl) -N-proparqylalicinamide (Compound No. 3-90) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N-propargylglycine, the product of the example 27, to give the title compound (76% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.45 (1 H, s), 7.84-7.80 (2H, m), 7.75-7.68 (4H, m), 7.49-7.41 (2H, m), 7.29-7.23 (1 H, m), 7.06 (2H, d.J = 8Hz), 6.71 (2H, d, J = 9Hz), 4.37 (1 H, dd, J = 19Hz, 2Hz), 4.26 (1 H , dd, J = 19Hz, 2Hz), 4.21 (1 H, dd, J = 10Hz, 5Hz), 3.65-3.47 (2H, m), 2.54-2.45 (1H, m), 2.30 (1 H, t, J = 2Hz), 1.83-1.75 (1H, m).

EXAMPLE 29 (±) -N-r3- (4-Chlorophenyl) propin-N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoetiD-glycine (Compound No. 3-192) (1) Benzyl ester of (±) -N- [3- (chlorophenyl)? Ropil] -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine A reaction was carried out in a manner similar to that described in Example 1 (3), using (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine benzyl ester, the product of example 21 (1), instead of the (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine allyl ester, and using 3- (4-chlorophenyl) propyl bromide instead of methyl iodide, to produce the desired compound (25% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.89-7.82 (2H, m), 7.77-7.68 (2H, m), 7.59 (2H, dt, J = 8Hz, 4Hz), 7.36-7.28 ( 3H, m), 7.25-7.14 (4H, m), 7.06 (2H, dt, J = 8Hz, 3Hz), 6.78 (2H, dt, J = 9Hz, 3Hz), 4.97 (1H, d, J = 12Hz ), 4.93 (1H, d, J = 12Hz), 4.72-4.62 (1 H, m), 3.86-3.77 (4H, m), 3.26-3.11 (1 H, m), 3.03-2.89 (1 H, m ), 2.51 (2H, dt, J = 7Hz, 3Hz), 2.37-2.23 (1H, m), 2.15-1.92 (2H, m), 1.33-1.22 (2H, m). (2) (±) -N- [3- (4-Chlorophenyl) propyl] -4- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -glycine A de-benzylation reaction was carried out in a similar manner to that described in example 5 (5) (a), using (±) -N- [3- (4-chlorophenyl) propyl] -4- (4-methoxybenzenesulfonyl) -2- (2-) benzyl ester phthalimidoethyl) -glycine, the product of (1) above, to give the title compound (22% yield) as a white powder. Melting point: 140-142 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.89-7.80 (2H, m), 7.79-7.71 (2H, m), 7.66 (2H, d, J = 9Hz), 7.22 (2H, d, J = 8Hz), 7.12 (2H, d, J = 8Hz), 6.86 (2H, d, J = 9Hz), 4.48 (1 H, t, J = 7Hz), 3.81 (3H, s), 3.59 (2H, t, J = 7Hz), 3.47-3.09 (1 H, m), 2.68-2.50 (2H, m), 2.40-2.22 (1 H, m). 2.16-1.94 (2H, m), 1.92-1.80 (2H, m).

EXAMPLE 30 (±) -Na-r3 4-Chlorophenyl) propin-N-hydroxy-Na- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) qylinamide (Compound No. 3-7) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N- [3- (4-chlorophenyl) propyl] -4- (4-methoxybenzenesulfonyl) -2- ( 2-phthalimidoethyl) glycine, the product of Example 29, to give the title compound (42% yield) as a white powder. Melting point: 158-160 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 10.71 (1 H, s), 8.97 (1 H, s), 7.90-7.82 (4H, m), 7.66 (2H, d, J = 9Hz), 7.31 (2H, d, J = 8Hz), 7.20 (2H, d, J = 8Hz), 7.02 (2H, d, J = 9Hz), 4.25 (1H, t, J = 7Hz), 3.83 (3H, s), 3.51-3.46 (2H, m), 3.23-3.04 (1H, m), 1.99-1.90 (3H, m), 1.84-1.70 (1 H, m).

EXAMPLE 31 (±) -N- (4-Methoxy-benzenesulfonyl) -2- (2-phthalimidoethyl) -N- (pyridin-3-iPmethylglycine (Compound No. 3-191) (1) Benzyl ester of (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N- (pyridin-3-yl) methylglycine A reaction was carried out in a manner similar to that described in example 1 (3), using (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine benzyl ester, the product of Example 21 (1), instead of the allyl ester of (± ) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, and using (pyridin-3-yl) methyl chloride in place of methyl iodide, to produce the desired compound (51% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.44 (1 H, d, J = 5Hz), 8.35 (1 H, s), 7.86-7.78 (2H, m), 7.77-7.63 (6H, m), 7.42-7.30 (2H, m), 7.27-7.22 (2H, m), 7.16 (1H, dd, J = 9Hz, 5Hz), 6.80 (2H, dt, J = 9Hz, 3Hz), 4.90 ( 2H, dd, J = 12Hz, 8Hz), 4.65 (1H, t, J = 7Hz), 4.50 (1H, d, J = 12Hz), 4.40 (1H, d, J = 12Hz), 3.82 (3H, s), 3.72-3.61 (2H, m), 2.38-2.22 (1H, m), 2.00-1.88 (1H, m). (2) (±) -N- (4-Methoxy-benzenesulfonyl) -2- (2-phthalimidoethyl) -N- (pyridin-3-yl) methylglycine A de-benzylation reaction was carried out in a similar manner to which is described in example 5 (5) (a), using (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N- (pyridin-3-y) benzyl ester ) methylglycine, the product of (1) above, to give the title compound (31% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-dd) d ppm: 8.45 (1 H, s), 8.40 (1 H, d, J = 4Hz), 7.90-7.80 (4H, m), 7.76-7.65 ( 3H, m), 7.31-7.24 (1H, m), 7.03 (2H, d, J = 9Hz), 4.44 (1H, d, J = 8Hz), 4.40 (1H, d, J = 8Hz), 4.32 (1 H, t, J = 7Hz), 3.83 (3H, s), 3.61-3.44 (2H, m), 2.34-2.21 (1 H, m), 1.75-1.64 (1 H, m).

EXAMPLE 32 (±) -N-Hydroxy-Na- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -Na- (pyridin-3-yl) methylqlycinamide (Compound No. 3-8) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N- (4-methoxy-benzenesulfonyl) -2- (2-phthalimidoethyl) -N- (pyridine-3 -yl) methylglycine, the product of Example 31, to give the title compound (35% yield) as a white powder. Fusion score: 98-100 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3-DMSO-d6) d ppm: 8.50 (1 H, s), 8.38 (1 H, d, J = 4Hz), 7.90-7.85 (4H, m), 7.76- 7.68 (3H, m), 7.31-7.26 (1 H, m), 7.00 (2H, d, J = 9Hz), 4.39 (2H, dd, J = 12Hz, 6Hz), 4.28 (1 H, t, J = 8Hz), 3.80 (3H, s), 3.59-3.46 (2H, m), 2.30-2.25 (1H, m), 1.70-1.62 (1H, m).

EXAMPLE 33 (±) -N-r3- (4-Chlorophenyl) propargin-N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoetiDglycine (Compound No. 3-171) (1) (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine methyl ester After the addition of trimethylsilyl chloride (0.65 g, 5.1 mmol) to a solution of (±) -N - (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine (1.08 g, 2.6 mmol), the product of Example 21, in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml), the mixture was heated to reflux for 2 hours. The solvent in the reaction mixture was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue to form a cake and produce the desired compound (96% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.92-7.74 (6H, m), 7.03-6.97 (2H, m), 5.50 (1H, br.d, J = 9Hz), 4.14-4.06 (1 H, m), 4.00-3.89 (4H, m), 3.82-3.71 (1H, m), 3.47 (3H, s), 2.23-2.15 (2H, m). (2) (±) -N- [3- (4-chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine methyl ester A reaction was carried out in a manner similar to which is described in Example 1 (3), using (±) -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine methyl ester, the product of (1) above, in place of the ester allyl of (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, and using 3- (4-chlorophenyl) propargyl bromide in place of methyl iodide, to produce the desired compound (97%) of yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.89-7.81 (4H, m), 7.75-7.68 (2H, m), 7.25-7.16 (4H, m), 6.94-6.88 (2H, m) , 4.71 (1 H, dd, J = 9Hz, 7Hz), 4.44 (1 H, d, J = 18Hz), 4.40 (1 H, d, J = 18Hz), 3.84-3.78 (4H, m), 3.54 ( 3H, s), 2.50-2.37 (1 H, m), 2.27-2.13 (1 H, m). (3) (±) -N- [3- (4-Chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine After addition of 1N aqueous solution of sodium hydroxide (5 ml) to a solution of (±) -N- [3- (4-chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine methyl ester (1.18 g, 2.0 mmol) ) in methanol (40 ml), the mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure; Hydrochloric acid (1 N, 6 ml) was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using dichloromethane / methanol = 25/1 as eluent, to give the title compound (0.41 g, 35% yield) as a white powder. Melting point: 142-143 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 7.85-7.80 (4H, m), 7.74-7.70 (2H, m), 7.30-7.20 (4H, m), 6.89-6.85 (2H, m) , 4.63 (1 H, t, J = 8Hz), 4.44 (1 H, d, J = 18Hz), 4.35 (1 H, d, J = 18Hz), 3.86-3.68 (5H, m), 2.50-2.42 ( 1 H, m), 2.19-2.10 (1 H, m).

EXAMPLE 34 (±) -N-f3- (4-Chlorophenol) propargin-N-hydroxy-Na- (4-methoxybenzenesulfonyl) -2- (phthalimidoethyl) glycinamide (Compound No. 3-5) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N- [3- (4-chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) -2- ( 2-phthalimidoethyl) glycine, the product of Example 33, to give the title compound (62% yield) as a white powder. Melting point: 138-139 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.44 (1 H, br s), 7.86-7.70 (6H, m), 7.31-7.22 (4H, m), 6.65 (2H, d, J = 9Hz), 4.49 (2H, s), 4.30 (1 H, dd, J = 10Hz, 5Hz), 3.74 (3H, s), 3.65-3.58 (1 H, m), 3.55- 3.45 (1 H, m ), 2.59-2.50 (1 H, m), 1.92-1.84 (1 H, m).

EXAMPLE 35 (±) -N-Methyl-N- (4-phenoxybenzenesulfoniP-2-f3- (guinazolin-2,4-dione-3-iPpropinglicine (1) (±) -2- [3- (1-Benzyloxymethylquinazolin-2,4-dione-3-yl) propyl] -N- (tert-butoxycarbonyl) glycine benzyl ester A reaction was carried out in a similar manner to that described in example 1 (1), using (±) -N- (tert-butoxycarbonyl) -2- (3-hydroxypropyl) glycine benzyl ester in place of the (±) -N- () allyl ester ( tert-butoxycarbonyl) homoserine, and using 1-benzyloxyquinazoline-2,4-dione in place of phthalimide, to produce the desired compound (85% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1 H (270 MHz, CDCb) d ppm: 8.17 (1 H, dd, J = 8 Hz, 1 Hz), 7.67 (1 H, dt, J = 8 Hz, 1 Hz), 7.47 (1 H, br.d, J = 8Hz), 7.36-7.23 (11H, m), 5.69 (2H, s), 5.20-5.07 (3H, m), 4.68 (2H, s), 4.44-4.33 (1H, m ), 4.05 (2H, br.t, J = 7Hz), 1.97-1.86 (1H, m), 1.81-1.64 (3H, m), 1.41 (9H, s). (2) (±) -2- [3- (1-Benzyloxymethylquinazolin-2,4-dione-3-yl) propyl] -N- (4-phenoxybenzenesulfonyl) glycine benzyl ester Reactions were carried out in a similar manner to the procedures described in example 1 (2) (a) and (b), using (±) -2- [3- (1-benzyloxymethylquinazolin-2,4-dione-3-yl) propyl benzyl ester] -N- (tert-butoxycarbonyl) glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to produce the desired compound (92% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 8.16 (1 H, dd, J = 8Hz, 1 Hz), 7.78-7.63 (3H, m), 7.47 (1 H, br.d, J = 8Hz), 7.42-7.16 (14H, m), 7.04-6.92 (4H, m), 5.68 (2H, s), 5.31 (1H, d, J = 9Hz), 4.93 (2H, s), 4.67 (2H , s), 4.10-3.98 (3H, m), 1.87-1.65 (4H, m). (3) Benzyl ester of (±) -2- [3- (1-benzyloxymethylquinazolin-2,4-dione-3-yl) propyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine Was carried performed a reaction in a manner similar to that described in example 1 (3), using benzyl ester of (±) -2- [3- (1-benzyloxymethylquinazolin-2,4-dione-3-yl) propyl] - N- (4-phenoxybenzenesulfonyl) -glycine, the product of (2) above, in place of the (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine allyl ester, to produce the desired compound (quantitative yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.18 (1 H, dd, J = 8Hz, 1 Hz), 7.72-7.64 (3H, m), 7.48 (1 H, br.d, J = 8Hz), 7.42-7.17 (14H, m), 7.02 (2H, br.d, J = 9Hz), 6.91-6.86 (2H, m), 5.70 (2H, s), 4.97 (1H, d, J = 13Hz), 4.90 (1 H, d, J = 13Hz), 4.81-4.75 (1 H, m), 4.68 (2H, s), 4.17-4.08 (2H, m), 2.81 (3H, s), 2.02- 1.72 (4H, m). (4) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- [3- (quinazolin-2,4-dione-3-yl) propyl] glycine. De-benzylation and de-inking reactions were carried out. hydroxymethylation, similarly to the procedures described in example 5 (5) (a) and (b), using benzyl ester of (±) -2- [3- (1-benzyloxymethylquinazoline-2,4-dione- 3-yl) propyl] -N-methyl-N- (4-phenoxy-benzenesulfonyl) glycine, the product of (3) above, to give the title compound (80% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 12.73 (1 H, br.s), 11.43 (1 H, s), 7.94-7.92 (1 H, m), 7.78-7.74 (2H , m), 7.68-7.63 (1 H, m), 7.47-7.43 (2H, m), 7.26-7.17 (3H, m), 7.10-7.04 (4H, m), 4.42 (1 H, dd, J = 10Hz, 5Hz), 3.96-3.85 (2H, m), 2.73 (3H, s), 1.84-1.75 (1 H, m), 1.67-1.48 (3H, m).

EXAMPLE 36 (±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-r3- (auinazolin-2,4-dione-3-yl) propylene glycine (Compound No. 1-26) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [3- (quinazoline-2,4- dione-3-yl) propyl] glycine, the product of Example 35, to give the title compound (97% yield) as a white powder. Melting point: 152-153 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 11.44 (1 H, s), 10.66 (1 H, d, J = 1 Hz), 8.89 (1 H, d, J = 1 Hz), 7.93 (1 H, d, J = 8Hz), 7.77-7.73 (2H, m), 7.68-7.64 (1 H, m), 7.47-7.43 (2H, m), 7.27-7.10 (5H, m), 7.07- 7.04 (2H, m), 4.15 (1H, t, J = 8Hz), 3.92-3.80 (2H, m), 2.83 (3H, s), 1.67-1.59 (1H, m), 1.53-1.34 (3H, m).

EXAMPLE 37 (±) -N- (4-Phenoxybenzenesulfonyl) -N-proparqyl-2-r2- (quinazolin-2,4-dione-3-Detinqlicine (Compound No. 1-179) (1) (±) -a- [N- (4-Phenoxybenzenesulfonyl) -N-propargylamino] ^ and -butyrolactone A reaction was carried out in a manner similar to that described in example 1 (3), using ( ±) -a- (4-phenoxybenzenesulfonylamino) -butyrolactone in place of the (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine allyl ester, and using propargyl bromide instead of iodide methyl, to produce the desired compound (89% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.93-7.87 (2H, m), 7.45-7.38 (2H, m), 7.27-7.20 (1 H, m), 7.10-7.02 (4H, m ), 4.80 (1H, dd, J = 11Hz, 9Hz), 4.50 (1H, dt, J = 9Hz, 2Hz), 4.32-4.18 (2H, m), 3.91 (1H, dd, J = 18Hz, 3Hz) , 2.95-2.78 (1 H, m), 2.66-2.54 (1 H, m), 2.32 (1 H, t, J = 3 Hz). (2) (±) -2- (2-Hydroxyethyl) -N- (4-phenoxybenzenesulfonyl) -N-propargylglycine allyl ester After the addition of a solution of sodium hydroxide (1.05 g, 25.5 mmol) in water ( 7 ml) to a suspension of (±) -a- [N- (4-phenoxybenzenesulfonyl) -N-propargylamino] -? - butyrolactone (8.42 g, 22.7 mmol) in ethanol (40 ml), the mixture was stirred at room temperature environment for 3 hours. The solvent in the reaction mixture was evaporated under reduced pressure. The residue, which was an amorphous solid, was dissolved in N, N-dimethylformamide (40 ml). After the addition of allyl bromide (2.15 ml, 25.4 mmol) to the solution, the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 3/1 as eluent, to give the desired compound (8.29 g, 85% yield) as a pale yellow oil. (3) (±) -N- (4-phenoxybenzenesulfonyl) -N-propargyl-2- [2- [1- (2-trimethylsilyl) ethoxymethylquinazolin-2,4-dione-3-yl] ethyl] gl allyl ester A reaction was carried out in a manner similar to that described in Example 1 (1), using (±) -2- (2-hydroxyethyl) -N- (4-phenoxybenzenesulfonyl) -N- allyl ester. propargylglycine, the product of (2) above, in place of the (±) -N- (tert-butoxycarbonyl) homoserine allyl ester, and using 1- (2-trimethylsilyl) ethoxymethylquinazolin-2,4- dione, instead of phthalimide, to produce the desired compound (23% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.18 (1 H, dd, J = 8Hz, 2Hz), 7.89-7.83 (2H, m), 7.70-7.63 (1 H, m), 7.46- 7.37 (3H, m), 7.30-7.18 (2H, m), 7.08-6.96 (4H, m), 5.82-5.68 (1H, m), 5.59 (2H, s), 5.27-5.16 (2H, m) , 4.75 (1H, dd, J = 9Hz, 7Hz), 4.56-4.38 (2H, m), 4.33-4.10 (4H, m), 3.74-3.67 (2H, m), 2.45-2.32 (1H, m) , 2.28-2.15 (2H, m), 0.98-0.91 (2H, m), -0.02 (9H, s). (4) (±) -N- (4-phenoxybenzenesulfonyl) -N-propargyl-2- [2- (quinozolin-2,4-dione-3-yl) ethyl] gylcin allyl ester described in Example 1 (2) (a), a reaction was carried out by removing the protecting group in position 1 of the quinazoline ring, using (±) -N- (4-phenoxybenzenesulfonyl) allyl ester - N-propargyl-2- [2- [1- (2-trimethylsilyl) ethoxymetholquinazolin-2,4-dione-3-yl] etl] glycine, the product of (3) above, for produce the desired compound (90% yield) as a colorless amorphous solid. (5) (±) -N- (4-Phenoxybenzenesulfonyl) -N-propargyl-2- [2- (quinazolin-2,4-dione-3-yl) ethyl] glycine An ester hydrolysis reaction was carried out in a manner similar to that described in example 33 (3), using (±) -N- (4-phenoxybenzenesulfonyl) -N-propargyl-2- [2- (quinazoline-2,4-dione-) allyl ester 3-yl) ethyl] glycine, to give the title compound (97% yield) as a white powder. Melting point: 194-195 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 12.97 (1 H, br.s), 11.46 (1 H, s), 7.91 (1 H, d, J = 7Hz), 7.82-7.79 (2H, m), 7.65 (1H, t, J = 7Hz), 7.48-7.44 (2H, m), 7.28-7.18 (3H, m), 7.11 (2H, d, J = 8Hz), 7.03-6.99 (2H, m), 4.46 (1 H, t, J = 7Hz), 4.19 (1 H, dd, J = 19Hz, 2Hz), 4.07-3.86 (3H, m), 3.17 (1 H, t, J = 2Hz), 2.33-2.22 (1 H, m), 1.98-1.89 (1 H, m).

EXAMPLE 38 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -Na-proparqyl-2-r2- (quinazolin-2,4-dione-3-yl) etinqlicinamide (Compound No. 1-89) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- (4-phenoxybenzenesulfonyl) -N-propargyl-2- [2- (quinozolin-2, 4-dione-3-yl) ethyl] glycine, the product of example 37, to give the title compound (89% yield) as a white powder. Melting point: 161-162 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 11.45 (1 H, s), 10.76 (1 H, s), 9.08 (1H, br.s), 7.91 (1 H, d, J = 8Hz), 7.89-7.84 (2H, m), 7.68-7.64 (1H, m), 7.48-7.43 (2H, m), 7.28-7.12 (5H, m), 7.07-7.02 (2H, m), 4.47 (1H, dd, J = 19Hz, 2Hz), 4.30-4.20 (2H, m), 3.87-3.73 (2H, m), 3.09 (1H, t, J = 2Hz), 2.15-2.06 (1H, m), 1.99-1.82 (1 H, m).

EXAMPLE 39 (±) -2T2- (5-Fluoropyrimidin-2,4-dione-3-yl) etn-N-methyl-N- (4-phenoxybenzenesulfonyl) (1) Benzyl ester of (±) -2- [2- (1-benzyloxymethyl-5-fluoropyrimidin-2,4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine. reaction in a manner similar to that described in Example 1 (1), using (±) -N- (tert-butoxycarbonyl) homoserine benzyl ester in place of the (±) -N- (tert-butoxycarbonyl) allyl ester homoserin, and using 1-benzyloxymethyl-5-fluoro-pyrimidine-2,4-dione in place of phthalimide, to produce the desired compound (54% yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.77 (2H, d, J = 9Hz), 7.44-7.27 (3H, m), 7.22-7.19 (2H, m), 7.04 (2H, d, J = 8Hz), 6.94 (2H, d, J = 9Hz), 5.74 (1H, d, J = 9Hz), 5.21 (2H, s), 4.94 (1H, d, J = 12Hz), 4.89 (1 H, d, J = 12Hz), 4.64 (2H, s), 4.18-4.15 (2H, m), 4.05-3.92 (1H, m), 2.25-2.06 (2H, m). (2) (±) -2- [2- (1-Benzyloxymethyl-5-fluoropyrimidin-2,4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine benzyl ester performed reactions similarly to the procedures described in example 1 (2) (a) and (b), using (±) -2- [2- (1-benzyloxymethyl-5-fluoropyrimidin-2-benzyl ester , 4-dione-3-yl) ethyl] -N- (tert-butoxycarbonyl) glycine, the product of (1) above, in place of the (±) -N- (tert-butoxycarbonyl) -2 allyl ester - (2-phthalimidoethyl) glycine, to produce the desired compound (65% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.70 (2H, d, J = 9Hz), 7.43-7.29 (12H, m), 7.24-7.18 (2H, m), 7.04 (2H, d, J = 8Hz), 6.89 (2H, d, J = 9Hz), 5.95 (1H, d, J = 9Hz), 5.22 (2H, s), 5.00 (1H, d, J = 12Hz), 4.94 (1 H, d, J = 12Hz), 4.63 (2H, s), 4.23-4.05 (2H, m), 4.00-3.86 (1 H, m), 2.32-2.16 (1 H, m), 2.12-2.00 (1H , m). (3) Benzyl ester of (±) -2- [2- (1-benzyloxymethyl-5-fluoropyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4- phenoxybenzenesulfonyl) glycine A reaction was carried out in a manner similar to that described in example 1 (3), using (±) -2- [2- (1-benzyloxymethyl-5-fluoropyrimidin-2,4-benzyl ester -dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) -glycine, the product of (2) above, instead of the allyl ester of (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, to produce the desired compound (91% yield) as a pale yellow amorphous solid.

Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.70 (2H, d, J = 9Hz), 7.43-7.29 (12H, m), 7.22-7.18 (2H, m), 7.04 (2H, d, J = 8Hz), 6.90 (2H, d, J = 9Hz), 5.23 (2H, s), 5.00 (1 H, d, J = 12Hz), 4.94 (1 H, d, J = 12Hz), 4.85-4.79 (1 H, m), 4.63 (2H, m), 4.11-3.98 (2H, m), 2.87 (3H, s), 2. 27-2.13 (1 H, m). (4) (±) -2- [2- (5-Fluoropyrimidin-2,4-dione-3-yl) ethyl] - N -methyl- (4-phenoxy-benzenesulfonyl) glycine performed de-benzylation and de-hydroxymethylation reactions, similarly to the procedures described in Example 5 (5) (a) and (b), using benzylic ester of (±) -2- [2- ( 1-benzyloxymethyl-5-fluoropyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine, the product of (3) above, to give the compound of the title (78% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 9.80 (1 H, d, J = 6Hz), 7.75 (2H, d, J = 9Hz), 7.39 (2H, t, J = 8Hz), 7.31 -7.17 (2H, m), 7.06-6.99 (3H, m), 4.79 (1H, t, J = 8Hz), 3.99 (2H, t, J = 7Hz), 2.83 (3H, s), 2.34-2.24 (1 H, m), 2.01-1.88 (1 H, m).

EXAMPLE 40 (±) -2-r2- (5-Fluoropyrimidin-2,4-dione-3-iPetin-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-31) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -2- [2- (5-fluoropyrimidin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine, the product of example 39, to give the title compound (41% yield) as a pale pink amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSOdβ) d ppm: 7.80 (3H, dd, J = 12Hz, 8Hz), 7.46 (2H, t, J = 8Hz), 7.25 (1H, t, J = 7Hz) , 7.15-7.05 (4H, m), 4.28 (1H, dd, J = 9Hz, 6Hz), 3.66-3.51 (2H, m), 2.91 (3H, s), 1.94-1.71 (2H, m).

EXAMPLE 41 (+) - N-Methyl-N- (4-phenoxybenzenesulfonyl) -2-r2- (thienor3.2-dlpyrimidin-2,4-dione-3-yl) etinglicine (1) (±) -a- [N-Methyl-N- (4-phenoxybenzenesulfonyl) amino] ^ -butyrolactone A reaction was carried out in a manner similar to that described in example 1 (3), using (±) -a- (4-phenoxybenzenesulfonylamino) ^ -butyrolactone, in place of (+) - N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, to produce the desired compound (98% yield) ) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.87-7.82 (2H, m), 7.45-7.36 (2H, m), 7.26-7.19 (1H, m), 7.10 (4H, m), 5.01 (1 H, dd, J = 12Hz, 9Hz), 4.43 (1 H, dt, J = 9Hz, 2Hz), 4.36 (1 H, ddd, J = 11 Hz, 9Hz, 6Hz), 2.78 (3H, s) , 2.55-2.29 (2H, m). (2) (±) -2- (2-hydroxyethyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine allyl ester A reaction was carried out in a manner similar to that described in example 37 (2) ), using (+) - a- [N-methyl-N- (4-phenoxybenzenesulfonyl) amino] -? - butyrolactone instead of (±) -a- [N- (4-phenoxybenzenesulfonyl) -N-propargylamino] ^ y-butyrolactone, to produce the desired compound (97% yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.81-7.75 (2H, m), 7.45-7.38 (2H, m), 7.25-7.19 (1H, m), 7.09-6.99 (4H, m ), 5.87-5.72 (1 H, m), 5.25-5.17 (2H, m), 4.83 (1 H, dd, J = 9Hz, 5Hz), 4.48-4.35 (2H, m), 3.83-3.72 (2H, m), 2.84 (3H, s), 2.42 (1 H, br.t, J = 7Hz), 2.25-2.12 (1 H, m), 1.92-1.79 (1 H, m). (3) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- [1- (2-trimethylsilyl) ethoxymethyl-thieno [3,2-d] pyrimidine-2,4-dione allyl ester -3-yl] ethyl] glycine A reaction was carried out in a manner similar to that described in Example 1 (1), using (±) -2- (2-hydroxyethyl) -N-methyl- allyl ester. N- (4-phenoxybenzenesulfonyl) glycine, the product of (2) above, in place of the (±) -N- (tert-butoxycarbonyl) homoserine allyl ester, and using 1- (2-trimethylsilyl) ethoxymethyl-triene [3,2 -d] pyrimidine-2,4-dione in place of phthalimide, to produce the desired compound (81% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.80-7.74 (2H, m), 7.74 (1 H, d, J = 5Hz), 7.44-7.36 (2H, m), 7.23-7.18 (1 H, m), 7.11-6.98 (5H, m), 5.81-5.66 (1H, m), 5.48 (2H, s), 5.26-5.17 (2H, m), 4.82 (1H, dd, J = 10Hz , 5Hz), 4.49-4.36 (2H, m), 4.21-4.04 (2H, m), 3.70-3.63 (2H, m), 2.97 (3H, s), 2.33-2.20 (1H, m), 2.14- 1.99 (1 H, m), 0.96-0.90 (2H, m), -0.02 (9H, s). (4) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (thieno [3,2-d] pyrimidin-2,4-dione-3-yl] ethyl] glycine Deprotection and ester hydrolysis reactions were performed successively, similarly to the procedures described in example 37 (4) and (5), using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) allyl ester ) -2- [2- [1- (2-trimethylsilyl) ethoxymethyl-thieno [3,2-d] pyrimidin-2,4-dione-3-yl] ethyl] glycine, to give the title compound (88% yield) ) as a white powder Melting point: 218-219 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 12.90 (1 H, br.s), 11.91 (1H, s), 8.07 (1 H, d, J = 5Hz), 7.81-7.76 (2H, m), 7.48-7.43 (2H, m), 7.29-7.23 (1 H, m), 7.15-7.04 (4H, m), 6.93 (1 H, d, J = 5Hz), 4.50 (1 H, dd, J = 10Hz, 6Hz), 3.86-3.75 (2H, m), 2.83 (3H, s), 2.17-2.07 (1 H, m) , 1.82-1.72 (1 H, m).

EXAMPLE 42 (+) - NH 4 -droxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-r 2 - (t-inor-2,3-dl-pyrimidin-2,4-dione-3-yl) ethynylamine (Compound No. 5-23) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (thieno [3,2-] d] pyrimidin-2,4-dione-3-yl] ethyl] glycine, the product of example 41, to give the title compound (92% yield) as a white powder Melting point: 186-187 ° C (with decomposition).

Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 11.89 (1 H, s), 10.75 (1 H, s), 8.95 (1 H, br.s), 8.07 (1 H, d, J = 5Hz), 7.79-7.76 (2H, m), 7.47-7.42 (2H, m), 7.26-7.22 (1H, m), 7.14-7.07 (4H, m), 6.92 (1H, d, J = 5Hz), 4.31 (1 H, dd, J = 9Hz, 7Hz), 3.75-3.60 (2H, m), 2.94 (3H, s), 1.91-1.72 (2H, m).

EXAMPLE 43 (+) - 2-r2- (3,7-Dimethylxanthin-1-yl) etin-N-methyl-N- (4-phenoxybenzenesulfoniP-glycine) (1) Allyl ester of (±) -2- (2-bromoethyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine After adding triphenylphosphine (4.72 g, 18.0 mmol) to an allyl ester solution of (± ) -2- (2-hydroxyethyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine (6.08 g, 15.0 mmol), the product of example 41 (2), in tetrahydrofuran (45 ml), was added a Carbon tetrabromide solution (5.97 g, 18.0 mmol) in tetrahydrofuran (20 ml) for 20 minutes, with ice cooling and with stirring. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 5/1 as eluent to produce the desired compound (6.05 g, 86% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.81-7.76 (2H, m), 7.45-7.38 (2H, m), 7.25-7.19 (1H, m), 7.09-6.99 (4H, m ), 5.82-5.68 (1 H, m), 5.29-5.21 (2H, m), 4.85 (1 H, dd, J = 10Hz, 5Hz), 4.53-4.40 (2H, m), 3.52-3.35 (2H, m), 2.82 (3H, s), 2.51-2.38 (1 H, m), 2.30-2.16 (1 H, m). (2) (+) - 2- [2- (3,7-Diethyl-1-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine allyl ester After addition of 3,7-dimethylxanthine (1.10 g, 6.1 mmol) to a suspension of sodium hydride (60%, 0.24 g, 6.0 mmol) in N, N-dimethylformamide (20 ml), the mixture was stirred at 50 ° C for 2 hours. After cooling to room temperature, an allylester solution of (±) -2- (2-bromoethyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine (2.34 g, 5.0 mmol) in N, was added. N-dimethylformamide (10 ml). This was heated at 80 ° C for 2 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added, and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 3/1 as eluent to produce the desired compound (0.86 g, 30% yield) as a colorless amorphous solid.

Melting point: 207-209 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.80-7.74 (2H, m), 7.51 (1 H, S), 7.43-7.36 (2H, m), 7.24-7.18 (1 H, m) , 7.07-6.97 (4H, m), 5.82-5.67 (1 H, m), 5.28-5.18 (2H, m), 4.82 (1 H, dd, J = 11 Hz, 6Hz), 4.49-4.37 (2H, m), 4.18-4.01 (2H, m), 3.98 (3H, s), 3.57 (3H, s), 2.97 (3H, s), 2.31-2.18 (1H, m), 2.12-1.98 (1H, m ). (3) (±) -2- [2- (3,7-Dimethyl-xanthin-1-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) -glycine A hydrolysis of the ester group was carried out in a similar manner to the one described in example 33 (3), using (+) - 2- [2- (3,7-dimethylxanthin-1-yl) ethyl] -N-methyl-N- (4-) allyl ester phenoxybenzenesulfonyl) glycine, the product of (2) above, to give the title compound (96% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb-DMSD-dβ) d ppm: 12.89 (1 H, br.s), 8.02 (1 H, s), 7.81-7.75 (2H, m), 7.48-7.42 ( 2H, m), 7.27-7.23 (1H, m), 7.13-7.06 (4H, m), 4.50 (1H, dd, J = 10Hz, 6Hz), 3.87-3.75 (5H, m), 3.41 (3H , s), 2.84 (3H, s), 2.13-2.05 (1 H, m), 1.82-1.72 (1 H, m).

EXAMPLE 44 (±) -2-r2- (3.7-D -methylxanthin-1-yichthon-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoni) D-glycinamide (Compound No. 5-27) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -2- [2- (3,7-dimethylxanthin-1-yl) ethylen-N-methyl-N- (4-phenoxybenzenesulfonyl) glycine, product of example 43, to give the title compound (87% yield) as a white powder. Melting point: 117-119 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 10.76 (1 H, s), 8.94 (1 H, s), 8.02 (1 H, s), 7.80-7.76 (2H, m), 7.46-7.41 (2H, m), 7.27-7.23 (1H, m), 7.14-7.07 (4H, m), 4.30 (1H, dd, J = 9Hz, 6Hz), 3.86 (3H, s), 3.76 -3.64 (2H, m), 3.40 (3H, s), 2.94 (3H, s), 1.88-1.72 (2H, m).

EXAMPLE 45 (+) - N-Methyl-2-r2 ^ 1-methylauinazolin-2,4-dione-3-yl) etin-N- (4-phenoxybenzenesulfonyl) (1) Allyl ester of (±) -N-methyl-2- [2- (1-methylquinazolin-2,4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine. reaction in a manner similar to that described in Example 1 (1), using (±) -2- (2-hydroxyethyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine, the product of the example 41 (2), instead of the (±) -N- (tert-butoxycarbonyl) homoserine allyl ester, and using 1-methylquinazoline-2,4-dione in place of phthalimide, to produce the desired compound (72% yield ) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.22-8.19 (1 H, m), 7.79-7.66 (3H, m), 7.43-7.36 (2H, m), 7.29-7.18 (3H, m ), 7.07-6.99 (4H, m), 5.81-5.67 (1H, m), 5.27-5.18 (2H, m), 4.83 (1H, dd, J = 10Hz, 5Hz), 4.47-4.37 (2H, m), 4.24-4.06 (2H, m), 3.60 (3H, s), 2.99 (3H, s), 2.35-2.22 (1H, m), 2.15-2.00 (1H, m). (2) (±) -N-Methyl-2- [2- (1-methyl-tyzolin-2,4-dione-3-yl) ethyl] -N- (4-phenoxy-benzenesulfonyl) glycine A group hydrolysis was carried out ester in a manner similar to that described in Example 33 (3), using (±) -N-methyl-2- [2- (1-methyl-cynazol-2,4-dione-3-yl) allyl ester ) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine, the product of (1) above, to give the title compound (74% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.22-8.18 (1 H, m), 7.78-7.67 (3H, m), 7.40-7.34 (2H, m), 7.30-7.15 (3H, m ), 7.05-6.96 (4H, m), 4.80 (1H, dd, J = 10Hz, 6Hz), 4.21-4.02 (2H, m), 3.59 (3H, s), 2.98 (3H, s), 2.37- 2.24 (1 H, m), 2.11-1.97 (1 H, m).

EXAMPLE 46 (+) - N-Hydroxy-Na-methyl-2-r2- (1-methylquinazolin-2,4-dione-3-yl) etn-Na- (4-phenoxybenzenesulfoni) Dichlinamide (Compound No. 5-15) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N-methyl-2- [2- (1-methylquinazolin-2,4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine, the product of example 45, to give the title compound (76% yield) as a white powder. Melting point: 184-185 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 10.77 (1 H, s), 8.95 (1 H, s), 8.04 (1 H, dd, J = 8 Hz, 1 Hz), 7.80- 7.76 (3H, m), 7.46-7.41 (3H, m), 7.31 (1H, t, J = 8Hz), 7.27-7.23 (1H, m), 7.14-7.06 (4H, m), 4.33 (1 H, dd, J = 9Hz, 6Hz), 3.85-3.74 (2H, m), 3.51 (3H, s), 2.95 (3H, s), 1.94-1.75 (2H, m).

EXAMPLE 47 (±) -N-Methyl-2-r7- (1-methylxanthin-1-yl) etin-N- (4-phenoxybenzenesulfonyl) (1) Allyl ester of (±) -N-methyl-2- [2- [7-methyl-3- (2-trimethylsilyl) ethoxymethylxanthin-1-yl] ethyl] -N- (4-phenoxybenzenesulfonyl) glycine A reaction was carried out in a manner similar to that described in Example 43 (2), using 7-methyl-3- (2-trimethylsilyl) ethoxymethylxanthine in place of 3,7-dimethylxanthine, to produce the desired compound ( 51% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.80-7.74 (2H, m), 7.51 (1 H, s), 7.43-7.36 (2H, m), 7.25-7.18 (1 H, m) , 7.08-6.98 (4H, m), 5.81-5.67 (1H, m), 5.53 (2H, s), 5.26-5.17 (2H, m), 4.81 (1H, dd, J = 10Hz, 5Hz), 4.49-4.46 (2H, m), 4.17-4.02 (2H, m), 3.98 (3H, s), 3.75-3.68 (2H, m), 2.96 (3H, s), 2.30-2.17 (1 H, m) , 2.12-1.98 (1 H, m), 1.01-0.97 (2H, m), -0.02 (9H, s). (2) (±) -N-Methyl-2- [2- (7-methylxanthin-1-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine. Deprotection and ester hydrolysis reactions were performed, similar to the procedures described in example 37 (4) and (5), using (±) -N-methyl-2- [2- [7-methyl-3- (2-trimethylsilyl) ethoxymethylxanthin-1- allyl ester il] ethyl] -N- (4-phenoxybenzenesulfonyl) glycine, product of (1) above, to give the title compound (92% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 12.90 (1 H, br.s), 11.89 (1 H, s), 7.93 (1 H, s), 7.81-7.76 (2H, m ), 7.48-7.43 (2H, m), 7.28-7.23 (1 H, m), 7.13-7.03 (4H, m), 4.49 (1 H, dd, J = 10Hz, 6Hz), 3.84 (3H, s) , 3.80-3.72 (2H, m), 2.84 (3H, s), 2.13-2.04 (1H, m), 1.80-1.70 (1H, m).

EXAMPLE 48 (±) -N-Hydroxy-N-methyl-2-r2- (7-methylxanthin-1-yl) etin-Na- (4-phenoxybenzenesulfoni) D-glycinamide (Compound No. 5-25) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-2- [2- (7-methylxanthin-1-yl) ethyl] -N- ( 4-phenoxybenzenesulfonyl) glycine, the product of Example 47, to give the title compound (78% yield) as a white powder. Melting point: 194-195 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 11.89 (1 H, s), 10.75 (1 H, d, J = 1 Hz), 8.94 (1 H, d, J = 1 Hz) , 7.93 (1 H, s), 7.82-7-76 (2H, m), 7.47-7.41 (2H, m), 7.26-7.22 (1 H, m), 7.13-7.07 (4H, m), 4.30 ( 1 H, dd, J = 9Hz, 6Hz), 3.83 (3H, s), 3.71-3.59 (3H, m), 2.94 (3H, s), 1.88-1.70 (2H, m).

EXAMPLE 49 (±) -Na-r3- (4-Chlorophenol) propargin-N-hydroxy-Na- (4-methoxybenzenesulfonyl) -valinamide (Compound No. 6-25) (1) Methyl ester of (±) -N- (4-methoxybenzenesulfonyl) valine A reaction was carried out in a manner similar to that of example 1 (2) (b), using methyl ester of (±) -valin and chloride of 4-methoxybenzenesulfonyl, to produce the desired compound (90% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.79-7.32 (2H, m), 6.98-6.93 (2H, m), 5.05 (1 H, d, J = 10Hz), 3.86 (3H, s ), 3.71 (1 H, dd, J = 10Hz, 5Hz), 3.48 (3H, s), 2.08-1.96 (1 H, m), 0.95 (3H, d, J = 7Hz), 0.87 (3H, d, J = 7Hz). (2) (±) -N- [3- (4-chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) valine methyl ester A reaction was carried out in a manner similar to that described in example 1 ( 3), using (±) -N- (4-methoxybenzenesulfonyl) valine methyl ester, the product of (1) above, and 3- (4-chlorophenyl) propargyl bromide, to produce the desired compound (84% yield ) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.88-7.83 (2H, m), 7.27-7.23 (2H, m), 7.18-7.12 (2H, m), 6.92-6.86 (2H, m) , 4.59 (1 H, d, J = 19 Hz), 4.32 (1 H, d, J = 19 Hz), 4.15 (1 H, d, J = 11 Hz), 3.80 (3 H, s), 3.51 (3 H, s ), 2.32-1.75 (1 H, m), 1.05 (3H, d, J = 7Hz), 0.95 (3H, d, J = 7Hz). (3) (±) -N- [3- (4-Chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) valine An ester hydrolysis reaction was carried out, similarly to that described in the example 33 (3), using methyl ester of (±) -N- [3- (4-chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) valine, the product of (2) above, to produce the desired compound (36 % yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.88-7.83 (2H, m), 7.27-7.21 (2H, m), 7.18-7.15 (2H, m), 6.90-6.86 (2H, m) , 4.49 (1 H, d, J = 19 Hz), 4.41 (1 H, d, J = 19 Hz), 4.13 (1 H, d, J = 10 Hz), 3.80 (3 H, s), 2.28-1.76 (1 H , m), 0.99 (3H, d, J = 7Hz), 0.97 (3H, d, J = 7Hz). (4) (±) -Na- [3- (4-Chlorophenyl) propargyl] -N-hydroxy-Na- (4-methoxybenzenesulfonyl) -valinamide A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -N- [3- (4-chlorophenyl) propargyl] -N- (4-methoxybenzenesulfonyl) valine, the product of (3) above, to produce the title compound (84% of performance) as a white powder. Melting point: 153-154 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.00 (1 H, s), 7.85 (2H, d, J = 9Hz), 7.57 (1 H, br.s), 7.27-7.26 (2H, m), 7.25-7.19 (2H, m), 6.90 (2H, d, J = 9Hz), 4.55 (1H, d, J = 19Hz), 4.50 (1H, d, J = 19Hz), 3.81 (3H, s), 3.69 (1 H, d, J = 11 Hz), 2.41-2.32 (1 H, m), 0.89 (3 H, d, J = 6 Hz), 0.71 (3 H, d, J = 6 Hz).

EXAMPLE 50 (±) -Na-r3- (4-Chlorophenyl) proparqin-N-hydroxy-Na- (4-phenoxybenzenesulfoni-P-valinamide (Compound No. 6-26) Reactions were carried out in a manner similar to the procedures described in example 49 (1), (2), (3) and (4), using (±) -valine methyl ester and 4-phenoxybenzenesulfonyl chloride as starting materials to give the title compound (9% total yield in the 4 steps) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 8.97 (1 H, s), 7.87 (2H, d, J = 9Hz), 7.74 (1 H, br.s), 7.38 (2H, t, J = 8Hz), 7.26-7.18 (5H, m), 6.97-6.95 (4H, m). 4.57 (1 H, d, J = 19 Hz), 4.52 (1 H, d, J = 19 Hz), 3.71 (1 H, d, J = 11 Hz), 2.44-2.31 (1 H, m), 0.91 (3 H, d, J = 6Hz), 0.76 (3H, d, J = 6Hz).

EXAMPLE 51 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -Na-propargylvalenamide (Compound No. 6-4) A reaction was carried out in a manner similar to that described in Example 49 (1), using 4-phenoxybenzenesulfonyl chloride in place of 4-methoxybenzenesulfonyl chloride. Using the product and propargyl bromide in place of 3- (4-chlorophenyl) propargyl bromide, a reaction was performed in a manner similar to that described in example 49 (2). In addition, using the resulting product, reactions were carried out in a manner similar to the procedures described in Example 49 (3) and (4), to give the title compound (24% total yield in the 4 steps) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 8.99 (1 H, s), 7.85 (2H, d, J = 9Hz), 7.45-7.39 (2H, m), 7.25-7.21 (1 H, m), 7.07-7.03 (4H, m), 4.37 (1H, dd, J = 19Hz, 2Hz), 4.30 (1H, dd, J = 19Hz, 2Hz), 3.60 (1H, d, J = 11 Hz), 2.36-2.27 (1 H, m), 2.22 (1 H, t, J = 2 Hz), 0.88 (3 H, d, J = 7 Hz), 0.69 (3 H, d, J = 7 Hz).

EXAMPLE 52 (+) - Na-r3- (4-Chlorophenol) proparqin-N-hydroxy-Na- (4-methoxy-benzenesulfonyl) -lanine (Compound No. 6-27) Reactions were carried out in a manner similar to the procedures described in example 49 (1), (2), (3) and (4), using (±) -alanine methyl ester and 4-phenoxybenzenesulfonyl chloride as starting materials, to give the title compound (58% total yield in the 4 steps) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.32 (1H, s), 7.85-7.82 (2H, m), 7.33-7.20 (4H, m), 6.95-6.91 (2H, m), 4.54 (1H, q, J = 7Hz), 4.33 (2H, s). 3.82 (3H, s), 1.32 (3H, d, J = 7Hz).

EXAMPLE 53 (±) -N-Methyl-N 4-phenoxybenzenesulfonyl) -2-r 2 - (pteridin-2,4-dione-3-yl) - etinqlicine A reaction was carried out in a manner similar to that described in example 41 (3), using 1- (2-trimethylsilyl) ethoxymethylpteridine-2,4-dione, instead of 1- (2-trimethylsilyl) ethoxymethyl. ltieno [3,2-d] pyrimidine-2,4-dione, and then, using the resulting allylic ester derivative, ester hydrolysis reactions were performed in a manner similar to that described in example 41 (4), to give the title compound (53% total yield) as a yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-dβ) d ppm: 12.25 (1 H, s), 8.67 (1 H, d, J = 2 Hz), 8.56 (1 H, d, J = 2 Hz), 7.81 (2H, d, J = 9Hz), 7.46 (2H, t, J = 8Hz), 7.25 (1H, t, J = 8Hz), 7.14-7.05 (4H, m), 4.53 (1H, dd, J = 10Hz, 5Hz), 3.92-3.80 (2H, m), 2.86 (3H, s), 2.23-2.12 (1 H, m), 1.93-1.79 (1 H. m).

EXAMPLE 54 (±) -N-Hydroxy-N -methyl-N- (4-phenoxybenzenesulfonyl) -2-r2- (pterin-2,4-dione-3-yl) etinglycinamide (Compound No. 5-21) A hydroxy-amidation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (pterindin-2) , 4-dione-3-yl) ethyl] glycine, to give the title compound (54% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-de) d ppm: 12.23 (1 H, s), 10.77 (1 H, s), 8.96 (1 H, t, J = 1 Hz), 8.67 (1 H , d, J = 2Hz), 8.56 (1 H, d, J = 2Hz), 7.81-7.78 (2H, m), 7.48-7.43 (2H, m), 7.25 (1 H, t, J = 7Hz), 7.16-7.09 (4H, m), 4.33 (1 H, t, J = 7Hz), 3.78-3.72 (2H, m), 2.96 (3H, s), 1.95-1.80 (2H, m).

EXAMPLE 55 (±) -N-r3- (4-Chlorophenyl) propargill-N- (4-phenoxybenzenesulfonyl) -2- (phthalimidoethyl) glycine Reactions were carried out in a manner similar to the procedures described in Example 27 (1) and (2), using 3- (4-chlorophenyl) propargyl bromide in place of propargyl bromide, to give the title compound (88% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.87-7.78 (4H, m), 7.74-7.68 (2H, m), 7.42-7.34 (2H, m), 7.26-7.17 (5H, m) , 7.01-6.96 (2H, m), 6.94-6.89 (2H, m), 4.67 (1 H, t, J = 7Hz), 4.46 (1 H, d, J = 19Hz), 4.35 (1H, d, J = 19Hz), 3.78 (2H, t, J = 7Hz), 2.52-2.39 (1H, m), 2.23-2.09 (1H, m).

EXAMPLE 56 (i) -Na-r3- (4-Chlorophenyl) proparqin-N-hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- (phthalimidoethyl) qlycinamide (Compound No. 3-136) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- [3- (4-chlorophenol) propargyl] -N- (4-phenoxybenzenesulfonyl) -2 - (2-phthalimidoetyl) glycine, the product of example 55, to give the title compound (61% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum H (400 MHz, CDCb) d ppm: 9.42 (1 H, br.s), 7.84-7.80 (2H, m), 7.75-7.67 (4H, m), 7.44-7.39 (2H, m ), 7.27-7.20 (6H, m), 7.00-6.98 (2H, m), 6.63 (2H, d, J = 9Hz), 4.52 (1H, d, J = 19Hz), 4.50 (1H, d, J = 19Hz), 4.29 (1 H, dd, J = 10Hz, 5Hz), 3.70-3.64 (1 H, m), 3.58-3.50 (1 H, m), 2.60-2.51 (1 H, m), 1.90- 1.81 (1 H, m).

EXAMPLE 57 (±) -N- (4-Phenoxybenzenesulfonyl) -N- (3-phenylproparqyl) -2- (2-phthalimidoetiP-glycine) Reactions were carried out in a manner similar to the procedures described in example 27 (1) and (2), using 3-phenylpropargyl bromide in place of propargyl bromide, to give the title compound (90% yield). ) as a pale yellow amorphous solid.

Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.89-7.79 (4H, m), 7.74-7.68 (2H, m), 7.40-7.16 (8H, m), 7.00-6.88 (4H, m) , 4.75 (1 H, t, J = 8 Hz), 4.46 (1 H, d, J = 19 Hz), 4.37 (1 H, d, J = 19 Hz), 3.87 (1 H, t, J = 7 Hz), 2.49 -2.37 (1 H, m), 2.23-2.09 (1 H, m).

EXAMPLE 58 (+) - N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -Na- (3-phenylproparqyl) -2- (2-phthalimidoetiPlycinamide (Compound No. 3-122) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- (4-phenoxybenzenesulfonyl) -N- (3-phenylpropargyl) -2- (2-phthalimidoethyl) glycine, the product of Example 57, to give the title compound (87% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.42 (1 H, br.s), 7.83-7.79 (2H, m), 7.74-7.69 (4H, m), 7.48-7.21 (9H, m ), 7.00-6.96 (2H, m), 6.62 (2H, d, J = 9Hz), 4.55 (1H, d, J = 19Hz), 4.49 (1H, d, J = 19Hz), 4.31 (1H , dd, J = 10Hz, 5Hz), 3.71-3.65 (1H, m), 3.59-3.52 (1H, m), 2.62-2.53 (1H, m), 1.91-1.83 (1H, m).

EXAMPLE 59 (±) -N- (2-Butynyl) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) qlucine Reactions were carried out in a manner similar to the procedures described in example 27 (1) and (2), using 1-methanesulfonyloxy-2-butyne instead of propargyl bromide, to give the title compound (63%) of yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.87-7.79 (4H, m), 7.75-7.68 (2H, m), 7.44-7.36 (2H, m), 7.23-7.17 (1H, m ), 7.07-7.03 (2H, m), 6.98-6.93 (2H, m), 4.62 (1H, t, J = 8Hz), 4.21 (1H, dq, J = 19Hz, 3Hz), 4.06 (1H , dq, J = 19Hz, 3Hz), 3.88-3.66 (2H, m), 2.51-2.38 (1H, m), 2.23-2.07 (1H, m), 1.72 (3H, t, J = 3Hz).

EXAMPLE 60 (±) -Na- (2-Butynyl) -N-hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoetiPlycinamide (Compound No. 3-106) A hydroxy-amidation reaction was carried out in a manner similar to that described in example 2, using (±) -N- (2-butinyl) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, the product of example 59, to give the Compound title (86% yield) as a pale yellow amorphous solid Nuclear magnetic resonance spectrum 1 H (400 MHz, CDCb) d ppm: 9.36 (1 H, br.s), 7.84-7.79 (2H, m), 7.74-7.68 (4H, m), 7.45-7.40 (2H, m), 7.30-7.22 (2H, m), 7.05 (2H, d, J = 8Hz), 6.75 (2H, d, J = 9Hz ), 4.28-4.12 (3H, m), 3.63-3.48 (2H, m), 2.52-2.44 (1 H, m), 1.83-1.75 (4H, m).

EXAMPLE 61 (±) -2-f2- (1,1-Dixo-1,2-benzisothiazol-3-one-2-yl) etiM-N-methyl-N- (4-phenoxybenzenesulfonyl) (Compound No. 2-178 ) A reaction was carried out in a manner similar to that described in example 43 (2), using 1,1-dixo-1,2-benzisothiazol-3-one instead of 3,7-dimethylxanthine, and in addition, using the resulting allylic ester derivative, a de-allylation reaction was performed in a manner similar to that described in Example 1 (4), to give the title compound (62% total yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-de) d ppm: 13.00 (1 H, br.s), 8.32 (1 H, d, J = 7Hz), 8.11-7.99 (3H, m), 7.81- 7.78 (2H, m), 7.48-7.43 (2H, m), 7.27-7.23 (1H, m), 7.13-7.05 (4H, m), 4.65 (1H, dd, J = 9Hz, 6Hz), 3.82 -3.75 (1 H, m), 3.66-3.57 (1 H, m), 2.80 (3 H, s), 2.38-2.29 (1 H, m), 2.00-1.90 (1 H, m).

EXAMPLE 62 (+) - 2-r 2 - (1,1-Dixo-1,2-benzisothiazol-3-one-2-yl) ethyn-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) qycinamide (Compound No. 2 -25) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -2- [2- (1,1-dixo-1,2-benzisothiazol-3-one-2- i) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) glycine, to give the title compound (65% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.23 (1 H, br.s), 8.02 (1 H, d, J = 7Hz), 7.95-7.82 (3H, m), 7.68-7.65 ( 2H, m), 7.44-7.39 (3H, m), 7.24 (1H, t, J = 7Hz), 7.10-7.07 (2H, m), 6.85-6.82 (2H, m), 4.51 (1H, dd , J = 9Hz, 6Hz), 3.78-3.71 (1 H, m), 3.61-3.54 (1 H, m), 2.91 (3H, s), 2.48-2.39 (1 H, m), 1.83-1.61 (1 H. m).

EXAMPLE 63 (±) -N-Met.l-2-r2- (6-methy1pyrimidin-2,4-dione-3-yl) et.l-N- (4-phenoxybenzenesulfonyl) D-glycine A reaction was carried out in a manner similar to that described in example 41 (3), using 6-methyl-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione instead of 1- (2-trimethylsilyl) ) ethoxymethyl thieno [3,2-d] pyrimidine-2,4-dione, and then, using the resulting allylic ester derivative, deprotection and ester hydrolysis reactions were performed in a manner similar to that described in Example 41 ( 4), to give the title compound (19% total yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-d6) d ppm: 11.14 (1 H, s), 7.79 (2H, d, J = 9Hz), 7.46 (2H, t, J = 8Hz), 7.25 (1 H, t, J = 8Hz), 7.13-7.07 (4H, m), 5.46 (1 H, s), 4.46 (1 H, dd, J = 10Hz, 6Hz), 3.70-3.65 (2H, m), 2.81 (3H, s), 2.12-2.00 (1 H, m), 1.79-1.66 (1H, m).

EXAMPLE 64 (±) -N-Hydroxy-Na-methyl-2-r2- (6-methylpyrimidin-2,4-dione-3-yl) etin-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-39) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-2- [2- (6-methylpyrimidin-2,4-dione-3-yl) ethyl] -N- (4-phenoxybenzenesulfonyl) glycine, the product of Example 63, to give the title compound (73% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 7.76 (1 H, br.s), 7.68 (2H, d, J = 9Hz), 7.39 (2H, t, J = 8Hz), 7.21 (1 H, t, J = 8Hz), 7. 08-7.05 (2H, m), 6.98 (2H, d, J = 9Hz), 5.49 (1 H, s), 4.48 (1H, dd, J = 8Hz, 6Hz), 3.79-3.75 (2H, m), 2.88 (3H, s), 2.30-2.23 (1 H, m), 2.09 (3H, s), 1.66- 1.61 (1 H, m).

EXAMPLE 65 (±) -N-Methyl-N- (4-phenoxybenzenesulfoniP-2-r2- (5-trifluoromethyl-pyrimidin-2,4-dione-3-yl) etinglicine A reaction was carried out in a manner similar to that described in Example 41 (3), using 5-trifluoromethyl-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione in place of 1- (2-trimet Lysilyl) ethoxymethotyne [3,2-d] pyrimidine-2,4-dione, and then, using the resulting allylic ester derivative, deprotection and ester hydrolysis reactions were performed in a manner similar to which is described in Example 41 (4), to give the title compound (27% total yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-d6) d ppm: 8.09 (1 H, s), 7.79 (2H, d, J = 9Hz), 7.49-7.43 (2H, m), 7.28-7.22 (1 H, m), 7.13-7.07 (4H, m), 4.48 (1 H, dd, J = 10Hz, 5Hz), 3.79-3.67 (2H, m), 2.81 (3H, s), 2.15-1.99 (1 H , m), 1.84-1.70 (1 H, m).

EXAMPLE 66 (±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-r2- (5- trifluoromethylpyrimidin-2,4-dione-3-iPetipglicinamide (Compound No. 5- 3H A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (5-trifluoromethylpyrimidin-2 , 4-dione-3-yl) ethyl] glycine, the product of Example 65, to give the title compound (39% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 10.51 (1 H, br.s), 9.89 (1 H, br.s), 8.41 (1 H, br.s), 7.69 (2H, d , J = 9Hz), 7.40-7.36 (2H, m), 7.20 (1H, t, J = 7Hz), 7.05-7.00 (4H, m), 4.56 (1H, br.s), 3.82-3.75 ( 2H, m), 2.81 (3H, s), 2.25-2.23 (1H, m), 1.79-1.78 (1H, m).

EXAMPLE 67 (+) - N-Methyl-N- (4-phenoxybenzenesulfoniP-2- (2-phthalimidomethyl) glycine (1) N- (4-Phenoxybenzenesulfonyl) serinol After adding dropwise triethylamine (10.12 g, 100 mmol) to a solution of serinol (3.64 g, 40 mmol) in a mixture of dioxane (100 ml) and water (200 ml). ml), the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 4-phenoxybenzenesulfonyl chloride (10.75 g, 40 mmol) in dioxane (100 ml), and this was stirred for 3 hours. The majority of the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield the desired compound (10.62 g, 82% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb-üMSO-dβ) d ppm: 7.84 (2H, d, J = 8Hz), 7.41 (2H, t, J = 8Hz), 7.22 (2H, t, J = 7Hz ), 7.09-7.01 (4H, m), 6.69 (1 H, d, J = 7Hz), 4.10-4.06 (1 H, m), 3.63-3.45 (4H, m). (2) N-Methyl-N- (4-phenoxybenzenesulfonyl) serinol After adding potassium carbonate (45.39 g, 328.4 mmol) to a solution of N- (4-phenoxybenzenesulfonyl) serinol (10.62 g, 32.84 mmole), the product of (1) above, in N, N-dimethylformamide (250 ml), methyl iodide (5.12 g, 36.12 mmol) was added to the mixture as drops. After stirring at room temperature for 2 hours, the same amount of methyl iodide was added and stirred for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure, ice water was added to the resulting residue, and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the desired compound (8.32 g, 75% yield) as a white powder.

Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb-DMSO-dd) d ppm: 7.81 (2H, d, J = 8Hz), 7.41 (2H, t, J = 8Hz), 7.22 (1 H, t, J = 7Hz), 7.08-7.00 (4H, m), 4.06-3.97 (1H, m), 3.70-3.56 (4H, m), 2.86 (3H, s). (3) (±) -0- (tert-Butyldimethylsilyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) serinol A solution of tert-butyldimethylsilyl chloride (3.53 g, 23.43 mmol) was added dropwise. ) in N, N-dimethylformamide (50 ml), to a solution of N-methyl-N- (4-phenoxybenzenesulfonyl) serol (8.32 g, 24.66 mmol), which is the product of example 67 (2), imidazole (4.13 g, 61.65 mmol) in N, N-dimethylformamide (200 ml), at room temperature and with stirring. The mixture was stirred for a further 2 hours. The solvent in the reaction mixture was evaporated under reduced pressure. Water was added to the residue, and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 2/1 as eluent to produce the desired compound (4.15 g, 38% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.78 (2H, d, J = 9Hz), 7.44-7.38 (2H, m), 7.25-7.19 (1H, m), 7.07-6.99 (4H , m), 4.01-3.96 (1 H, m), 3.74-3.69 (2H, m), 3.66 (2H, d, J = 6Hz), 2.88 (3H, s), 0.84 (9H, s), 0.02 ( 6H, s). (4) (±) -1- (tert-Butyldimethylsilyoxymethyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2-phthalimidoethylamine A reaction was carried out in a manner similar to that is described in example 1 (1), using (±) -0- (tert-butyldimethylsilyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) serinol, the product of (3) above, instead of the allylic ester of (±) -N- (tert-butoxycarbonyl) homoserine, to produce the desired compound (93% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.82-7.77 (2H, m), 7.73-7.69 (2H, m), 7.59 (2H, d, J = 8Hz), 7.39 (2H, t, J = 8Hz), 7.20 (1H, t, J = 7Hz), 6.98 (2H, d, J = 8Hz), 6.74 (2H, d, J = 8Hz), 4.37-4.31 (1H, m), 4.02 -3.93 (1 H, m), 3.72-3.63 (3H, m), 2.97 (3H, s), 0.88 (9H, s), 0.04 (3H, s), 0.02 (3H, s). (5) (±) -1-Hydroxymethyl-N-methyl-N- (4-phenoxybenzenesulfonyl) -2-phthalimidoethylamine After the addition of a 1 M solution of tetrabutylammonium fluoride (19.11 ml, 19.11 mmol) in tetrahydrofuran, a a solution of (±) -1- (tert-butyldimethylsilyloxymethyl) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2-phthalimidoethylamine (7.40 g, 12.74 mmoles), the product of (4) above, in tetrahydrofuran (50 ml), the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure. Water was added to the resulting residue, and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column, using hexane / ethyl acetate = 2/1 as eluent to produce the desired compound (1.70 g, 29% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.84-7.78 (2H, m), 7.75-7.70 (2H, m), 7.65 (2H, d, J = 9Hz), 7.39 (2H, t, J = 8Hz), 7.21 (2H, t, J = 8Hz), 7.00 (2H, d, J = 8Hz), 6.78 (2H, d, J = 9Hz), 4.41-4.31 (1H, m), 3.84- 3.62 (4H, m), 2.98 (3H, s). (6) (±) -1-Formyl-N-methyl-N- (4-phenoxybenzenesulfonyl) -2-phthalimidoethylamine Oxalyl chloride (0.51 g, 4.00 mmol) and dimethyl sulfoxide (0.63 g, 8.01 mmol) were dissolved in dichloromethane (10 ml), and the solution was cooled to -78 ° C. To this solution was added dropwise and with stirring, a solution of (±) -1-hydroxymethyl-N-methyl-N- (4-phenoxybenzenesulfonyl) -2-phthalimidoethylamine (1.70 g, 3.64 mmoles), the product of (5) above, in dichloromethane (25 ml), and this was stirred for 30 minutes. To this mixture was added dropwise triethylamine (1.84 g, 18.2 mmol), and this was stirred at room temperature for 2 hours. Ice water and then, this was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield the desired compound (1.58 g, 93% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCI3) d ppm: 9.57 (1 H, s), 7.83-7.80 (2H, m), 7.76-7.72 (2H, m), 7.62 (2H, d, J = 9Hz ), 7.40 (2H, t, J = 8Hz), 7.24-7.20 (1H, m), 7.00 (2H, d, J = 8Hz), 6.76 (2H, d, J = 9Hz), 5.00-4.96 (1 H, m), 4.08-3.95 (2H, m), 2.98 (3H, s). (7) (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidomethyl) glycine An aqueous solution (10 ml) of sodium chlorite (0.92 g, 10.2 mmol) was added and sodium dihydrate diacid phosphate (1.06 g, 6.80 mmol) to a solution of 2-methyl-2-butene (0.95 g, 13.6 mmol) and (±) -l-formyl-N-methyl-N- (4-phenoxy) benzenesulfonyl) -2-phthalimidoethylamine (1.58 g, 3.40 mmole), which is the product of (6) above, in a mixture of tert-butanol (12 ml) and N, N-dimethylacetamide (5 ml). The mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction mixture and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column, using dichloromethane / methanol = 10/1 as eluent, to yield the title compound (0.60 g, 34% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCI3) d ppm: 7.94-7.83 (2H, m), 7.80-7.71 (2H, m), 7.69-7.59 (2H, m), 7.41-7.37 (2H, m) , 7.25-7.20 (1 H, m), 7.01 (2H, d, J = 7Hz), 6.83-6.77 (2H, m), 5.18-5.12 (1 H, m), 4.21-4.02 (2H, m), 2.94 (3H, s).

EXAMPLE 68 (±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidomethyl-P-glycinamide (Compound No. 3-25) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidomethyl) glycine, the product of Example 67, to give the title compound (81% yield) as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 11.06 (1 H, s), 9.08 (1 H, s), 7.86 (4H, s), 7.66 (2H, d, J = 9Hz) , 7.46 (2H, t, J = 8Hz), 7.26 (1H, t, J = 8Hz), 7.10 (2H, d, J = 8Hz), 6.87 (2H, d, J = 9Hz), 4.67-4.63 ( 1 H, m), 4.05-3.98 (1 H, m), 3.63-3.58 (1 H, m), 2.88 (3 H, s).

EXAMPLE 69 N-Methyl-N- (4-phenoxybenzenesulfoniP-2 (S) - (2-phthalimidoethyl) glycine (Compound No. 3-179) Reactions were carried out in a manner similar to the procedures described in example 1, using optically active N- (tert-butoxycarbonyl) homoserine allyl ester, instead of the allylic ester of (±) -N- (tert-butoxycarbonyl) homoserine, to give the title compound (49% total yield) as a white powder.

Melting point: 155 - 156 ° C Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 7.87-7.82 (2H, m), 7.77-7.70 (4H, m), 7.42-7.36 (2H, m) , 7.23-7.19 (1 H, m), 7.06-6.96 (4H, m), 4.76 (1H, dd, J = 10Hz, 6Hz), 3.82-3.67 (2H, m), 2.93 (3H, s), 2.36 -2.27 (1 H, m), 2.05-1.94 (1 H, m). HPLC analysis: retention time 36.8 minutes < experimental conditions > column: CHIRALCEL OJ-R (product of Daicel Chem. Ind. Ltd inner diameter: 0.46 cm, length: 15 cm, grain size: 5 μm, eluent: acetonitrile / triethylamine phosphate buffer (0.2% (v / v) , pH 2.2) = 2/3 flow rate: 1.0 ml / minute temperature: 30 ° C detection: UV 254 nm EXAMPLE 70 N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2 (S) - (2-phthalimidoetiP-glycinamide (Compound No. 3-26) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using N-methyl-N- (4-phenoxybenzenesulfonyl) -2 (S) - (2-phthalimido-methyl) glycine, the product of Example 69, to give the title compound (90% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.37 (1 H, br.s), 7.84-7.80 (2H, m), 7.75-7.70 (2H, m), 7.60 (2H, d, J = 9Hz), 7.45-7.22 (4H, m), 7.09-7.07 (2H, m), 6.82 (2H, d, J = 9Hz), 4.33 (1H, dd, J = 9Hz, 5Hz), 3.70-3.61 (1 H, m), 3.51-3.43 (1 H, m), 2.93 (3 H, s), 2.38-2.29 (1 H, m), 1.61-1.52 (1 H, m). HPLC analysis: retention time 42.6 minutes «experimental conditions > column: CHIRALCEL OJ-R (product of Daicel Chem. Ind. Ltd inner diameter: 0.46 cm, length: 15 cm, grain size: 5 μm eluent: acetonitrile / triethylamine phosphate buffer (0.2% (v / v), pH 2.2) = 3/7 flow rate: 1.0 ml / minute temperature: 40 ° C detection: UV 254 nm EXAMPLE 71 N-Methyl-N- (4-phenoxybenzenesulfonyl) -2 (R) - (2-phthalimidoethyl) glycine (Compound No. 3-179) Reactions were carried out in a manner similar to that described in Example 69, using N- (tert-butoxycarbonyl) -D-homoserine allyl ester in place of N- (tert-butoxycarbonyl) -L-homoserine allyl ester , to give the title compound as a white powder. Melting point: 155 - 157 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 7.87-7.82 (2H, m), 7.77-7.70 (2H, m), 7.42-7.37 (2H, m), 7.22-7.19 (1H, m ), 7.06-6.96 (4H, m), 4.76 (1 H, dd, J = 10Hz, 6Hz), 3.82-3.67 (2H, m), 2.93 (3H, s), 2.36-2.27 (1 H, m) , 2.05-1.94 (1 H, m). HPLC analysis: retention time 34.2 minutes < experimental conditions > The same as in example 69.

EXAMPLE 72 N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoniP-2 (R) - (2-phthalimidoetiP-qlicinamide (Compound No. 3-26) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using N-methyl-N- (4-phenoxybenzenesulfonyl) -2 (R) - (2-phthalimidoethyl) glycine, the product of example 71, to give the title compound (93% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.36 (1 H, br.s), 7.84-7.80 (2H, m), 7.75-7.70 (2H, m), 7.62-7.59 (2H, m ), 7.45-7.40 (2H, m), 7.26-7.23 (2H, m), 7.08 (2H, d, J = 8Hz), 6.83 (1H, d, J = 9Hz), 4.33 (1H, dd, J = 9Hz, 5Hz), 3.67-3.61 (1H, m), 3.51-3.43 (1H, m), 2.93 (3H, s), 2.92-2.38 (1H, m), 1.60-1.52 (1H , m). HPLC analysis: retention time 39.0 minutes <experimental conditions > The same as in example 70.

EXAMPLE 73 (±) -2-r2- (6,7-Dihydro-5H-cyclopentadipyrimidin-2,4-dione-3-yl) ethy-N-methyl- N- (4-phenoxybenzenesulfonyl) glycine A reaction was carried out in a manner similar to that described in Example 41 (3), using 1- (2-trimethylsilyl) ethoxymethyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-2, 4-dione, instead of 1- (2-trimethylsilyl) ethoxymethyltiene [3,2-d] pyrimidin-2,4-dione, followed by deprotection reactions and ester hydrolysis on the product resulting, according to example 41 (4), to give the title compound (23% total yield) as a white powder.

Nuclear magnetic resonance spectrum 1 H (270 MHz, DMSO-dβ) d ppm: 11.38 (1 H, s), 7.78 (2 H, d, J = 9 Hz), 7.49-7.43 (2 H, m), 7.25 (1 H, t, J = 8Hz), 7.13-7.07 (4H, m), 4.47 (1H, dd, J = 10Hz, 6Hz), 3.69 (2H, t, J = 8Hz), 2.83 (3H, s), 2.69- 2.64 (2H, m), 2.58-2.47 (2H, m), 2.10-1.91 (3H, m), 1.76-1.62 (1H, m).

EXAMPLE 74 (±) -2-r2- (6.7-Dihydro-5H-cyclopentadipyrimidin-2,4-dione-3-iPetin-N-hydroxy-Na-meth1 N- (4-phenoxybenzenesulfonyl) glycinamide (Compound No 5-68) A hydroxylation reaction was carried out in a manner similar to that described in Example 2, using (±) -2- [2- (6,7-dihydro-5H-cyclopenta [d] pyrimidin-2, 4-dione-3-yl) -ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) -glycine, the product of example 73, to give the title compound (49% yield) as a white powder. Melting point: 207 - 209 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-de) d ppm: 11.40 (1 H, s), 10.73 (1 H, s), 8.95 (1 H, d, J = 3Hz), 7.79-7.75 (2H , m), 7.48-7.43 (2H, m), 7.25 (1H, t, J = 7Hz), 7.14-7.08 (4H, m), 4.27 (1H, dd, J = 9Hz, 7Hz), 3.63- 3.51 (2H, m), 2.92 (3H, s), 2.66 (2H, t, J = 7Hz), 2.51-2.48 (2H, m), 1.99-1.92 (2H, m), 1.84-1.74 (1H, m), 1.73-1.63 (1 H, m).

EXAMPLE 75 (±) -N-r4- (4-Chlorophenoxy) benzenesulfonyl-N-methyl-2- (2-phthalimidoethyl) glycine A reaction was carried out in a manner similar to that described in Example 1 (2) (b), using 4- (4-chlorophenoxy) benzenesulfonyl chloride in place of 4-phenoxybenzenesulfonyl chloride, followed by methylation of the product , according to example 1 (3), and then by de-allylation of the product according to example 1 (4), to give the title compound (71% total yield) as a pale yellow powder. Melting point: 166 - 167 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 7.87-7.82 (2H, m), 7.80-7.70 (4H, m), 7.38-7.33 (2H, m), 7.03-6.96 (4H, m) , 4.76 (1 H, dd, J = 10Hz, 6Hz), 3.84-3.64 (2H, m), 2.92 (3H, s), 2.48-2.35 (1 H, m), 2.06-1.92 (1 H, m) .

EXAMPLE 76 (±) -Na-f4- (4-Chlorophenoxy-benzenesulfonyl-N-hydroxy-Na-methyl-2- (2-phthalimidoetiP-glycinamide (Compound No. 3-181) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- [4- (4-chlorophenoxy) benzenesulfonyl] -N-methyl-2- (2 phthalimido-ethyl) glycine, the product of example 75, to give the title compound (90% yield) as a white powder. Melting point: 90 - 93 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.34 (1 H, br.s), 7.85-7.80 (2H, m), 7.77-7.72 (2H, m), 7.62 (2H, d, J = 9Hz), 7.42-7.23 (3H, m), 7.04-7.00 (2H, m), 6.86-6.82 (2H, m), 4.33 (1H, dd, J = 9Hz, 5Hz), 3.68-3.62 (1 H, m), 3.50-3.43 (1 H, m), 2.93 (3 H, s), 2.37-2.28 (1 H, m), 1.61-1.53 (1 H, m).

EXAMPLE 77 (±) -N-Ethyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoetiPglycine A reaction was carried out in a manner similar to that described in example 1 (3), using ethyl iodide instead of methyl iodide, followed by a de-allylation reaction according to example 1 (4) to give the title compound (92% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.88-7.81 (2H, m), 7.79-7.69 (4H, m), 7.43-7.35 (2H, m), 7.23-7.17 (1H, m ), 7.06-7.02 (2H, m), 6.97-6.92 (2H, m), 4.57 (1H, dd, J = 8Hz, 6Hz), 3.84-3.67 (2H, m), 3.50-3.37 (1 H, m), 3.33-3.20 (1 H, m), 2.44-2.31 (1 H, m), 2.03-1.90 (1 H, m), 1.33 (3H, t, J = 7Hz).

EXAMPLE 78 (±) -Na-Ethyl-N-hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- (phthalimidoetiP-qlicinamide A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-ethyl-N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) glycine, product of example 77, to give the title compound (88% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.49 (1 H, br.s), 7.84-7.78 (2H, m), 7.74-7.70 (2H, m), 7.60 (2H, d, J = 9Hz), 7.44-7.40 (2H, m), 7.31-7.22 (2H, m), 7.06 (2H, d, J = 8Hz), 6.76 (2H, d, J = 9Hz), 4.17 (1H, dd , J = 9Hz, 5Hz), 3.56-3.32 (4H, m), 2.45-2.36 (1H, m), 1.67-1.55 (1H, m), 1.26 (3H, t, J = 7Hz).

EXAMPLE 79 (±) -N- (4-PhenoxybenzenesulfoniP-2- (2-phthalimidoethyl) -N-propylqcyline A reaction was carried out in a manner similar to that described in example 1 (3), using propyl iodide instead of methyl iodide, followed by a de-allylation reaction of the product according to example 1 ( 4), to give the title compound (86% yield) as a pale yellow amorphous solid.

Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.86-7.71 (2H, m), 7.76-7.69 (4H, m), 7.44-7.36 (2H, m), 7.26-7.18 (1H, m ), 7.07-7.03 (2H, m), 6.94-6.89 (2H, m), 4.49 (1 H, t, J = 7Hz), 3.76-3.65 (2H, m), 3.32-3.09 (2H, m), 2.43-2.31 (1 H, m), 1.97-1.66 (3H, m), 0.89 (3H, t, J = 8Hz).

EXAMPLE 80 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -Na-propyl-glycinamide (Compound No. 3-58) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoethyl) -N-propylglycine, the product of the example 79, to give the title compound (96% yield) as a colorless amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.49 (1 H, br.s), 7.84-7.80 (2H, m), 7.74-7.70 (2H, m), 7.61-7.57 (2H, m ), 7.45-7.40 (2H, m), 7.26-7.20 (2H, m), 7.06 (2H, d, J = 8Hz), 6.75-6.72 (2H, m), 4.16 (1H, dd, J = 10Hz , 5Hz), 3.55-3.32 (3H, m), 3.23-3.16 (1H, m), 2.44-2.36 (1H, m), 1.75-1.50 (3H, m), 0.88 (3H, t, J = 7Hz).

EXAMPLE 81 (+) - 2-r2- (2,3-Dimethylmaleimido) etn-N-methyl-N- (4-phenoxybenzenesulfoniP-glycine) A reaction was carried out in a manner similar to that described in Example 41 (3), using 2,3-dimethylmaleimide in place of 1- (2-trimethylsilyl) ethoxymethyl-thieno [3,2-d] pyrimidin-2, 4-dione, followed by deprotection reactions and ester hydrolysis on the resulting allyl ester compound according to example 41 (4), to give the title compound (29% total yield) as a yellow amorphous solid pale. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.77-7.73 (2H, m), 7.46-7.37 (2H, m), 7.21 (1 H, t, J = 7Hz), 7.07-6.99 (4H , m), 4.69 (1 H, dd, J = 10Hz, 6Hz), 4.65-4.42 (2H, m), 2.88 (3H, s), 2.27-2.17 (1 H, m), 2.03-1.83 (7H, m).

EXAMPLE 82 (±) -2-r2- (2,3-Dimethylmaleimido) etin-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) Pyrlinamide (Compound No. 5-17) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -2- [2- (2,3-d, methylmaleimido) ethyl] -N-methyl-N- ( 4-phenoxybenzenesulfonyl) glycine, the product of example 81, to give the title compound (73% yield) as a pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.41 (1 H, br.s), 7.68 (2H, d, J = 9Hz), 7.44-7.39 (2H, m), 7.23 (1 H, t, J = 7Hz), 7.09-7.06 (2H, m), 7.02-6.98 (2H, m), 4.29 (1 H, dd, J = 9Hz, 6Hz), 3.48-3.42 (1 H, m), 3.27 -3.20 (1 H, m), 2.90 (3H, s), 2.25-2.17 (1 H, m), 1.96 (6H, s), 1.60-1.51 (1 H, m).

The following compounds (examples 83 to 88) were obtained according to example 81 or 82 above.

EXAMPLE 83 (±) -2-r2- (4,5-Dichlorophthalimido) ethin-N-methyl-N- (4-phenoxybenzenesulfoniP-glycine) A white powder (14% of total yield). Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-d6) d ppm: 8.08 (2H, s), 7.83 (2H, d, J = 9Hz), 7.47-7.41 (2H, m), 7.23 (1H, t , J = 7Hz), 7.12-7.08 (2H, m), 7.02-6.98 (2H, m), 4.21 (1H, dd, J = 9Hz, 6Hz), 3.63-3.44 (2H, m), 2.76 (3H , s), 2.31-2.16 (1 H, m), 1.73-1.56 (1 H, m).

EXAMPLE 84 (±) -2-r2- (4,5-Dichlorophthalimido) -etin-N-hydroxy-Na-methyl-Na- (4-phenoxy-benzenesulfoni-P-glycinamide (Compound No. 5-74) A white powder (64% yield). Melting point: 155 -156 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 10.73 (1 H, d, J = 1 Hz), 8.96 (1 H, d, J = 1 Hz), 8.17 (2H, s), 7.79-7.75 (2H, m), 7.49-7.44 (2H, m), 7.26 (1H, t, J = 7Hz), 7.19-7.14 (2H, m), 7.10-7.07 (2H, m), 4.30- 4.26 (1 H, m), 3.52-3.40 (2H, m), 2.88 (3H, s), 2.00-1.93 (1 H, m), 1.86-1.78 (1 H, m).

EXAMPLE 85 (±) -N-Methyl-2-f2- (4-methylphthalimido) etin-N- (4-phenoxybenzenesulfonyl) glycine A white powder (53% of total yield). Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.77-7.70 (3H, m), 7.63 (1 H, s), 7.50 (1 H, d, J = 8Hz), 7.42-7.35 (1 H , m), 7.22-7.17 (2H, m), 7.06-7.03 (2H, m), 7.00-6.95 (2H, m), 4.75 (1H, dd, J = 10Hz, 6Hz), 3.82-3.62 (2H, m), 2.92 (3H, s), 2.51 (3H, s), 2.36-2.23 (1 H, m), 2.04-1.92 (11-1, m).

EXAMPLE 86 (±) -N-Hydroxy-Na-methyl-2-r2- (4-methylphthalimido) etn-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-76) A white powder (83% yield). Melting point: 157 - 158 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.41 (1 H, s), 7.68 (1 H, d, J = 8Hz), 7.60-7.58 (3H, m), 7.54-7.49 (1 H , m), 7.46-7.40 (2H, m), 7.26-7.22 (1 H, m), 7.09-7.06 (2H, m), 6.82 (2H, d, J = 9Hz), 4.32 (1 H, dd, J = 10Hz, 5Hz), 3.65-3.59 (1H, m), 3.48-3.41 (1H, m), 2.92 (3H, s), 2.50 (3H, s), 2.35-2.27 (1H, m), 1.58-1.49 (1 H, m).

EXAMPLE 87 (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2-r2- (3,4-pyridinedicarboxyimido) -ethyglycine A white powder (35% of total yield). Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-dβ) d ppm: 9.11-9.09 (2H, m), 7.90-7.87 (1 H, m), 7.81-7.77 (2H, m), 7.49-7.43 (2H , m), 7.25 (1 H, t, J = 7Hz), 7.14-7.06 (4H, m), 4.52 (1 H, dd, J = 9Hz, 6Hz), 3.71-3.50 (2H, m), 2.81 ( 3H, s), 2.31-2.17 (1 H, m), 1.94-1.80 (1 H, m).

EXAMPLE 88 (±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-r2- (3,4-pyridinedicarboxyimido) ethillglycinamide (Compound No. 5-5) A white powder (95% yield). Melting point: 99 - 101 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-de) d ppm: 10.74 (1 H, d, J = 2Hz), 9.11-9.09 (2H, m), 8.97-8.96 (1 H, m), 7.89- 7.88 (1 H, m), 7.79-7.76 (2H, m), 7.49-7.44 (2H, m), 7.26 (1 H, t, J = 7Hz), 7.17-7.15 (2H, m), 7.12-7.06 (2H, m), 4.31-4.27 (1 H, m), 3.55-3.44 (2H, m), 2.89 (3H, s), 2.03-1.96 (1 H, m), 1.94-1.82 (1 H, m ).

EXAMPLE 89 (±) -2-r2- (6,7-Dimethoxyguinazolin-2,4-dione-3-yl) etin-N-methyl-N- (4-phenoxybenzenesulfone) Glycine A reaction was carried out in a manner similar to that described in Example 41 (3), using 6,7-dimethoxy-1- (2-trimethylsilyl) ethoxymethylquinazoline-2,4-dione, instead of 1- ( 2-trimethylsilyl) ethoxymethyl-thieno [3,2-d] pyrimidine-2,4-dione, followed by deprotection reactions and ester hydrolysis on the resulting allyl ester compound, according to example 41 (4), give the title compound (53% total yield) as a white powder.

Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-de) d ppm: 11.24 (1 H, s), 7.79-7.75 (2H, m), 7.48-7.42 (2H, m), 7.29-7.21 (2H, m ), 7.12-7.04 (4H, m), 6.69 (1 H, s), 4.51 (1 H, dd, J = 9Hz, 6Hz), 3.86-3.80 (5H, m), 3.78 (3H, s), 2.85 (3H, s), 2.20-2.07 (1 H, m), 1.83-1.69 (1 H, m).

EXAMPLE 90 (±) -2-f2- (6,7-Dimethoxy-nazoyl-2,4-dione-3-yl) -ethyl-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) pyrlinamide (Compound No. 5-19) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -2- [2- (6,7-dimethoxyquinazolin-2,4-dione-3-yl) ethyl] -N-methyl-N- (4-phenoxybenzenesulfonyl) -glycine, the product of the example 89, to give the title compound (60% yield) as a white powder. Melting point: 146 - 148 ° C 1 H nuclear magnetic resonance spectrum (400 MHz, DMSO-de) d ppm: 11.26 (1 H, s), 10.75 (1 H, s), 8.95 (1 H, s), 7.79-7.76 (2H, m), 7.46-7.41 (2H, m), 7.28 (1 H, s), 7.24 (1 H, t, J = 7Hz), 7.13-7.07 (4H, m), 6.68 (1 H, s), 4.32 (1 H, dd, J = 9Hz, 7Hz), 3.83 (3H, s), 3.77 (3H, s), 3.74-3.67 (2H, m), 2.95 (3H, s), 1.93 -1 .83 (1 H, m), 1.81-1.74 (1 H, m).

EXAMPLE 91 (+) - N-r4- (4-Fluorophenoxy) benzenesulfonin-N-methyl-2- (2-phthalimidoetiPglycine A reaction was carried out in a manner similar to that described in Example 1 (2) (b), using 4- (4-fluorophenoxy) benzenesulfonyl chloride in place of 4-phenoxybenzenesulfonyl chloride, followed by methylation of the product according to example 1 (3), and then by de-allylation of the product according to example 1 (4), to give the title compound (82% total yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.88-7.82 (2H, m), 7.78-7.72 (4H, m), 7.12-6.93 (6H, m), 4.76 (1H, dd, J = 9Hz, 6Hz), 3.84-3.61 (2H, m), 2.92 (3H, s), 2.38-2.25 (1 H, m), 2.05-1.90 (1 H, m).

EXAMPLE 92 (±) -Na-r4- (4-Fluorofenoxpbenzenesulfonin-N-hydroxy-Na-methyl-2- (2-phthalimidoetiPlycinamide (Compound No. 3-182) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N- [4- (4-fluorophenoxy) benzenesulfonyl] -N-methyl-2- (2-phthalimidoethyl) glycine, to give the title compound (93% yield) as a white powder. Melting point: 100 - 101 ° C 1 H nuclear magnetic resonance spectrum (270 MHz, CDCI3) d ppm: 9.38 (1 H, br.s), 7.87-7.72 (4H, m), 7.64-7.58 (2H, m ), 7.23 (1 H, br.s), 7.16-7.03 (4H, m), 6.82 (2H, d, J = 8Hz), 4.33 (1 H, dd, J = 10Hz, 5Hz), 3.70-3.60 ( 1 H, m), 3.52-3.41 (1 H, m), 3.92 (3 H, s), 2.40-2.26 (1 H, m), 1.65-1.53 (1 H, m).

EXAMPLE 93 (+) - 2- [2- (6-Chloropyrimidin-2,4-dione-3-yl) etn-N-methyl-N- (4-phenoxybenzenes? LfoniPqlicine A reaction was carried out in a manner similar to that described in Example 41 (3), using 6-chloro-1- (2-trimethylsilyl) ethoxymethylpyrimidin-2,4-d-one instead of 1- (2-trimethylsilyl) ethoxymethyltin [3,2-d] pyrimidine-2,4-dione, followed by deprotection reactions and ester hydrolysis on the resulting allyl ester compound, according to example 41 (4), to give the title compound (70% total yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-d6) d ppm: 12.41 (1 H, br.s), 7.78 (2H, d, J = 7Hz), 7.47 (2H, m), 7.26 (1 H, m), 7.12 (4H, m), 5.89 (1 H, s), 4.47 (1 H, dd, J = 9Hz, 5Hz), 3.70 (2H, br.t, J = 6Hz), 2.82 (3H, s ), 2.08 (1 H, m), 1.76 (1 H, m).

EXAMPLE 94 (±) -2-r2- (6-Chloropyrimidin-2,4-dione-3-yl) etin-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-84) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (+) - 2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -N -methyl-N- (4-phenoxybenzenesulfonyl) glycine, the product of Example 93, to give the title compound (68% yield) as a white powder. Melting point: 144 - 145 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 12.46 (1 H, br.s), 10.73 (1 H, s), 8.93 (1 H, s), 7.77 (2H, dd, J = 9Hz, 2Hz), 7.46 (2H, m), 7.26 (1H, t, J = 8Hz), 7.13 (2H, d, J = 8Hz), 7.09 (2H, d, J = 9Hz), 5.87 (1 H, s), 4.28 (1 H, dd, J = 9 Hz, 7 Hz), 3.57 (2 H, m), 2.91 (3 H, s), 1.81 (1 H, m), 1.73 (1 H, m).

EXAMPLE 95 (±) -N-Methyl-N- (4-phenoxybenzenesulfonyl) -2-r2- (6-trifluoromethylpyrimidin-2,4-dione-3-yl) etinqlicine A reaction was carried out in a manner similar to that described in example 41 (3), using 6-trifluoromethyl-1- (2-trimethylsilyl) ethoxymethylpyrimidin-2,4-d-one, instead of 1 - (2-trimethylsilyl) ethoxymethyl-ene [3,2-d] pyrimidine-2,4-dione, followed by deprotection reactions and ester hydrolysis of the resulting allylic ester compound according to example 41 ( 4), to give the title compound (71% total yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-dβ) d ppm: 7.82-7.77 (2H, m), 7.43-7.36 (2H, m), 7.24-7.18 (1 H, m), 7.08-6.98 (4H , m), 6.02 (1 H, s), 4.71 (1 H, dd, J = 11 Hz, 6 Hz), 4.04-3.88 (2 H, m), 2.93 (3 H, s), 2.32-2.19 (1 H, m), 2.06-1.91 (1 H, m).

EXAMPLE 96 (±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-f2- (6-trifluoromethyl-pyrimidin-2,4-dione-3-8l) etinglycinamide (Compound No. 5- 88) A hydroxylation reaction was carried out in a manner similar to that described in example 2, using (±) -N-methyl-N- (4-phenoxybenzenesulfonyl) -2- [2- (6-trifluoromethylpyrimidin- 2,4-dione-3-yl) ethylene glycine, the product of Example 95, to give the title compound (95% yield) as a white powder. Melting point: 179 - 180 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 12.45 (1 H, br.s), 10.75 (1 H, br.s), 8.95 (1 H, br.s), 7.81-7.76 (2H, m), 7.48-7.43 (2H, m), 7.28-7.24 (1H, m), 7.15-7.05 (4H, m), 6.21 (1H, s), 4.28 (1H, dd, J = 9Hz, 7Hz), 3.70-3.56 (2H, m), 2.91 (3H, s), 1.88-1.72 (2H, m).

EXAMPLE 97 2 (R) -r 2 - (6-Chloropyrimidin-2,4-dione-3-yl) -etin-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-84) Reactions were carried out in a manner similar to the procedures described in Examples 93 and 94, using D-homoserin as the starting material, to give the title compound as a white powder. The 1 H nuclear magnetic resonance spectrum of the product was the same as that of the compound of Example 94, which is a racemate of the product. HPLC analysis: retention time 8.9 minutes. < Experimental conditions > column: CHIRALCEL OD-RH (product of Daicel Chem. Ind. Ltd). Inner diameter: 0.46 cm, length: 15 cm, grain size 5 μm eluent: acetonitrile / triethylamine phosphate buffer (0.2% (v / v), pH 2.2) = 55/45 flow rate: 0.5 ml / minute temperature : 20 ° C detection: UV 254 nm EXAMPLE 98 2 (S) -r2- (6-Chloropyrimidin-2,4-dione-3-yl) etin-N-hydroxy-Na-methyl-Na- (4- phenoxybenzenesulfoniPlycinamide (Compound No. 5-84) Reactions were carried out in a manner similar to the procedures described in example 97, using L-homoserin as the starting material, to give the title compound as a white powder. The 1 H nuclear magnetic resonance spectrum of the product was the same as that of the compound of Example 94, which is a racemate of the product. HPLC analysis: retention time 12.1 minutes. < Experimental conditions > The same as in example 97.

EXAMPLE 99 N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2 (R) -r2- (6-trifluoromethyl-pyrimidin-2,4-dione-3-yl) etinqlicinamide (Compound No. 5-88 ) Reactions were carried out in a manner similar to the procedures described in Examples 95 and 96, using D-homoserin as a starting material, to give the title compound as a white amorphous solid. The 1 H nuclear magnetic resonance spectrum of the product was the same as that of the compound of Example 96, which is a racemate of the product. HPLC analysis: retention time 10.3 minutes. < Experimental conditions > The same as in example 97.

EXAMPLE 100 N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2 (S) -f2- (6-trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethylene glycinamide (Compound No. 5 -88) Reactions were carried out in a manner similar to the procedures described in example 99, using L-homoserin as the starting material, to give the title compound as a white amorphous solid. The 1 H nuclear magnetic resonance spectrum of the product was consistent with the spectrum of the compound of Example 96, which is a racemate of the product. HPLC analysis: retention time 13.2 minutes. < Experimental conditions > The same as in example 97.

The following compounds of Examples 101 to 145 were prepared in a manner similar to that appropriately selected from the methods described in Examples 1 to 100.

EXAMPLE 101 (+) - Hydroxy-Na- (4-phenoxybenzenesulfonyl) -Na-propargyl-2-r2- (pyrimidin-2,4-dione-3-yl) etinqluccinamide (Compound No. 5- 30) The title compound was prepared in a manner similar to the procedures described in Examples 14 and 28. White amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-de) d ppm: 11.14 (1 H, s), 10.69 (1 H, s), 9.07 (1 H, s), 7.82 (2H, d, J = 9Hz ), 7.51-7.37 (3H, m), 7.25 (1 H, t, J = 8Hz), 7.14 (2H, d, J = 9Hz), 7.06 (2H, d, J = 9Hz), 5.55 (1H, d, J = 7Hz), 4.45-4.40 (1 H, m), 4.29-4.11 (2H, m), 3.71-3.53 (2H, m), 3.08 (1 H, s), 2.10-1.93 (1 H, m), 1.81-1.69 (1 H, m).

EXAMPLE 102 (±) -Hydroxy-Na-methyl-2-r2- (2,3-naphthalenedicarboxyimido) etn-Na- (4-phenoxybenzenesulfoniP-glycinamide (Compound No. 5-1) The title compound was prepared in a manner similar to that described in Example 2. White powder. Melting point: 192 - 194 ° C. Nuclear magnetic resonance spectrum 1 H (400 MHz, DMSO-d6) d ppm: 10.76 (1 H, t, J = 1 Hz), 8.97 (1 H, t, J = 2 Hz), 8.50 (2 H, s), 8.29 -8.25 (2H, m), 7.80-7.77 (4H, m), 7.48-7.43 (2H, m), 7.25 (1H, t, J = 7Hz), 7.18-7.03 (4H, m), 4.33 (1H , t, J = 7Hz), 3.57-3.45 (2H, m), 2.91 (3H, s), 2.07-1.98 (1 H, m), 1.94-1.78 (1 H, m).

EXAMPLE 103 (±) -Hydroxy-Na- (4-phenoxybenzenesulfoniP-Na-propargyl-2-r2- (pteridin-2,4-dione-3-iPetinglicinamide (Compound No. 5-22) The title compound was prepared in a manner similar to the procedures described in Examples 28 and 54. Pale yellow powder. Melting point: 101 - 104 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 12.22 (1 H, br.s), 10.76 (1 H, d, J = 2Hz), 9.08 (1 H, t, J = 2Hz) , 8.67 (1 H, d, J = 2Hz), 8.55 (1 H, d, J = 2Hz), 7.91-7.83 (2H, m), 7.48-7.44 (2H, m), 7.27-7.24 (1 H, m), 7.17-7.06 (4H, m), 4.49 (1 H, dd, J = 19Hz, 2Hz), 4.32-4.20 (2H, m), 3. 87-3.74 (2H, m), 3.09 (1 H, t, J = 2Hz), 2.14-2.05 (1 H, m), 1.99-1.89 (1 H, m).

EXAMPLE 104 (±) -2-r2- (5,6-Dimethylpyrimidin-2,4-dione-3-yl) et.nN-hydroxy-Na- (4-phenoxy-benzenesulfoniP-Na-proparqylglycinamide (Compound No. 4 -89) The title compound was prepared in a manner similar to the procedures described in Examples 18 and 28. White powder. Melting point: 180 - 181 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb-DMSO-de) d ppm: 8.82-8.77 (1 H, br.s), 7.77 (2H, d, J = 9Hz), 7.40 (2H, t, J = 9Hz), 7.22 (1 H, t, J = 8Hz), 7.17 (2H, d, J = 9Hz), 6.95 (2H, d, J = 9Hz), 5.54 (1H, d, J = 8Hz), 4.35 -4.32 (1 H, m), 4.29-4.22 (2H, m), 3.83-3.75 (2H, m), 2.56 (3H, s), 2.10 (3H, s), 2.08-1.70 (2H, m).

EXAMPLE 105 (±) -NH'droxy-Na-meth1-Na- (4-phenoxybenzenesulfonyl) -2-r2- (6-phenylpyrimidin-2,4-dione-3-iPetinglicinamide (Compound No. 5- 90) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 64. White powder. Melting point: 179 - 181 ° C (with decomposition).

Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 11.44 (1 H, br.s), 10.75 (1 H, br.s), 8.96 (1 H, br.s), 7.81-7.72 (4H, m), 7.57-7.42 (5H, m), 7.62-7.22 (1H, m), 7.14-7.06 (4H, m), 5.95 (1H, d, J = 2Hz), 4.32 (1H , dd, J = 9Hz, 7Hz), 3.70-3.59 (2H, m), 2.94 (3H, s), 1.92-1.72 (2H, m).

EXAMPLE 106 (±) -2-r2- (6-Ethylpyrimidine-2,4-dione-3-iPetip-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenes? LphoniPycinomide (Compound No. 5-86 ) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 64. White powder. Melting point: 177 - 179 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-dβ) d ppm: 11.13 (1 H, s), 10.73 (1 H, s), 8.95 (1H, s), 7.77 (2H, dt, J = 9Hz, 3Hz), 7.45 (2H, t, J = 8Hz), 7.25 (1H, t, J = 8Hz), 7.14-7.08 (4H, m), 5.45 (1H, s), 4.27 (1H, dd, J = 9Hz, 7Hz), 3.63-3.47 (2H, m), 2.92 (3H, s), 2.32 (2H, q, J = 7Hz), 1.85-1.76 (1 H, m), 1.74-1.64 (1 H, m), 1.10 (3 H, t, J = 7 Hz).

EXAMPLE 107 (±) -Na-r4- (3-Chlorophenoxy) benzenesulfonyl-N-hydroxy-Na-methyl-2- (2-phthalimidoetiP-glycinamide (Compound No. 3-183) The title compound was prepared in a manner similar to that described in Example 2. White powder. Melting point: 81 - 84 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.41 (1 H, br.s), 7.85-7.81 (2H, m), 7.76-7.72 (2H, m), 7.66-7.63 (2H, m ), 7.37-7.21 (2H, m), 7.10 (1 H, t, J = 2Hz), 6.98-6.96 (1 H, m), 6.90-6.86 (2H, m), 4.34 (1 H, dd, J = 9Hz, 5Hz), 3.68-3.62 (1 H, m), 3.50-3.42 (1 H, m), 2.94 (3H, s), 2.38-2.29 (1 H, m), 1.62-1.54 (1 H, m).

EXAMPLE 108 (±) -2-r2- (5-Fluoropyrimidin-2,4-dione-3-yl) -etin-N-hydroxy-Na- (4-phenoxy-benzenesulfonyl) -Na-propargylglycinamide (Compound No. 5-32) The title compound was prepared in a manner similar to the procedures described in Examples 28 and 40. Pale brown amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMSO-d6) d ppm: 11.11 (1 H, s), 10.75 (1 H, s), 9.08 (1 H, s), 7.88-7.79 (3H, m), 7.47 (2H, dd, J = 9Hz, 7Hz), 7.26 (1H, t, J = 7Hz), 7.15 (2H, d, J = 9Hz), 7.08 (2H, d, J = 9Hz), 4.50-4.42 (1 H, m), 4.24-4.18 (2H, m), 3.76-3.61 (2H, m), 3.20 (1 H, s), 2.09-2.00 (1 H, m), 1.85-1.76 (1 H, m).

EXAMPLE 109 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfoniP-Na-propargyl-2-r2- (5-trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethylyglycinamide (Compound No. 5-38 ) The title compound was prepared in a manner similar to the procedures described in Examples 28 and 66. Pale brown powder. Melting point: 170 - 171 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-de) d ppm: 11.07 (1 H, s), 10.66 (1 H, s), 9.11 (1 H, s), 7.88-7.77 (3H, m), 7.44 (2H, dd, J = 9Hz, 7Hz), 7.27 (1H, t, J = 7Hz), 7.16 (2H, d, J = 9Hz), 7.08 (2H, d, J = 9Hz), 4. 49-4.40 (1H, m), 4.22-4.13 (2H, m), 3.77-3.62 (2H, m), 3.18 (1 H, s), 2.09- 1.91 (1 H, m), 1.88-1.77 (1 H, m).

EXAMPLE 110 (+) - 2-r2- (1.1-Dioxo-1,2-benzois-1-azo-3-one-2-y-Di-p-N-hydroxy-Na- (4-phenoxybenzenesulfoniP-Na-proparqyl-kininamide (Compound No. 2 -89) The title compound was prepared in a manner similar to the procedures described in Examples 28 and 62. Yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.31 (1 H, s), 8.02 (1 H, d, J = 7Hz), 7.94-7.81 (3H, m), 7.76 (2H, d, J = 9Hz), 7.70-7.65 (1 H, m), 7.49-7.46 (1 H, m), 7.41 (2H, t, J = 8Hz), 7.23 (1 H, t, J = 7Hz), 7.08 ( 2H, d, J = 8Hz), 6.75 (2H, d, J = 8Hz), 4.44-4.36 (2H, m), 4.40-4.10 (1H, m), 3.74-3.59 (2H, m), 2.60- 2.51 (1H, m), 2.10-1.99 (1H, m).

EXAMPLE 111 (+) - Na-r4- (3-Fluorophenoxy) benzenesulfonyl-N-hydroxy-Na-methyl-2- (2-phthalimidoetiP-glycinamide (Compound No. 3-184) The title compound was prepared in a manner similar to that described in Example 2. Pale yellow amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.42 (1 H, br.s), 7.84-7.61 (6H, m), 7.42-7.34 (2H, m), 6.97-6.80 (4H, m ), 4.33 (1 H, dd, J = 9 Hz, 5 Hz), 3.68-3.62 (1 H, m), 3.50-3.42 (1 H, m), 2.94 (3 H, s), 2.38-2.29 (1 H, m), 1.63-1.54 (1 H, m).

EXAMPLE 112 (+) - N-Hydroxy-Na-methyl-2-r2- (5-methyl-triene-2,3-d1-pyrimidine-2,4-dione-3-iPetyl-1-Na- (4-phenoxybenzenesulfonyl) -qycinamide (Compound No. 5 -92) The title compound was prepared in a manner similar to that described in Example 2. White powder. Melting point: 142 - 144 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-dβ) d ppm: 12. 17 (1 H, s), 10.76 (1 H, s), 9.40 (1 H, s), 7.78 (2 H, d, J = 7 Hz), 7.44 (2 H, t, J = 8 Hz), 7.25 (1 H , t, J = 7Hz), 7.13-7.07 (4H, m), 6.69 (1 H, s), 4.33-4.29 (1 H, m), 3.68-3.56 (2H, m), 2.94 (3H, s) , 2.34 (3H, s), 1.85-1.71 (2H, m).

EXAMPLE 113 (±) -N-Hydroxy-Na-methyl-N- (4-phenoxybenzenesulfoniP-2-r2- (pyrimidor-2,3-d1-pyrimidin-2,4-dione-3-yl) -etiHqlicinamide (Compound No. 5 -93) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 6.

White powder Melting point: 125 - 126 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 11.99 (1 H, br.s), 10.76 (1 H, br.s), 8.95 (1 H, t, J = 2Hz), 8.62 (1 H, dd, J = 5Hz, 2Hz), 8.29 (1 H, dd, J = 8Hz, 2Hz), 7.80-7.77 (2H, m), 7.47-7.42 (2H, m), 7.29-7.23 (2H , m), 7.14-7.07 (4H, m), 4.32 (1H, dd, J = 9Hz, 7Hz), 3.79-3.67 (2H, m), 2.95 (3H, s), 1.90-1.81 (2H, m) .

EXAMPLE 114 (±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-r2- (thienor3,4-d1-pyrimidin-2,4-dione-3-yl) etH-glycinamide (Compound No. 5-94) The title compound was prepared in a manner similar to that described in Example 2. White powder. Melting point: 135 - 137 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (270 MHz, DMDO-d6) d ppm: 11.98 (1 H, s), 10.70 (1 H, s), 9.35 (1 H, s), 8.28 (1 H, d, J = 3Hz), 7.80 (2H, d, J = 9Hz), 7.44 (2H, t, J = 8Hz), 7.26 (1H, t, J = 8Hz), 7.14-6.98 (4H, m), 6.89 (1H , d, J = 3Hz), 4.20-4.11 (1 H, m), 3.66-3.50 (2H, m), 2.92 (3H, s), 2.00-1.93 (1 H, m), 1.90-1.75 (1 H , m).

EXAMPLE 115 (±) -N-Hydroxy-Na-methy1-2-r2- (7-methyl-t-linoy3.2-dl-pyrimidin-2,4-dione-3-yl) -etn-Na- ( 4-phenoxybenzenesulfonyl) glycinamide (Compound No. 5-95) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 42. White powder. Melting point: 170 - 171 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (270 MHz, DMDO-dβ) d ppm: 12.10 (1 H, s), 10.69 (1 H, s), 9.21 (1 H, s), 7.80 (2H, dt, J = 9Hz ), 7.43 (2H, t, J = 8Hz), 7.26 (1H, t, J = 8Hz), 7.16-7.00 (5H, m), 4.21-4.08 (1H, m), 3.60-3.43 (2H, m), 2.91 (3H, s), 2.40 (3H, s), 1.98-1.65 (2H, m).

EXAMPLE 116 (±) -2-r2- (5-Fluoro-6-methylpyrimidin-2,4-dione-3-yl) et.pN-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) q-cinnamide (Compound No 5-96) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 18. White powder. Melting point: 196 - 198 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-dβ) d ppm: 11.16 (1H, s), 10.73 (1 H, s), 8.94 (1 H, s), 7.77 (2H, dt, J = 9Hz, 2Hz), 7.46 (2H, t, J = 8Hz), 7.26 (1H, t, J = 7Hz), 7.14 (2H, d, J = 8Hz), 7.10 (2H, dt, J = 9Hz, 2Hz), 4.28 (1 H, dd, J = 9Hz, 7Hz), 3.62-3.55 (2H, m), 2.91 (3H, s), 2.08 (3H, d, J = 3Hz), 1.87-1.68 (2H, m).

EXAMPLE 117 (±) -N-Hydroxy-Na-methyl-2-r2- (1-methylimidazolidin-2,4-dione-3-yl) etin-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-97) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 4. White amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-dβ) d ppm: . 70 (1 H, s), 8.98 (1 H, s), 7.77 (2 H, d, J = 9 Hz), 7.47 (2 H, t, J = 8 Hz), 7.26 (1 H, t, J = 8 Hz), 7.16 (2H, d, J = 8Hz), 7.10 (2H, d, J = 9Hz), 4.22 (1H, t, J = 8Hz), 3.92 (2H, s), 3.25-3.14 (2H, m), 2.87 (3H, s), 2.84 (3H, s), 1.91-1.80 (1 H, m), 1.71- 1.62 (1 H, m).

EXAMPLE 118 (+) - N-Hydroxy-2-r2- (imidazolidin-2,4-dione-3-yl) etin-Na-methyl-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-50) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 4. White powder. Melting point: 146 - 147 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 10.71 (1 H, s), 8.97 (1 H, s), 8.06 (1 H, s), 7.77 (2H, dt, J = 9Hz , 3Hz), 7.47 (2H, t, J = 8Hz), 7.26 (1H, t, J = 7Hz), 7.15 (2H, d, J = 8Hz), 7.10 (2H, dt, J = 8Hz, 3Hz) , 4.24 (1 H, t, J = 8Hz), 3.88 (2H, s), 3.24-3.11 (2H, m), 2.87 (3H, s), 1.89-1.80 (1 H, m), 1.75-1.64 ( 1 H, m).

EXAMPLE 119 (±) -N-Hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2-r2- (1,5,5-trimethyl-imidazolidin-2,4-dione-3-yl) -ethyl-glycineamide (Compound No. 5- 54) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 4. White powder. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 10.72 (1H, s), 8.97 (1 H, br.s), 7.77 (2H, dt, J = 9Hz, 3Hz), 7.47 (2H , t, J = 7Hz), 7.26 (1 H, t, J = 7Hz), 7.16 (2H, d, J = 7Hz), 7.10 (2H, dt, J = 9Hz, 3Hz), 4.24 (1H, t , J = 8Hz), 3.28-3.15 (2H, m), 2.86 (3H, s), 2.78 (3H, s), 1.92-1.83 (1 H, m), 1.74-1.65 (1 H, m).

EXAMPLE 120 (±) -N-Hydroxy-Na-methyl-Na-r (4-pyridin-4-yl) oxybenzenesulfonin-2-r2- (thienor-3,2-d? Pyrrmidin-2,4) -dione-3-yl) ethillglicinamide (Compound No. 5-98) The title compound was prepared in a manner similar to the procedures described in Examples 2, 20 and 42. White powder. Melting point: 167 - 168 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-dβ) d ppm: 11.90 (1 H, br.s), 10.74 (1 H, br.s), 8.97 (1 H, br.s), 8.50 (2H , d, J = 6Hz), 8.07 (1 H, d, J = 5Hz), 7.89-7.86 (2H, m), 7.35-7.32 (2H, m), 7.05 (2H, dd, J = 5Hz, 1 Hz), 6.93 (1 H, d, J = 5Hz), 4.30 (1 H, dd, J = 9Hz, 6Hz), 3.75-3.58 (2H, m), 3.00 (3H, s), 1.93-1.73 (2H, m).

EXAMPLE 121 (±) -2-r2- (6-Chloro-1-methylpyrimidin-2,4-dione-3-yl) etin-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide (Compound No 7-212) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 46. White powder. Melting point: 90 - 93 ° C Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 10.74 (1 H, br.s), 8.95 (1 H, br.s), 7.80-7.75 ( 2H, m), 7.48-7.44 (2H, m), 7.28-7.24 (1 H, m), 7.15-7.06 (4H, m), 6.07 (1 H, s), 4.27 (1 H, dd, J = 9Hz, 7Hz), 3.70-3.55 (2H, m), 3.42 (3H, s), 2.91 (3H, s), 1.86-1.68 (2H, m).

EXAMPLE 122 (±) -2-r2- (6-Chloro-1-methyl-pyrimidin-2,4-dione-3-yl) etN-methyl-N- (4-phenoxy-benzenesulfonyl) (Compound No. 7-222) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 45. White powder. Melting point: 115 - 117 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-dβ) d ppm: 7.78-7.74 (2H, m), 7.42-7.37 (2H, m), 7.23-7.19 (1H, m), 7.06-6.99 (4H , m), 5.93 (1 H, s), 4.74 (1 H, dd, J = 10Hz, 6Hz), 4.02-3.89 (2H, m), 3.55 (3H, s), 2.92 (3H, s), 2.28 -2.20 (1H, m), 2.05-1.94 (1 H, m).

EXAMPLE 123 (±) -Na-r4- (4-Chlorophenoxy) benzenesulfonin-2-r2- (6-chloropyrimidin-2,4-dione-3-yl) etin-N-hydroxy-N-methylglycinamide (Compound No. 7-181) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 94. White powder. Melting point: 171-173 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 12. 38 (1 H, br.s), 10.72 (1 H, s), 7.78 (2H, dt, J = 9Hz, 3Hz), 7.50 (2H, dt, J = 9Hz, 4Hz), 7.17 (2H, dt, J = 9Hz, 4Hz), 7.14-7.12 (2H, m), 5.90 (1 H, s), 4.27 (1 H, dd, J = 9Hz, 6Hz), 3.63-3.51 (2H, m), 2.91 (3H, s), 1.86-1.75 (1 H, m), 1.75-1.69 (1 H, m).

EXAMPLE 124 (+) - 2-r2- (6-Chloropyrimidin-2,4-dione-3-yl) etin-Na-r4- (4-fluorophenoxy) -benzenesulfonin-N-hydroxy-Na-methylglycinamide ( Compound No. 7-182) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 94. White powder. Melting point: 190 - 191 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 12.38 (1 H, s), 10.72 (1 H, s), 7.76 (2H, dt, J = 9Hz, 3Hz), 7.32-7.26 ( 2H, m), 7.23-7.18 (2H, m), 7.08 (2H, dt, J = 9Hz, 3Hz), 5.89 (1H, s), 4.27 (1H, dd, J = 9Hz, 7Hz), 3.63 -3.54 (2H, m), 2.90 (3H, s), 1.86-1.79 (1 H, m), 1.77-1.67 (1 H, m).

EXAMPLE 125 (±) -Na-r4- (4-Chlorophenoxy) benzenesulfonin-N-hydroxy-N-methyl-2-r2- (6-trifluoromethylpyrimidin-2,4-dione-3-yl) ethylyglycinamide (Compound No 8- 181) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 96. White powder. Melting point: 173 - 174 ° C (with decomposition).

Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 12.40 (1 H, br.s), 10.74 (1 H, br.s), 8.94 (1 H, br.s), 7.80-7.77 (2H, m), 7.51-7.47 (2H, m), 7.19-7.11 (4H, m), 6.20 (1H, s), 4.28 (1H, dd, J = 8Hz, 7Hz), 3.67-3.56 ( 2H, m), 2.92 (3H, s), 1.88-1.71 (2H, m).

EXAMPLE 126 (±) -Na-r4- (4-Fluorophenoxy) benzenesulfonium-N-hydroxy-Na-methyl-2-r2- (6-trifluoromethylpyrimidin-2,4-dione-3-yl) etinglycinamide (Compound No 8- 182) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 96. White powder. Melting point: 163 - 164 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 12.40 (1 H, br.s), 10.74 (1 H, br.s), 8.95 (1 H, br.s), 7.79-7.75 (2H, m), 7.33-7.26 (2H, m), 7.24-7.17 (2H, m), 7.11-7.05 (2H, m), 6.21 (1H, s), 4.28 (1H, dd, J = 9Hz, 7Hz), 3.70-3.57 (2H, m), 2.90 (3H, s), 1.88-1.71 (2H, m).

EXAMPLE 127 (±) -Na-r4- (3-Chlorophenoxy) benzenesulfonyl-N-hydroxy-Na-methyl-2-r2- (6-trifluoromethylpyrimidin-2,4-dione-3-iPetinglicinamide (Compound No. 8- 194 ) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 96. White powder. Melting point: 168 - 169 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-dβ) d ppm: 12.41 (1 H, br.s), 10.74 (1 H, br.s), 8.96 (1 H, br.s), 7.82-7.79 (2H, m), 7.47 (1H, t, J = 8Hz), 7.31 (1H, dd, J = 8Hz, 2Hz), 7.24 (1H, t, J = 2Hz), 7.18-7.07 (3H, m), 6.21 (1H, s), 4.28 (1H, dd, J = 8Hz, 6Hz), 3.67-3.55 (2H, m), 2.93 (3H, s), 1.88-1.72 (2H, m).

EXAMPLE 128 (±) -Na-r4- (3-Chlorophenoxy) benzenesulfonin-2-f2- (6-chloro-pyrimidine-2,4-dione-3-iPetin-N-hydroxy-N -methylqlicinamide (Compound No. 7 -194) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 94. White powder. Melting point: 168 - 170 ° C (with decomposition).

Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 12.41-12.35 (1 H, br.s), 10.73 (1 H, s), 8.95 (1 H, s), 7.79 (2H, dt , J = 9Hz, 3Hz), 7.47 (1 H, t, J = 8Hz), 7.31 (1 H, dd, J = 8Hz, 2Hz), 7.25 (1 H, t, J = 2Hz), 7.16 (2H, dt, J = 9Hz, 3Hz), 7.11 (1H, dd, J = 8Hz, 2Hz), 5.89 (1H, s), 4.26 (1H, dd, J = 9Hz, 7Hz), 3.66-3.50 (2H , m), 2.92 (3H, s), 1.86-1.68 (2H, m).

EXAMPLE 129 (±) -2-r2- (6-Chloropyrimidin-2,4-dione-3-yPetip-Na-ethyl-N-hydroxy-Na- (4-phenoxybenzenesulfoni-P-glycinamide (Compound No. 7-42) The title compound was prepared in a manner similar to the procedures described in Examples 78 and 94. Pale pink amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-dβ) d ppm: 12.38 (1 H, br.s), 10.67 (1 H, s), 8.98 (1 H, s), 7.81 (2H, d, J = 9Hz), 7.46 (2H, t, J = 8Hz), 7.26 (1H, t, J = 7Hz), 7.14 (2H, d, J = 8Hz), 7.08 (2H, d, J = 9Hz), 5.88 (1 H, s), 4.21 (1 H, t, J = 8Hz), 3.69-3.61 (1 H, m), 3.59-3.52 (2H, m), 3.24 (1 H, dq, J = 15Hz, 7Hz ), 1.90-1.82 (1 H, m), 1.77-1.68 (1 H, m), 1.20 (3H, t, J = 7Hz).

EXAMPLE 130 (±) -2-r2- (6-Chloropyrimidin-2,4-dione-3-yl) etin-Na-r4- (3-fluorophenoxy) -benzenesulfonin-N-hydroxy-Na-methylglycinamide (Compound No. 7-196) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 94. Pale yellow powder. Melting point: 147 - 148 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 12.40-12.36 (1 H, br.s), 10.74 (1 H, s), 8.94 (1 H, s), 7.78 (2H, d) , J = 9Hz), 7.51-7.45 (1H, m), 7.16 (2H, d, J = 9Hz), 7.11-7.01 (2H, m), 6.97 (1H, d, J = 8Hz), 5.76 ( 1 H, s), 4.25 (1 H, t, J = 8Hz), 3.68-3.43 (2H, m), 2.93 (3H, s), 1.87-1.65 (2H, m).

EXAMPLE 131 (±) -2-y2- (6-Chloropyrimidin-2,4-dione-3-yl) etin-N-hydroxy-Na-methyl-Na-r4- (pyridin-4-yl) Oxybenzenesulfoninglicinamide (Compound No. 7-26) The title compound was prepared in a manner similar to the procedures described in Examples 2, 20 and 94. Pale brown powder. Melting point: 163-165 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 12.43 (1 H, br.s), 10.72 (1 H, s), 8.96 (1 H, s), 8.52 (2H, br.s ), 7.86 (2H, d, J = 9Hz), 7.34 (2H, d, J = 9Hz), 7.06 (2H, d, J = 5Hz), 5.89 (1H, s), 4.26 (1H, dd, J = 9Hz, 6Hz), 3.62-3.50 (2H, m), 2.96 (3H, s), 1.87-1.70 (2H, m).

EXAMPLE 132 (±) -Na-r4- (3-Fluorophenoxy) benzenesulfonyl-N-hydroxy-Na-methyl-2-f2- (6-trifluoromethylpyrimidin-2,4-dione-3-yl) ethyl-glycinamide (Compound No. 8- 196) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 96. White powder. Melting point: 168 - 169 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 12.41 (1 H, br.s), 10.74 (1 H, br.s), 8.96 (1 H, br.s), 7.82-7.79 (2H, m), 7.47 (1H, dd, J = 15Hz, 8Hz), 7.19-7.16 (2H, m), 7.15-7.03 (2H, m), 6.97 (1H, dd, J = 8Hz, 2Hz), 6.21 (1 H, s), 4.28 (1 H, dd, J = 9Hz, 7Hz), 3.68-3.51 (2H, m), 2.93 (3H, s), 1. 91-1.71 (2H, m).

EXAMPLE 133 (±) -N-Hydroxy-Na-methyl-Na-r4- (pyridin-4-iPoxibenzenesulfonin-2-r2- (6-trifluoromethyipyrimidin-2,4-dione-3-yl) ethylyglycinamide (Compound No. 8 - 26] The title compound was prepared in a manner similar to the procedures described in Examples 2, 20 and 96. White powder. Melting point: 116 - 118 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 10.77 (1 H, br.s), 8.97 (1 H, br.s), 8.52-8.50 (2H, m), 7.87-7.83 ( 2H, m), 7.34-7.32 (2H, m), 7.06-7.04 (2H, m), 5.99 (1H, s), 4.25 (1H, dd, J = 9Hz, 7Hz), 3.64-3.51 (2H) , m), 2.98 (3H, s), 1.87-1.68 (2H, m).

EXAMPLE 134 (±) -2-r2- (6-Chloropyrimidine-2,4-dione-3-iPetin-N-hydroxy-Na-propyl-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 7-58) The title compound was prepared in a manner similar to the procedures described in Examples 80 and 94. Pale pink amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 12.38 (1 H, br.s), 10.65 (1 H, s), 8.98 (1 H, s), 7.81 (2H, d, J = 9Hz), 7.46 (2H, t, J = 8Hz), 7.15 (1H, t, J = 7Hz), 7.14 (2H, d, J = 7Hz), 7.08 (2H, d, J = 9Hz), 5.88 (1 H, s), 4.19 (1 H, t, J = 8 Hz), 3.65-3.54 (2 H, m), 3.41 (1 H, dt, J = 16 Hz, 8 Hz), 3.08 (1 H, dt, J = 16Hz, 8Hz), 1.90-1.82 (1 H, m), 1.74-1.60 (3H, m), 0.78 (3H, t, J = 7Hz).

EXAMPLE 135 (±) -Na-Ethyl-N-hydroxy-Na- (4-phenoxybenzenesulfonyl) -2-r2- (6-trifluoromethylpyrimidin-2,4-dione-3-yl) etinglycinamide (Compound No. 8-42 The title compound was prepared in a manner similar to the procedures described in Examples 78 and 96. Pale pink amorphous solid.

Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 12. 39 (1 H, br.s), 10.69 (1 H, br.s), 8.99 (1 H, br.s), 7.83-7.78 (2H, m), 7.48-7.43 (2H, m), 7.27- 7.23 (1 H, m), 7.15-7.05 (4H, m), 6.20 (1 H, s), 4.23 (1 H, t, J = 7Hz), 3.74-3.53 (3H, m), 3.40-3.32 ( 1 H, m), 1.94-1.72 (2H, m), 1.20 (3H, t, J = 7Hz).

EXAMPLE 136 (±) -N-Hydroxy-Na- (4-phenoxybenzenesulfonyl) -Na-propyl-2-r2- (6-trifluoromethyl-pyrimidin-2,4-dione-3-yl) ethylyglycinamide (Compound No 8-58) The title compound was prepared in a manner similar to the procedures described in Examples 80 and 96. Pale pink amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 12.39 (1 H, br.s), 10.66 (1 H, br.s), 8.98 (1 H, br.s), 7.84-7.78 (2H, m), 748-7.43 (2H, m), 7.27-7.24 (1H, m), 7.15-7.05 (4H, m), 6.20 (1H, s), 4.21 (1H, t, J = 8Hz), 3.72-3.56 (2H, m), 3.47-3.33 (1H, m), 3.15-3.05 (1H, m), 1.94-1.85 (1H, m), 1.80-1.61 (3H, m ), 0.78 (3H, t, J = 7Hz).

EXAMPLE 137 (+) - NH 4 -dioxy-Na-methyl-2-r 2 - (1-methyl-6-trifluoromethyl-pyrimidin-2,4-dione-3-yl) -etin-Na- (4-phenoxybenzenesulfonyl) glycinamide ( Compound No. 8-212) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 46. White amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 9.36 (1 H, br.s), 7.73 (2H, d, J = 9Hz), 7.44-7.38 (2H, m), 7.30-7.21 (1 H, m), 7.09-6.99 (4H, m), 6.66 (1 H, br.s), 6.23 (1 H, s), 4.39 (1 H, t, J = 7Hz), 3.86-3.67 ( 2H, m), 3.50 (3H, s), 2.93 (3H, s), 2.33-2.24 (1H, m), 1.83-1.73 (1H, m).

EXAMPLE 138 (±) -2-r2- (5-Chloropyrimidin-2,4-dione-3-yl) etin-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 5-35) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 40. Pale pink amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 11.56 (1 H, br.d, J = 6Hz), 10.73 (1 H, br.s), 8.95 (1 H, br.s) , 7.90 (1 H, d, J = 5Hz), 7.79-7.76 (2H, m), 7.48-7.43 (2H, m), 7.25 (1 H, t, J = 7Hz), 7.15-7.07 (4H, m ), 4.28 (1 H, dd, J = 9Hz, 7Hz), 3.70-3.57 (2H, m), 2.91 (3H, s), 1.87-1.69 (2H, m).

EXAMPLE 139 N-r4- (3-Chlorophenoxy) benzenesulfonin-N-hydroxy-Na-methyl-2 (R) -r2- (guannazolin-2,4-dione-3-yl) ethyglycinamide (Compound No. 1-) 182) The title compound was prepared in a manner similar to the procedures described in Examples 2, 6 and 72. White powder.

Melting point: 137 - 140 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 11.45 (1 H, br.s), 10.76 (1 H, br.s), 8.95 (1 H, br.s), 7.93-7.91 (1 H, m), 7.82-7.79 (2H, m), 7.67-7.63 (1 H, m), 7.48-7.43 (1 H, m), 7.31-7.06 (7H, m), 4.32 (1 H, dd, J = 9Hz, 6Hz), 3.82-3.67 (2H, m), 2.97 (3H, s), 1.94-1.76 (2H, m).

EXAMPLE 140 Na-r4- (3-Chlorophenoxy) benzenesulfonyl-1-N-hydroxy-Na-methyl-2 (R) -f2- (thieno- [3,2-dl-pyrimidin-2,4-dione-3-! l) Ethylqlicinamide (Compound No. 5-99) The title compound was prepared in a manner similar to the procedures described in Examples 2, 42 and 72. White powder. Melting point: 192 - 194 ° C (with decomposition). Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 11.88 (1 H, br.s), 10.74 (1 H, t, J = 2Hz), 8.94 (1 H, t, J = 2Hz) , 8.07 (1 H, d, J = 5 Hz), 7.81-7.79 (2 H, m), 7.48-7.43 (1 H, m), 7.30 (1 H, d, J = 8 Hz), 7.24 (1 H, dd , J = 4Hz, 2Hz), 7.17-7.07 (3H, m), 6.92 (1H, d, J = 5Hz), 4.30 (1H, dd, J = 9Hz, 6Hz), 3.75-3.59 (2H, m ), 2.95 (3H, s), 1.92-1.72 (2H, m).

EXAMPLE 141 Na-r4- (3-Chlorophenoxy-benzenesulfonyl-N-hydroxy-Na-methyl-2 (R) - (2-phthalimidoetiPlycinamide (Compound No. 3-183) The title compound was prepared in a manner similar to the procedures described in Examples 2 and 72. White amorphous solid. The 1 H nuclear magnetic resonance spectrum of the product was the same as that shown in Example 107. HPLC analysis: retention time: 22.0 minutes < Experimental conditions > column: CHIRALCEL OJ-R (product of Daicel Chem. Ind. Ltd) inner diameter: 0.46 cm, length: 15 cm, grain size 5 μm eluent: acetonitrile / triethylamine phosphate buffer (0.2% (v / v), pH 2.2) = 35/65 flow rate: 0.5 ml / minute temperature: 40 ° C detection: UV 254 nm EXAMPLE 142 (±) -2- (1,1-dimethyl-2-phthalimidoetiP-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoni) D-glycinamide (Compound No. 3-32) A 4-phenoxybenzylsulfonylation reaction was carried out, in a manner similar to that described in example 1 (2) (b), using benzyl ester of (±) -2- (1,1-dimethyl-2) phthalimidoethyl) glycine as starting material, followed by an N-methylation reaction according to example 1 (3), by a de-benzylation reaction according to example 5 (5) (a) and then by a hydroxy-amidation reaction according to example 2, to give the title compound as a white powder. Melting point: 189 - 190 ° C. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-de) d ppm: 10.79 (1 H, s), 9.03 (1 H, s), 7.90-7.84 (4H, m), 7.50-7.46 (2H, m) , 7.29-7.25 (1 H, m), 7.19-7.16 (2H, m), 7.11 (2H, dt, J = 9Hz, 3Hz), 4.19 (1 H, s), 3.87 (1 H, d, J = 14Hz), 3.51 (1 H, d, J = 14Hz), 3.00 (3H, s), 1.01 (3H, s), 0.94 (3H, s).

EXAMPLE 143 (+) - Na-Cyclopropyl-N-hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimidoetiP-glycinamide (Compound No. 3-193) Cyclization and allyl esterification reactions were carried out, similarly to the procedures described in example 37 (2), using (±) -a- [N-cyclopropyl-N- (4-phenoxybenzenesulfonyl) amino] -? - butyrolactone as starting material, followed by phytaminidation according to example 1 (1), by dealkylation according to 1 (4), and then by hydroxylation according to example 2, to give the compound of the title as a white amorphous solid. Nuclear magnetic resonance spectrum 1H (400 MHz, DMDO-d6) d ppm: 10.59 (1 H, s), 8.97 (1 H, br.s), 7.87-7.79 (4H, m), 7.47 (2H, t, J = 8Hz), 7.27 (1 H, t, J = 8Hz), 7.15 (2H, d, J = 9Hz), 7.05 (2H, dt, J = 9Hz, 3Hz), 4.33 (1 H, t, J = 7Hz), 3.54-3.45 (1 H, m), 3.43-3.35 (1 H, m), 2.29-2.24 (1H, m), 2.20-2.11 (1 H, m), 1.93-1.83 (1 H, m ), 1.11-0.99 (1 H, m), 0.89-0.83 (1 H, m), 0.75-0.68 (1 H, m), 0.63-0.58 (1 H, m).

EXAMPLE 144 (±) -2-r2- (6-Acetyl-pyrimidin-2,4-dione-3-yl) -etin-N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfoni) P-glycinamide (Compound No. 9-153) The title compound was prepared in a manner similar to the procedure described in Example 94. White powder. Melting point: 167 - 169 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb-DMDO-dβ) d ppm: 9.92 (1H, br.s), 9.38 (1 H, br.s), 8.31 (1 H, br.s), 7.77- 7.72 (2H, m), 7.45-7.37 (2H, m), 7.25-7.19 (1H, m), 7.08-6.98 (4H, m), 6.30 (1H, d, J = 2Hz), 4.93 (1 H, t, J = 8Hz), 3.87-3.73 (2H, m), 2.96 (3H, s), 2.52 (3H, s), 2.27-2.11 (1H, m).

EXAMPLE 145 (±) -2-r2- (6-Ethoxycarbonylpyr8midin-2,4-dione-3-yl) et.nN-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) qlycinamide (Compound No 9-10) The title compound was prepared in a manner similar to the procedures described in Example 94. White powder. Melting point: 159-160 ° C. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 9.50 (1 H, br.s), 8.99 (1 H, br.s), 7.73-7.68 (2H, m), 7.45-7.38 (2H, m), 7.26-7.19 (1 H, m), 7.09-6.99 (4H, m), 4.47-4.39 (3H, m), 3.87-3.71 (2H, m), 2.90 (3H, s), 2. 37-2.23 (1 H, m), 1.78-1.63 (1 H, m), 1.39 (3H, t, 7Hz).

REFERENCE EXAMPLES REFERENCE EXAMPLE 1 Benzyl ester of N- (tert-butoxycarbonyl) homoserine A solution of di-tert-butylcarbonate (36.40 g, 166.8 mmol) in dioxane (100 mL) was added to a solution of (±) -a-amino-γ-butyrolactone hydrobromide (25.28 g, 138.9 mmol) in a dioxane / water mixture = 1/1 (200 ml). 20 minutes were added by adding dropwise to the mixture a solution of sodium hydroxide (12.58 g, 321.1 mmol) in water (100 ml), with ice cooling and with stirring. This mixture was stirred for 30 minutes with cooling with ice and then at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Water (300 ml) was added to the residue and the mixture was acidified with citric acid (25 g), and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (200 ml), and a solution of sodium hydroxide (5.44 g, 138.9 mmol) in water (33 ml) was added to the solution by cooling with ice. After leaving this mixture overnight at room temperature, it was concentrated under reduced pressure. The resulting residue was dissolved in N, N-dimethylformamide (150 ml), benzyl bromide (16.5 ml, 138.7 mmol) was added to the solution, the mixture was stirred overnight at room temperature, and then concentrated under pressure. reduced. To the residue was added a saturated aqueous solution of ammonium chloride, and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (39.75 g, 93% yield) as a pale yellow oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.41-7.31 (5H, m), 5.40 (1 H, br.d, J = 8Hz), 5.19 (2H, s), 4.58-4.48 (1 H, m), 3.77-3.58 (2H, m), 3.12 (1H, br.s), 2.23-2.11 (1 H, m), 1.73-1.58 (1 H, m), 1.45 (9H, s).

REFERENCE EXAMPLE 2 Allylic ester of (±) -N- (tert-butoxycarboniPhomoserine Reactions were carried out in a manner similar to the procedures described in reference example 1, using allyl bromide in place of benzyl bromide, to give the title compound (89% yield) as a colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 5.91 (1 H, ddd, J = 17Hz, 12Hz, 6Hz), 5.40-5.25 (3H, m), 4.67 (2H, d, J = 6Hz) , 4.57-4.48 (1 H, m), 3.79-3.63 (2H, m), 3.17 (1 H, br.s), 2.24-2.12 (1 H, m), 1.69- 1.59 (1 H, m), 1.45 (9H, s).

REFERENCE EXAMPLE 3 1-Benzyloxymethylpyrimidin-2,4-dione After adding N, 0-bis (trimethylsilyl) acetoamide (18.5 ml, 74.8 mmol) dropwise to a suspension of pyrimidine-2,4-dione (3.36 g, 30.0 mmol) in dichloromethane (90 ml) at room temperature environment, the mixture was stirred for 2 hours. Tetra-n-butylammonium iodide (1.12 g, 3.0 mmol) was added to the reaction mixture, and subsequently benzyloxymethyl chloride (4.4 mL, 31.7 mmol) was added. This mixture was stirred for 3 hours at room temperature. The reaction mixture was neutralized with water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous solution of sodium thiosulfate and with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure. The solid residue was washed with diisopropyl ether and collected by filtration, to give the title compound (6.00 g, 86% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.50 (1 H, br.s), 7.36-7.28 (6H, m), 5.74 (1 H, dd, J = 7Hz, 2Hz), 5.23 ( 2H, s), 4.62 (2H, s).

REFERENCE EXAMPLE 4 1-Benzyloxymethylquinazoline-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using quinazolin-2,4-dione in place of pyrimidin-2,4-dione, to give the title compound (82). % yield) as a white solid. Nuclear magnetic resonance spectrum 1H (270 MHz, DMSO-dβ) d ppm: 11.63 (1 H, s), 8.00 (1 H, dd, J = 8Hz, 2Hz), 7.77 (1 H, dt, J = 8Hz, 2Hz), 7.52 (1 H, d, J = 8Hz), 7.33-7.26 (6H, m), 5.61 (2H, s), 4.62 (2H, s).

REFERENCE EXAMPLE 5 1- (2-Trimethylsilyl) ethoxymethylquinazoline-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using quinazolin-2,4-dione in place of pyrimidine-2,4-dione, and using 2- (trimethyl) chloride. Lyl) ethoxymethyl instead of benzyloxymethyl chloride, to give the title compound (87% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.65 (1 H, br.s), 8.23 (1 H, dd, J = 8Hz, 2Hz), 7.72 (1 H, dt, J = 8Hz, 2Hz), 7.51 (1 H, d, J = 8Hz), 7.32 (1H, t, J = 8Hz), 5.60 (2H, s), 3.74 (2H, t, J = 8Hz), 0.97 (2H, t, J = 8Hz), -0.02 (9H, s).

REFERENCE EXAMPLE 6 1-Benzyloxymethyl-5-methylpyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 5-methylpyrimidin-2,4-d-ion in place of pyrimidine-2,4-dione, to give the title compound (98% yield) as a yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.78 (1 H, br.s), 7.33 (5H, s), 7.11 (1 H, s), 5.21 (2H, s), 4.62 (2H , s), 1.19 (3H, s).

REFERENCE EXAMPLE 7 1-Benzyloxymethyl-5,6-dimethylpyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 5,6-d.methylpyrimidin-2,4-dione in place of pyrimidine-2,4-dione, to give the compound of the title (78% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.46 (1 H, s), 7.38-7.26 (5H, m), 5.44 (2H, s), 4.65 (2H, s), 2.35 (3H, s), 1.94 (3H, s).

REFERENCE EXAMPLE 8 1-Benzyloxymethyl-5-fluoropyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 5-fluoropyridin-2,4-dione in place of pyrimidine-2,4-dione, to give the compound of the title (87% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3-DMSO-d6) d ppm: 11.60-11.52 (1 H, br.s), 7.47 (1 H, d, J = 6Hz), 7.39-7.27 (5H, m ), 5.20 (2H, s), 4.62 (2H, s).

REFERENCE EXAMPLE 9 (±) -a- (4-Phenoxybenzenesulfonylamino) -? - butyrolactone Triethylamine (20.0 ml, 143.9 mmol) was added to a suspension of a-amino-γ-butyrolactone hydrobromide (7.28 g, 40.0 mmol) in dichloromethane (80 ml), and then 20 minutes were added by adding dropwise to the mixture. a solution of 4-phenoxybenzenesulfonyl chloride (11.0 g, 40.9 mmol) in dichloromethane (40 ml), with ice-cooling. After stirring this mixture for 2 hours at room temperature, the solvent in the reaction mixture was evaporated under reduced pressure. The residue was acidified with water and hydrochloric acid (1 N), and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 2/1 as eluent, to give the title compound (8.74 g, 73% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 7.88-7.82 (2H, m), 7.46-7.39 (2H, m), 7.26-7.21 (1H, m), 7.10-7.03 (4H, m ), 5.18 (1 H, br.d, J = 3Hz), 4.45 (1 H, t, J = 9Hz), 4.21 (1 H, ddd, J = 12Hz, 9Hz, 6Hz), 3.93 (1 H, ddd) , J = 12Hz, 8Hz, 3Hz), 2.80-2.70 (1 H, m), 2.37-2.22 (1 H, m).

REFERENCE EXAMPLE 10 1- (2-Trimethylsilyl) ethoxymethylthienof3,2-d1-pyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using thieno [3,2-d] pyrimidine-2,4-dione in place of pyrimidine-2,4- dione, and using 2- (trimethylsilyl) ethoxymethyl chloride in place of benzyloxymethyl chloride, to give the title compound (87% yield) as a pale yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.62 (1 H, br.s), 7.78 (1 H, d, J = 6Hz), 7.13 (1 H, d, J = 6Hz), 5.46 (2H, s), 3.67 (2H, t, J = 8Hz), 0.93 (2H, t, J = 8Hz), -0.02 (9H, s).

REFERENCE EXAMPLE 11 7-Methyl-3- (2-trimethylsilyl) ethoxymethylxanthine Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 7-methylxanthine in place of pyrimidine-2,4-dione, and using 2- (trimethylsilyl) ethoxymethyl chloride in place of chloride of benzyloxymethyl, to give the title compound (69% yield) as a pale yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.09 (1 H, br.s), 7.55 (1 H, s), 5.51 (2H, s), 3.97 (3H, s), 3.75-3.69 (2H, m), 1.01-0.95 (2H, m), -0.02 (9H, s).

REFERENCE EXAMPLE 12 1- (2-Trimethylsilyl) ethoxymethylpteridin-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using pteridin-2,4-dione in place of pyrimidine-2,4-dione, and using 2- (trimethylsilyl) ethoxymethyl chloride Instead of benzyloxymethyl chloride, to give the title compound (53% yield) as a yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 9.01 (1 H, br.s), 8.71 (1 H, d, J = 2 Hz), 8.66 (1 H, d, J = 2 Hz), 5.77 (2H, s), 3.80- 3.74 (2H, m), 1.02-0.96 (2H, m), 0.01 (9H, s).

REFERENCE EXAMPLE 13 6-Methyl-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 6-methylpyrimidine-2,4-dione in place of pyrimidine-2,4-dione, and using 2- (trimethylsilyl) chloride ) ethoxymethyl instead of benzyloxymethyl chloride, to give the title compound (56% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.70 (1 H, br.s), 5.58 (1 H, s), 5.28 (2H, s), 3.68-3.62 (2H, m), 2.34 (3H, s), 0.96-0.87 (2H, m), -0.01 (9H, s).

REFERENCE EXAMPLE 14 5-Trifluoromethyl-1- (2-trimethylsilyl) ethoxymethyl-pyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 5-trifluoromethyl-pyrimidine-2,4-dione in place of pyrimidine-2,4-dione, and using 2-chloride. (trimethylsilyl) ethoxymethyl in place of benzyloxymethyl chloride, to give the title compound (76% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 8.48 (1 H, br.s), 7.81 (1 H, s), 5.17 (2H, s), 3.66-3.60 (2H, m), 0.98 -0.92 (2H, m), -0.03 (9H, s).

REFERENCE EXAMPLE 15 1- (2-Tritymethylsilyo-methoxymethyl-6,7-dihydro-5H-cyclopentafd] pyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 6,7-dihydro-5H-cyclopenta [d] pyrimidine-2,4-dione, in place of pyrimidine-2,4 -dione, and using 2- (trimethylsilyl) ethoxymethyl chloride in place of benzyloxymethyl chloride, to give the title compound (71% yield) as a pale yellow powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCI3) d ppm: 8.38 (1 H, br.s), 5.17 (2H, s), 3.67-3.60 (2H, m), 2.97-2.91 (2H, m), 2.76-2.69 (2H, m), 2.18-2.07 (2H, m), 0.96-0.89 (2H, m), 0.01 (9H, s).

EXAMPLE OF REFERENCE 16 6,7-Dimethoxy-1- (2-trimethylsilyl) ethoxymethylquinazoline-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 6,7-dimethoxyquinazoline-2,4-dione in place of pyrimidine-2,4-dione, and using 2- (trimethylsilyl) ethoxymethyl, in place of benzyloxymethyl chloride, to give the title compound (93% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (270 MHz, DNSO-dβ) d ppm: 11.52 (1 H, s), 7.48 (1 H, s), 7.03 (1 H, s), 5.62 (2 H, s), 4.00 ( 3H, s), 3.92 (3H, s), 3.73 (2H, t, J = 8Hz), 0.98 (2H, t, J = 8Hz), 0.04 (9H, s).

REFERENCE EXAMPLE 17 6-Chloro-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described. in reference example 3, using 6-chloropyrimidin-2,4-dione in place of pyrimidine-2,4-dione, and using 2- (trimethylsilyl) ethoxymethyl chloride in place of benzyloxymethyl chloride, for give the title compound (71% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 9.10 (1 H, br.s), 5.93 (1 H, s), 5.45 (2H, s), 3.68 (2H, t, J = 8Hz) , 0.96 (2H, t, J = 8Hz), 0.01 (9H, s).

EXAMPLE OF REFERENCE 18 6-Trifluoromethyl-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione Reactions were carried out in a manner similar to the procedures described in Reference Example 3, using 6-trifluoromethylpyrimidin-2,4-dione in place of pyrimidine-2,4-dione, and using 2-chloride. (trimethylsilyl) ethoxymethyl in place of benzyloxymethyl chloride, to give the title compound (48% yield) as a colorless oil.

Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.84 (1 H, br.s), 6.24 (1 H, d, J = 2Hz), 5.32 (2H, s), 3.73-3.68 (2H, m), 0.97-0.90 (2H, m), 0.01 (9H, s).

REFERENCE EXAMPLE 19 6-Phenyl-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.28 (1 H, br.s), 7.55-7.45 (5H, m), 5.66 (1 H, d, J = 2Hz), 5.00 (2H, s), 3.61-3.55 (2H, m), 0.94-0.87 (2H, m), -0.01 (9H, s).

REFERENCE EXAMPLE 20 6-Ethyl-1- (2-trimethylsilyPethoxymethylpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.80-8.74 (1 H, br.s), 5.60 (1 H, s), 5.29 (2H, s), 3.64 (2H, t, J = 8Hz), 2.67 (2H, q, J = 7Hz), 1.22 (3H, t, J = 7Hz), 0.90 (2H, t, J = 8Hz), 0.01 (9H, s).

REFERENCE EXAMPLE 21 5-Methyl-1- (2-trimethylsilyl) ethoxymethylthienof2,3-d, pyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.46 (1 H, br.s), 6.54 (1H, d, J = 1 Hz), 5.43 (2H, s), 3.71-3.65 (2H, m), 2.51 (3H, d, J = 1 Hz), 1.00-0.94 (2H, m), 0.01 (9H, s).

REFERENCE EXAMPLE 22 1- (2-Trimethylsilyl) ethoxymethylpyrido 2,3-d-pyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.96 (1 H, br.s), 8.73 (1 H, dd, J = 5Hz, 2Hz), 8.47 (1 H, dd, J = 8Hz, 2Hz), 7.37 (1 H, dd, J = 8Hz, 5Hz), 5.80 (2H, s), 3.81-3.74 (2H, m), 1.03-0.96 (2H, m), -0.02 (9H, s).

REFERENCE EXAMPLE 23 1- (2-Trimethylsilyl) ethoxymethyltienor3,4-dlpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.30 (1 H, d, J = 3Hz), 8.10 (1 H, br.s), 6.96 (1 H, d, J = 3Hz), 5.46 (2H, s), 3.72-3.65 (2H, m), 1.01-0.94 (2H, m), -0.02 (9H, s).

REFERENCE EXAMPLE 24 7-Methyl-1- (2-trimethylsilyl) ethoxymethyltienor3,2-dlpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.71 (1 H, br.s), 7.42 (1 H, s), 5.62 (2H, br.s), 3.79-3.73 (3H, m) , 2.60 (3H, s), 1.01-0.95 (2H, m), -0.02 (9H, s).

REFERENCE EXAMPLE 25 5-Fluoro-6-methyl-1- (2-tritymethylsilypetoxymethylpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.34-8.21 (1 H, br.s), 5.29 (2H, s), 3.66 (2H, t), 2.38 (3H, d, J = 4Hz ), 0.94 (2H, t, J = 8Hz), 0.01 (9H, s).

REFERENCE EXAMPLE 26 5-Chloro-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.48 (1 H, br.s), 7.54 (1 H, s), 5.14 (2H, s), 3.67-3.60 (2H, m), 0.99 -0.92 (2H, m), 0.03 (9H, s).

REFERENCE EXAMPLE 27 6-Acetyl-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. White powder. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.49 (1 H, br.s), 5.90 (1 H, d, J = 2Hz), 5.35 (2H, s), 3.53-3.47 (2H, m), 2.51 (3H, s), 0.91-0.85 (2H, m), 0.00 (9H, s).

REFERENCE EXAMPLE 28 6-Ethoxycarbonyl-1- (2-trimethylsilyl) ethoxymethylpyrimidine-2,4-dione The title compound was prepared in a manner similar to the procedures described in reference example 5. Colorless oil. Nuclear magnetic resonance spectrum 1H (270 MHz, CDCb) d ppm: 8.72 (1 H, br.s), 6.11 (1 H, d, J = 2Hz), 5.52 (2H, s), 4.39 (2H, q, J = 7Hz), 3.55-3.48 (2H, m), 1.38 (3H, t, J = 7Hz), 0.91-0.85 (2H, m), -0.01 (9H, s).

REFERENCE EXAMPLE 29 1-Methyl-6-trifluoromethylpyrimidine-2,4-dione A solution of pyrimidine-2,4-dione (158 mg, 0.88 mmol) in anhydrous tetrahydrofuran (1 ml) was added dropwise to a suspension of potassium terbutoxide (99 mg, 0.88 mmol) in tetrahydrofuran (2 ml), with cooling with ice; the mixture was stirred for 1 hour at room temperature. Methyl trifluoromethanesulfonate (100 μl, 0.88 mmol) was added dropwise to the reaction mixture under ice cooling. This mixture was stirred at the same temperature for 12 hours. The reaction mixture was poured into 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 8/2 as eluent, to give the title compound (105 mg, 62% yield) as a white powder. Nuclear magnetic resonance spectrum 1 H (270 MHz, CDCl 3) d ppm: 8.58 (1 H, br.s), 6.21 (1 H, br.s), 3.50 (3 H, q, J = 1 Hz).

REFERENCE EXAMPLE 30 Benzyl ester hydrochloride of (±) -2- (1,1-dimethyl-2-phthalimidoethyl) glycine After adding potassium phthalimide (3.71 g, 21.1 mmol) to a solution of DL-pantolactone (2.61 g, 20.1 mmol) in N, N-dimethylformamide (40 ml), the mixture was stirred for 16 hours at 150 ° C. After cooling the reaction mixture to room temperature, benzyl bromide (2.6 ml, 21.9 mmol) and potassium carbonate (3.0 g, 21.6 mmol) were also added, and this was stirred for 2 hours. Water was added to the reaction mixture and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane / ethyl acetate = 3/1 as eluent to give (±) -2-hydroxy-3,3-dimethylphthalimidobutanoic acid benzyl ester (3.27 g). , 42% yield) as a colorless oil. 2.00 g (5.44 mmol) of the product were dissolved in dichloromethane (7.5 ml), and pyridine (554 μl, 6.85 mmol) was added. After cooling the mixture to -78 ° C, trifluoromethanesulfonic acid anhydride (962 μl, 5.72 mmol) was added and this was stirred for 20 minutes at -78 ° C, and then stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added to the residue. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N, N-dimethylformamide (30 ml) and sodium azide (707 mg) was added to the solution., 10.9 mmoles). After stirring the mixture for 4 hours at 50 ° C, water was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield (±) -2-azido-3,3-dimethyl-4-phthalimidobutanoic acid benzyl ester, as a pale yellow oil (This product was used in the next reaction without further purification). Nuclear magnetic resonance spectrum 1H (400 MHz, CDCI3) d ppm: 7.89-7.85 (2H, m), 7.78-7.73 (2H, m), 7.41-7.33 (5H, m), 5.25 (2H, s), 4.00 (1 H, s), 3.81 (1 H, d, J = 15 Hz), 3.65 (1 H, d, J = 15 Hz), 1.07 (3 H, s), 0.97 (3 H, s). The azide compound thus obtained (the whole amount) was dissolved - in methanol (22 ml) and to the solution was added a solution of hydrogen chloride in dioxane (4N, 1.63 ml, 6.53 mmol); Platinum oxide (38 mg, 0.17 mmol) was added to the mixture and this was stirred under a hydrogen atmosphere for 10 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (620 mg, 28% yield) as a white powder. Mass spectrum (El) m / z: 366 [M +].

REFERENCE EXAMPLE 31 (±) -a-rN-Cyclopropyl-N- (4-phenoxybenzenesulfonyl) aminoW-butyrolactone After adding potassium carbonate (18.24 g, 132.0 mmol) to a solution of cyclopropylamine (5.50 mL, 80.0 mmol) and (±) -a-bromo-β-butyrolactone (3.32 mL, 42.0 mmol) in acetonitrile (80 mL) , the mixture was stirred for 8 hours at room temperature. Water was added to the reaction mixture and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column, using hexane / ethyl acetate = 1/1 as eluent to give (±) -ac.-cyclopropylamino-γ-butyrolactone (4.10 g, 73% yield). ) as a yellow oil. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCb) d ppm: 4.41 (1 H, dd, J = 16Hz, 10Hz), 4.27-4.18 (1 H, m), 3.69 (1 H, t, J = 9Hz) , 2.60-2.52 (1H, m), 2.29-2.24 (1H, m), 0.51-0.46 (2H, m), 0.44-0.36 (2H, m). 4.10 g (29.0 mmol) of the product were dissolved in dichloromethane (60 ml), 4-phenoxybenzenesulfonyl chloride (9.35 g, 34.8 mmol) and triethylamine (5.04 ml, 36.3 mmol) were added to the solution, and the mixture was stirred for 60 hours at room temperature. 1N Hydrochloric acid was added to the reaction mixture and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column, using hexane / ethyl acetate = 4/1 as eluent, to give the title compound (8.54 g, 79% yield) as a white powder. Nuclear magnetic resonance spectrum 1H (400 MHz, CDCI3) d ppm: 7.97 (2H, dt, J = 9Hz, 3Hz), 7.41 (2H, t, J = 8Hz), 7.25 (1H, t, J = 8Hz) , 7.09 (2H, d, J = 8Hz), 7.05 (2H, dt, J = 9Hz, 3Hz), 4.80 (1H, dd, J = 13Hz, 11Hz), 4.52 (1H, t, J = 9Hz ), 4.29 (1 H, dd, J = 16Hz, 9Hz), 2.78-2.67 (1H, m), 2.58-2.51 (1 H, m), 2.48-2.41 (1 H, m), 0.83-0.76 (1 H, m), 0.74-0.69 (2H, m), 0.69-0.62 (1 H, m).

EXAMPLES OF FORMULATION EXAMPLE OF FORMULATION 1 Powder In a mixer, 5 g of the compound of the example were mixed 72, 895 g of lactose and 100 g of corn starch, to obtain a powder.

EXAMPLE OF FORMULATION 2 Granules After mixing 5 g of the compound of Example 72, 865 g of lactose and 100 g of low substituted hydroxypropyl cellulose, 300 g of a 10% aqueous solution of hydroxypropylcellulose were added, followed by kneading. This mixture was converted into granules using an extrusion granulation machine, followed by drying to obtain the granules.

EXAMPLE OF FORMULATION 3 Tablets After mixing 5 g of the compound of example 72, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate in a blender, the mixture was converted into tablets with a tabletting machine for get the tablets.

EXAMPLES OF PROOF EXAMPLE OF TEST 1 Inhibition test of MMP-13 (in vitro) MMP-13 exists in chondrocytes and in chondrosarcoma cells, and Freije et al. (Freije, JMP et al., J. Biol. Chem., Vol 269, 16766-16773, 1994) have reported the DNA sequence corresponding to the amino acid sequence of its precursor (proMMP-13). Therefore, proMMP-13 can be expressed according to conventional methods by acquiring proMMP-13 cDNAs from chondrocytes and chondrosarcoma cells, incorporating this into an ordinarily used vector, and introducing this vector into cells suitable for transforming the cells. For example, an inhibition test of MMP-13 can be performed by treating recombinant proMMP-13 obtained according to the manner described above, with p-aminophenylmercuric (II) acetate (APMA) to convert proMMP-13 to active MMP-13, and then using this as an enzyme to measure the activity of MMP-13 in the presence or absence of a test compound, using a fluorescent substrate. (1) Expression of recombinant pro-MMP-13 Using conventional methods, human chondrosarcoma mRNA HCS-2/8, which is a chondrosarcoma cell line established by Takigawa et al. (Jpn. J. Cancer Res., Vol. 85, 364-371, 1994) and, through a reverse transcription polymerase chain reaction (RT-PCR), proMMP-13 cDNA was obtained. The following were used as primers: 5'-gctgagctcatgcatccaggggtcctggctgcc-3 '(Sequence No. 1 of the Sequence Listing) and 5'-cgaqqtaccattaccccaaatqctcttcagqa-3' (Sequence No. 2 of the Sequence Listing), which contain the enzyme cleavage site of restriction sacl or Kpnl (portions indicated by the underline). The amplified cDNA was incorporated into the expression vector pcDL-SR 296 (provided by Dr. Yutaka Takebe of the National Institute of Health) by coupling at the cleavage sites of the restriction enzyme sacl and Kpnl (Takara Shuzo Co., Ltd .) (the resulting vector is referred to as "pSR -proMMP-13"). Simultaneously, the amplified cDNA was also incorporated into pUC19 (Takara Shuzo Co., Ltd.), and it was confirmed that the amplified cDNA nucleotide sequence was identical to the reported sequence (Freije, JMP et al., J. Biol. Chem. , Vol 269, 16766-16773, 1994). By means of electroporation, the pSR-proMMP-13 gene was introduced into COS-1 cells developed in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum ("Current Protocols in Molecular Biology"). Molecular Biology-, 9.3.1, CURRENT PROTOCOLS). After 12 hours, the medium was replaced with DMEM that did not contain fetal bovine serum, followed by culture for 48 hours for the expression of proMMP-13. The resulting culture supernatant was then used as the proMMP-13 fraction. (2) Measurement of MMP-13 activity The fraction of proMMP-13 obtained in (1) was treated for 1 hour at 37 ° C with 1 mM APMA (Sigma) to convert it into active MMP-13, which is then used as an enzyme solution. In addition, 7-methoxycoumarin-4-yl (MOCAc) -Pro-Leu-Gly-Leu-2,4-dinitrophenyl (DPa) -Ala-Arg-NH2 (peptide) was used as the substrate. This enzyme solution and the substrate (20 M) were added to a buffer solution of 50 mM Tris-HCl (pH 7.5) containing 0.15 M sodium chloride, 10 mM calcium chloride, 0.05% Brij 35, and sodium azide. 0.02% to bring the final volume to 0.1 ml, followed by reaction for 1 hour at 37 ° C. After stopping the reaction by adding 0.1 ml of 3% acetic acid, the activity of the enzyme was determined by measuring with a fluorophotometer (Labsystems Fluoroskan II) at an excitation wavelength of 330 nm and emission wavelength of 390 nm . The rate of inhibition was determined according to the activity of the enzyme in the presence and absence of the test compound, followed by the calculation of 50% inhibitory concentration (C o) - CUADR0 10 Cl50 test compound (nM) Compound of example 42 0.47 Compound of example 139 0.43 Compound of example 140 0.32 As shown in Table 10 above, the compounds of the present invention exhibited excellent MMP-13 inhibitory activity.

EXAMPLE OF TEST 2 Aglicanase inhibition test (in vitro) An aglicanase inhibition test can be performed, for example, by measuring the activity of aglicanase in the presence or absence of a test compound, according to the method of Nagase et al. (H. Nagase and JF Woessner, Analytical Biochemistry, vol. 107, 385-392, 1980). The enzyme used for the measurement of the activity of aglicanase can be extracted from the mammalian cartilage tissue or from its cultivated medium. The extraction is carried out by combining various types of chromatography, and the activity of the aglicanase can be detected in the purification procedures by adding substrate (aglycan) to an eluted fraction and testing whether the substrate has been decomposed or not. It can be determined whether or not the substrate has been decomposed by immunoblotting the reaction liquid using an antibody that binds to the epitope, CNLeNIEGE, which is produced by decomposition of aglycan (substrate) with aglycanase (enzyme). It should be noted that the antibody that binds to CNLeNIEGE can be prepared according to the method of Sandy et al (J.D. Sandy et al., Journal of Biological Chemistry, vol.270, 2550-2556, 1995). (1) Preparation of aglicanase Bovine nasal septum cartilage was cultured for 7 days at 37 ° C in the presence of 1 m retinoic acid in DMEM [containing N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid ( HEPES) 20 mM, bovine seroalbumin (BSA) at 0.005%, supplement of nsulin-transferin medium sodium selenite 5 g / ml, 1% penicillin and 1% streptomycin], changing the medium once a day. The culture liquid collected from day 3 to day 7 was subjected to chromatography [carrier: Q-sepharose (Pharmacia), mobile phase: buffer solution of 20 mM Tris-HCl (pH 7.2) containing 5 mM calcium chloride] and was collected the fraction that passed through the column. This fraction was then subjected to additional chromatography [carrier: Zn-chelating sepharose (Pharmacia), mobile phase: Tris-HCl buffer (pH 7.2) containing 5 mM calcium chloride and 0.5 M sodium chloride], followed by elution using imidazole as a mobile phase. A fraction of the resulting eluted fractions in which the aglicanase activity was confirmed were pooled. Then, this fraction was subjected to additional chromatography [carrier: LCA-agarose (Honen Corporation), mobile phase: 20 mM aqueous solution of 2- (N-morpholino) ethanesulfonic acid (pH 6.5) containing 5 mM calcium chloride and sodium 0.25 M], followed by elution using 2-methylmanopyranoside as the mobile phase. A fraction of the resulting eluted fractions in which the aglicanase activity was confirmed was collected, and this fraction was used as the liquid enzyme for the measurement of the aglyxase activity. Apart from this, antibody was prepared which binds to CNLeNIEGE according to the method of Sandy et al. (JD Sandy et al., Journal of Biological Chemistry, vol.270, 2550-2556, 1995), and this antibody was used in the assay. nmunoblotting to detect the activity of aglicanase in the aforementioned methods of purification of aglicanase. Immunoblotting was performed according to conventional methods. (2) Measurement of Aglicanase Activity Measurement of aglicanase activity was performed using a modification of the protease activity measuring method using polyacrylamide particles, Nagase et al. (H. Nagase and JF Woessner, Analytical Biochemistry, vol 107, 385-392, 1980). The aglycan used as substrate was isolated from bovine nasal septum cartilage according to a centrifugation in cesium chloride sedimentation equilibrium ("New Biochemical Experimentation Course, 3, Saccharides II" -New course of biochemical experimentation, 3, Saccharides II -, 4-7, Tokyo Kagaku Dojin Publishing, 1991). Using this aglycan, polyacrylamide particles were prepared with aglycan according to the method of Nagase et al. (H. Nagase and J.F. Woessner, Analytical Biochemistry, vol.107, 385-392, 1980). Particularly, first the aglycan (dry weight: 480 mg) was added to 28 ml of liquid A [1 M Tris-HCl buffer solution (pH 8.5) containing N, N, N ', N'-tetramethylethylene diamine (TEMED) at 0.2%], and the mixture was stirred for 1 hour at 4 ° C. Then, 8 ml of liquid B (aqueous solution containing 3 g of acrylamide and 61 mg of bis-acrylamide in 10 ml) and 12 ml of liquid C (aqueous solution containing 0.112 g of ammonium persulfate in 20 ml) were added to this suspension. ), followed by stirring and allowing to stand for about one hour at room temperature. The polymerized gel was sliced into thin sections, followed by homogenization in cold water to transform the gel into particles. After washing these particles with water, they were dehydrated using acetone, and then air dried to evaporate the acetone. The resulting powder was passed through a screen (mesh size: 420 μm) to remove the large particles. The liquid enzyme obtained in (1) and the test compound were pipetted into a 96-well plate, and subsequently a suspension I was added [50 mM Tris-HCl buffer solution (pH 7.2) containing calcium chloride. mM and sodium chloride 0.25 M, in which the aforementioned polyacrylamide particles containing aglycan were suspended, such that the final concentration of the polyacrylamide particles containing aglycan was 10 mg / ml], to make the amount of each reaction liquid 100. μl. After allowing to react at 37 ° C for 2.5 hours, the reaction was stopped by adding 20 μl of 100 mM ethylenediaminetetraacetic acid to the reaction liquid. Then, this reaction liquid was centrifuged (for 10 minutes at 4 ° C and 2500 rpm); 10 μl of the supernatant was transferred to a different 96-well plate and 190 μl of 1, 9-dimethylmethylene blue solution was added, followed immediately by measurement of the optical absobancia at 525 nm. Using the resulting measured values as indicators of aglicanase activity, the rates of inhibition of the aglicanase activity in the presence and absence of the test compound were determined, followed by the calculation of the 50% inhibitory concentration (Cl50).

TABLE 11 IC50 Test Compound (nM) Compound of Example 6 7.0 Compound of Example 18 7.6 Compound of Example 42 5.4 Compound of Example 72 4.9 Compound of Example 141 2.9 Compound of Example 139 3.7 Compound of Example 140 2.2 As shown in table 11, the compounds of the present invention demonstrated excellent aglyngase inhibitory action.

EXAMPLE OF TEST 3 Test of inhibition of the decomposition of cartilage tissue (in vitro) A test of inhibition of the decomposition of cartilage tissue can be performed, investigating the action that inhibits the decomposition of proteoglycan and collagen, which are the two main components of cartilage tissue; the cartilage tissue used in the test can be prepared, for example, according to the method of Ellis et al (Ellis, A.J. and others, BBRC, 201, 94, 1994). The degree of decomposition of proteoglycan can be determined by measuring the amount of glycosaminoglycan formed by the decomposition of proteoglycan, while the degree of decomposition of collagen can be determined by measuring the amount of hydroxyproline formed by the decomposition of collagen. (1) Preparation of cartilage tissue Cartilage samples were taken from bovine nasal septum according to the method of Ellis et al. (Ellis, AJ et al., BBRC, 201, 94, 1994), followed by immersion of these in medium. Leibovitz L-15 (Gibco BRL) cooled with ice, containing 500 g / ml of gentamicin and 100 g / ml of chloromycetin, to remove connective tissue and other tissues and obtain only cartilage. The following procedure was carried out on a clean work table. The resulting cartilage was sliced into sections with a thickness of 2 mm to prepare cartilage pieces (2 mm x 2 mm). After washing them twice with Hank's balanced salt solution (HBSS), the cartilage pieces were grown in a 24-well plate. In this case, 600 I of medium I [DMEM medium containing 25 mM HEPES, 0.05% BSA, 2 mM glutamine, 100 g / ml of streptomycin, 100 U / ml of penicillin and 2.5 Dg / ml of amphotericin] were added to each well. and three pieces of cartilage, and this was grown for 24 hours at 37 ° C. The resulting culture was used in the next test. (2) Proteoglycan Decomposition Inhibitory Action (a) Proteoglycan Decomposition Reaction The cartilage pieces obtained in (1) were cultured for 7 days at 37 ° C in 600 μl of medium I and in the presence of 1 μM retinoic acid. . In this case, dimethyl sulfoxide, or a solution in dimethyl sulfoxide of the test compound, was added simultaneously with the addition of retinoic acid to a volume of 1/1000 of the medium. After cultivation, the medium was collected and the amount of glycosaminoglycan in said medium measured as an indicator of the degree of decomposition of proteoglycan. (b) Measurement of glycosaminoglycan The measurement of glycosaminoglycan was performed according to the method of binding to the blue pigment of dimethylmethylene. Particularly, 250 μl of the reactive pigment (aqueous solution with 16 mg of 1, 9-dimethylmethylene blue, 3.04 g of glycine, 2.37 g of sodium chloride and 95 ml of 0.1 M hydrogen chloride in 1 liter, pH 3.0 was added. ) to 10 μl of the collected medium, followed immediately by the measurement of the optical absorbance at 525 nm to determine the amount of proteoglycan. In this case, chondroitin sulfate A (Sigma, 5 to 180 μg / ml, porcine rib cartilage) was used as the reference sample.

The proteoglycan decomposition inhibiting action of the test compound was determined from the ratio between the amount of proteoglycan in the group in which the test compound was added and the amount of proteoglycan in the group in which dimethyl sulfoxide was added. (3) Collagen decomposition inhibiting action (a) Collagen decomposition reaction The pieces of cartilage obtained in (1) were cultured for 7 days at 37 ° C in 600 μl of medium I and in the presence of 10 ng / ml of Interleukin 1a (IL-1a, Genzyme) and 50 ng / ml Oncostatin M (Genzyme). In this case, dimethyl sulfoxide, or a solution in dimethyl sulfoxide of the test compound, was added simultaneously with the addition of I L-1 a and Oncostatin M to a volume of 1/1000 of the medium. After the culture, the medium was collected and the culture was repeated three times under the same conditions (for a total of 4 weeks of culture). All the liquids collected from the culture were combined, and the amount of hydroxyproline in the combined culture liquid was measured as an indication of the degree of decomposition of collagen. (b) Measurement of hydroxyproline 100 μl of the culture liquid collected in (3) (a) above was transferred to a round bottom centrifuge tube and screw tip, followed by the addition of 100 μl of 12 N hydrochloric acid and by hydrolysis at 105 ° C for 16 hours (Heating Block HF-61, Yamato Science, Ltd.). 100 μl of this reaction liquid was then transferred to a disposable glass tube and dried with a centrifuge evaporator. 500 μl of a mixture of isopropanol and water (1: 1) was added to this disposable glass tube to dissolve the dried solid. In addition, 250 μl of Chloramine T reagent (consisting of a mixture of 0.141 g of Chloramine T (p-toluenesulfonylchloramine, Sigma), 2 ml of water, 3 ml of methyl cellosolve and acetate-citrate buffer was added (comprising acetate-citrate buffer solution an aqueous solution containing 7.5 g of citric acid monohydrate, 6 ml of glacial acetic acid and 60 g of sodium acetate trihydrate in 500 ml, pH 6.0], followed by stirring and allowing to stand at room temperature In addition, after adding 250 μl of 3.15 M perchloric acid, stirring and allowing to stand at room temperature for 5 minutes, 250 μl of 20% dimethylaminobenzaldehyde (Sigma) in methyl cellosolve solution was added.; it was stirred and allowed to react at 60 ° C for 20 minutes. Then, the reaction liquid was cooled to room temperature for 5 minutes and transferred to a microplate in a 200 DI portion, followed by measurement of the optical absorbance at 557 nm. Apart from the above, L-hydroxyproline (Sigma) was dissolved in a mixture of isopropanol-water (1: 1); 500 μl of the resulting solution was transferred to a disposable glass tube to prepare a standard curve (in this case, the solution was prepared in such a way that the amount of L-hydroxyproline in the tube was in the range of 0.05 μg to 2 μl. μg). 250 μl of the mentioned aforementioned Chloramine T reagent was added to this solution, after which the same procedure as above was developed to prepare the standard curve by measuring the optical absorbance at 557 nm. The inhibitory action of the collagen decomposition of the test compound was determined from the ratio between the amount of hydroxyproline in the group in which the test compound was added, and the amount of hydroxyproline in the group in which sulfoxide was added. of dimethyl. In this test, the compounds of the present invention showed excellent cartilage tissue breakdown inhibiting activity.

TEST EXAMPLE 4 MMP-13 Inhibition Test of Test Compound Orally Administered (Ex vivo) An inhibition test of MMP-13 was carried out according to the procedures described in test example 1 above, on a solution obtained by removing the protein from samples of blood extracted at fixed times after oral administration of the test compound. , as an indication of oral absorption capacity and hemodynamics. Particularly, the test compound was suspended in 0.5% tragacanth and the suspension was administered orally at 5 ml / kg to rats (Wister-lmamichi: 5 to 6 weeks of age) that had fasted overnight. Blood was drawn from the caudal vein in the presence of heparin at fixed times after administration (1, 2 or 4 hours). This blood was transferred to an Eppendorf tube and centrifuged at 12,000 rpm for 3 minutes. The plasma was transferred to a different tube, followed by the addition of an equal volume of acetonitrile and allowing to stand undisturbed for 10 minutes at 4 ° C. This was then centrifuged at 12,000 rpm for 3 minutes, followed by collection of the supernatant. This supernatant was concentrated and dried with a centrifuge evaporator, after which a small amount of dimethyl sulfoxide was added to dissolve. The activity of MMP-13 was then measured according to part (2) of test example 1 above in the presence of the resulting solution. The same procedure was developed on samples of blood drawn from the caudal vein of animals in which the drug was not administered, and this was used as a control. The inhibition rate was calculated from the MMP-13 activities of the control and drug administration groups. In this test, the compounds of the present invention showed excellent oral absorption and hemodynamic capacity.

EXAMPLE OF TEST 5 Test of inhibition of osteoarthritis (OA) of natural occurrence (in vivo) This test can be performed according to the method of Bendele et al. (Bendele, A.M. and Hulmán, J.F., Arthritis and Rheumatism, vol.31, 561-563, 1998). (1) Preparation of an OA model of natural occurrence and administration of the drug Six-week-old male guinea pigs purchased from Japan Charles River were given free access to water and feed, and two animals were bred in each cage. After continuing to raise the animals until 6 months of age, they were divided into three groups (of 6 animals each), in such a way that the average body weights of each group were almost equal. A group was immediately taken for euthanasia, followed by extirpation of the knee joints, which were then used for pathological study of tissue. One of the two remaining groups was designated as the drug administration group and the other as a control group. The animals of the control group were given solid laboratory diet ordinary for guinea pigs, while the animals of the drug administration group were given solid laboratory diet for guinea pigs with the test compound. The animals were reared under these conditions until 12 months of age. Afterwards, all the animals were sacrificed in euthanasia, the knee joints were excised and used for the pathological study of tissue. (2) Pathological study of tissue After removing the soft tissue, including the tendons of the patella and leaving the joint capsule, the left and right knee joints were immersed for 24 hours in a 10% formalin buffer. phosphate (PBS), followed by decalcification for 2 weeks using the Surgi Path Decalcifier (Surgi Path Medical Industries). The knee joints were divided into anterior and posterior portions and further decalcified for one or two days. After fixing the articulation tissue thus obtained in paraffin, thin sections were prepared for hematoxylin-eosin staining (6 μm thick) and toluidine staining (8 μm thick) of the joint tissue. Sections were also prepared every 150 to 200 Dm to allow observation of the entire surface of the joint (a total of 6 sections). The left and right joints of all the animals in each group were observed from the point of view of pathological tissues in a blind test, and an OA appearance score was assigned based on the following standards.

A score of 0 was given when changes were observed in the middle tibial patella and femoral condoyle in the absence of lesions. A score of 1 was given when disturbances, reductions or other small foci of chondrocytes were observed in the superficial layer of the joint cartilage and decreased staining with toluidine blue and separation of the superficial layer in the matrix was observed. A score of 2 was given when foci similar to "1" were also seen in the upper layer of the intermediate layer of cartilage. A score of 3 was given when the foci generally covered the surface layer of cartilage and had also spread to the lower layer of the intermediate layer. A score of 4 was given when definite perturbations (disappearance of chondrocytes and proteoglycan) had reached the deep layer, but not the maximum point. A score of 5 was given when the parturbations had covered all the cartilage and had reached the maximum point. For each group, the total score of the joints of the left and right knee was averaged, and the rate of inhibition for the drug administration group was calculated against the control group. In this test, the compounds of the present invention showed excellent inhibitory action of the appearance of OA. It should be noted that the inhibitory action on osteoarthritis can also be evaluated by preparing an animal model of arthritis according to the method of Colombo et al. (Colombo et al., Arthritis and Rheumatism, vol.26, No. 7 Qulio 1983), 875-886), administering the compound of the present invention to those animals, and performing an evaluation according to the method of Toshiyuki Kikuchi et al. (Toshiyuki Kikuchi et al., Osteoarthritis and Cartilage (1996) 4, 99-110).

INDUSTRIAL APPLICABILITY As the compounds of the present invention strongly inhibit both MMP-13 and aglicanase, they are useful as preventive or therapeutic agents for arthritis (and particularly osteoarthritis), and as drugs for inhibiting metastasis, invasion or development of cancer (and particularly cancer of the mom).

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the following formula (I), or a pharmaceutically acceptable salt, ester or other derivative thereof: wherein: R1 represents a hydroxyl group or a hydroxyamino group; R2 represents a hydrogen atom, a lower alkyl group, defined below, a lower alkyl group, defined below, substituted with at least one group selected from the group of substituents as defined below, a cycloalkyl group having 3 to 7 carbon atoms, or a group of the formula -A-R6, wherein A represents a lower alkylene group, defined below, or a lower alkylene group, defined below, interrupted by an oxygen atom, a group of formula -S (0) m- or a group of formula -N (R9) -; and R6 represents a group of the following formula (II), (III) or (IV): (III) (IV) (ll) wherein X represents an oxygen atom, a sulfur atom, a group of formula -N (R10) - or a group of formula -C (R1) (R12); Y represents an oxygen atom, a carbonyl group, a group of formula -S (0) n-, a group of formula -N (R10) - or a group of formula-C (R11) (R12); R7 and R8 can be the same or different and each represents a hydrogen atom, a lower alkyl group, defined below, a carboxyl group, a group selected from the group of substituents as defined below, a lower alkyl group, further defined forward, replaced by at least one group selected from the group of substituents as defined below, a lower alkoxy group, defined later, replaced by at least one group selected from the group of substituents to defined below, a lower alkylthio group, which is defined later, replaced by at least one group selected from the group of substituents as defined below, a lower alkylsulfinyl group, defined later, replaced by at least one group selected from the group of substituents as defined below, or a lower alkylsulfonyl group, defined below, substituted with at least one group selected from the group of substituents a defined below, or R7 and R8 may form, together with the atom or atoms carbon to which they are attached, a non-aromatic hydrocarbon ring, defined below, a non-aromatic heterocyclic ring, defined below, a non-aromatic hydrocarbon ring, defined below, substituted with at least one selected group of the group of substituents a defined below, and of the group of substituents β defined below, a non-aromatic heterocyclic ring, defined below, substituted with at least one group selected from the group of substituents to be defined below, and from the group of substituents ß defined below, an aryl ring, defined below, a heteroaryl ring, defined below, a ring of aryl, defined below, substituted by at least one group selected from the group of substituents a defined below and from the group of substituents β defined below, or a heteroaryl ring, defined below, substituted by at least one group selected from the group of substituents defined below and from the group of substituents β defined below; and R9, R10, R11 and R12 may be the same or different, and each represents a hydrogen atom or a lower alkyl group, which is defined below, and in addition R11 and R12 may form, together with the atom or atoms of carbon to which they are attached, a non-aromatic hydrocarbon ring, defined below, a non-aromatic heterocyclic ring, defined below, a non-aromatic hydrocarbon ring, defined below, substituted with at least one group selected from the group of substituents a defined below and of the group of substituents ß defined below, or a non-aromatic heterocyclic ring, defined below, substituted by at least one group selected from the group of substituents a defined below and from the group of substituents β defined further ahead; with the proviso that, when R7 and R8 are attached to the same carbon atom, R7 and R8 do not form, together with the carbon atom to which they are attached, an aryl ring, defined below, a heteroaryl ring, defined below, an aryl ring, defined below, substituted by at least one group selected from the group of substituents a defined below and from the group of substituents β defined below, nor a heteroaryl ring, further defined forward, substituted by at least one group selected from the group of substituents a defined below and from the group of substituents β defined below; and m and n can be the same or different and each represents 0, 1 or 2; R3 represents a hydrogen atom, a lower alkyl group, defined below, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group, defined below, an alkynyl group, defined below, a lower alkyl group, defined below, substituted by at least one group selected from the group of substituents a defined below, a cycloalkyl group having from 3 to 7 carbon atoms substituted with at least one group selected from the group of substituents as defined below and of the group of substituents β defined below, an alkenyl group, defined below, substituted with at least one group selected from the group of substituents a defined below, or an alkynyl group, defined below, substituted by at least one group selected from the group of substituents as defined below; R4 represents an arylene group, defined below, a heteroarylene group, defined below, an arylene group, defined below, substituted with at least one group selected from the group of substituents a defined below and from the group of substituents ß defined above below, or a heteroarylene group, defined below, substituted by at least one group selected from the group of substituents a defined below and from the group of substituents β defined below; and R5 represents a lower alkyl group, defined below, a lower alkyl group, defined below, substituted with at least one group selected from the group of substituents a defined below, an aryl group, defined below, a heteroaryl group, defined below, an aryl group, defined below, substituted by at least one group selected from the group of substituents a defined below and from the group of substituents β defined below, or a heteroaryl group, defined below, substituted by less with a group selected from the group of substituents a defined below and from the group of substituents β which is defined below; with the proviso that, when R2 represents a hydrogen atom, a lower alkyl group, defined below, a lower alkyl group, defined below, substituted with at least one group selected from the group of substituents as defined below, or a cycloalkyl group having from 3 to 7 carbon atoms, R3 represents an alkynyl group, defined below, or an alkynyl group, defined below, substituted with at least one group selected from the group of substituents a defined below; the group of substituents a consists of: halogen atoms, cycloalkyl groups having from 3 to 7 carbon atoms, lower alkoxy groups, defined below, lower halogenoalkoxy groups, defined below, lower alkanoyl groups, defined below, alkylthio groups lower, defined below, lower halogenoalkylthio groups, defined below, lower alkylsulfinyl groups, defined below, lower alkylsulfonyl groups, defined below, amino groups, lower monoalkylamino groups, defined below, di (lower alkyl) amino groups, defined below, cyano groups, nitro groups, aryl groups, defined below, heteroaryl groups, defined below, aryloxy groups, defined below, heteroaryloxy groups, defined below, arylthio groups, defined below, heteroarylthio groups, defined below. , aryl groups, defined below, substituted by at least one g rupo selected from the group of substituents? which is defined below, heteroaryl groups, defined below, substituted by at least one group selected from the group of substituents? defined below, aryloxy groups, defined below, substituted by at least one group selected from the group of substituents? defined below, heteroaryloxy groups, defined below, substituted with at least one group selected from the group of substituents? defined below, arylthio groups, defined below, substituted by at least one group selected from the group of substituents? which is defined below, and heteroarylthio groups, defined below, substituted by at least one group selected from the group of substituents? defined later; the group of substituents β consists of: lower alkyl groups, defined below and lower halogenoalkyl groups, defined below; and the group of substituents? consists of: halogen atoms, lower alkyl groups, defined below, lower halogenoalkyl groups, defined below, lower alkoxy groups, defined below, lower halogenoalkoxy groups, defined below, lower alkylthio groups, defined below, lower halogenoalkylthio groups , defined below, nitro groups and cyano groups; the lower alkyl group in the definition of R 2, R 3, R 5, R 7, R 8, R 9, R 10, R 11, R 12, the group of substituents β and the group of substituents α, and the lower alkyl portion of the lower alkyl group substituted by less with a group selected from the group of substituents a in the definition of R2, R3, R5, R7 and R8, is a straight or branched chain alkyl group having from 1 to 6 carbon atoms;e. the lower alkylene group in the definition of A is a straight or branched alkylene group having from 1 to 6 carbon atoms; the lower alkylene group interrupted by an oxygen atom, a group of the formula -S (0) m- or a group of the formula -N (R9) - in the definition of A, is a group in which said hydrogen atom is present. oxygen, group of formula S (0) m- or group of formula -N (R9) -, between two carbon atoms of the lower alkylene group defined above; the lower alkoxy group in the definition of the group of substituents a and the group of substituents,, and the lower alkoxy portion of the lower alkoxy group substituted with at least one group selected from the group of substituents a in the definition of R7 and R8, is a group in which an oxygen atom is attached to the lower alkyl group defined above; the lower alkylthio group in the definition of the group of substituents a and the group of substituents?, and the lower alkylthio portion of the lower alkylthio group substituted with at least one group selected from the group of substituents a in the definition of R7 and R8, is a group in which a sulfur atom is bonded to the lower alkyl group defined above; the lower alkylsulfinyl group in the definition of the substituent group a, and the lower alkylsulfinyl portion of the lower alkylsufinyl group substituted with at least one group selected from the group of substituents in the definition of R7 and R8, is a group in which it is attached a sulfinyl moiety (-SO-) to the lower alkyl group defined above; the lower alkylsulfonyl group in the definition of the substituent group a, and the lower alkylsulfonyl portion of the lower alkylsulfonyl group substituted with at least one group selected from the group of substituents a in the definition of R7 and R8, is a group in which a sulfonyl moiety (-S02-) attached to the lower alkyl group defined above; the non-aromatic hydrocarbon ring which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, the non-aromatic hydrocarbon ring portion of the non-aromatic hydrocarbon ring substituted with at least one group selected from group of substituents a and of the group of substituents β, which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, the non-aromatic hydrocarbon ring which is formed by R11 and R12 together with the atom or atoms of carbon to which they are attached, and the non-aromatic hydrocarbon ring portion of the non-aromatic hydrocarbon ring substituted with at least one group selected from the group of substituents a and the group of substituents β, which is formed by R11 and R12 together with the carbon atom or atoms to which they are attached, is a saturated or unsaturated hydrocarbon ring having from 3 to 7 carbon atoms; the non-aromatic heterocyclic ring which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, the non-aromatic heterocyclic ring portion of the non-aromatic heterocyclic ring substituted with at least one group selected from the group of substituents a and the group of substituents β, which is formed by R7 and R8 together with the atom or carbon atoms to which they are attached, the non-aromatic heterocyclic ring which is formed by R11 and R12 together with the carbon atom or atoms to which they are attached, and the non-aromatic heterocyclic ring portion of the non-aromatic heterocyclic ring substituted with at least one group selected from the group of substituents a and the group of substituents β, which is formed by R11 and R12 together with the atom or carbon atoms to which they are attached, is a saturated or partially saturated 5- to 7-membered heterocyclic ring containing from 1 to 3 ato sulfur, oxygen and / or nitrogen; the aryl ring which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, and the aryl ring portion of the aryl ring substituted by at least one group selected from the group of substituents a and group of substituents ß, which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, is an aromatic hydrocarbon ring having from 6 to 10 carbon atoms, said ring may optionally be fused with a cycloalkyl group having from 3 to 10 carbon atoms; the heteroaryl ring which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, and the heteroaryl ring portion of the heteroaryl ring substituted with at least one group selected from the group of substituents a and group of substituents ß, which is formed by R7 and R8 together with the carbon atom or atoms to which they are attached, is a 5-7 membered aromatic heterocyclic ring containing from 1 to 3 sulfur, oxygen and / or or nitrogen; said ring may optionally be fused with another cyclic group; the alkenyl group and the alkenyl portion of the alkenyl group substituted by at least one group selected from the group of substituents a in the definition of R3, is a straight or branched alkenyl group having from 3 to 10 carbon atoms; the alkynyl group and the alkynyl portion of the alkynyl group substituted with at least one group selected from the group of substituents a in the definition of R3, is a straight or branched alkynyl group having from 3 to 10 carbon atoms; the arylene group and the arylene portion of the arylene group substituted with at least one group selected from the group of substituents a and the group of substituents β in the definition of R4 is a divalent aromatic hydrocarbon ring having from 6 to 10 carbon atoms; said group may optionally be fused with a cycloalkyl group having from 3 to 10 carbon atoms; the heteroarylene group and the heteroarylene portion of the heteroarylene group substituted with at least one group selected from the group of substituents β and the group of substituents a in the definition of R 4 is a divalent aromatic heterocyclic ring of 5 to 7 members containing 1 to 3 atoms of sulfur, oxygen and / or nitrogen; said group may optionally be fused with another cyclic group; the aryl group in the definition of R5 and the group of substituents a, the aryl portion of the aryl group substituted with at least one group selected from the group of substituents a and the group of substituents ß in the definition of R5, and the aryl portion of the aryl group substituted with at least one group selected from the group of substituents? in the definition of the group of substituents a, is a monovalent aromatic hydrocarbon ring having from 6 to 10 carbon atoms; said group may optionally be fused with a cycloalkyl group having from 3 to 10 carbon atoms; the heteroaryl group in the definition of R 5 and the group of substituents a, the heteroaryl portion of the heteroaryl group substituted with at least one group selected from the group of substituents a and the group of substituents β in the definition of R 5, and the heteroaryl portion of the heteroaryl group substituted with at least one group selected from the group of substituents? in the definition of the group of substituents a, is a 5-7 membered monovalent aromatic heterocyclic group containing from 1 to 3 sulfur, oxygen and / or nitrogen atoms; said group may optionally be fused with another cyclic group; the lower halogenoalkoxy group in the definition of the group of substituents a and of the substituent group α, is a group in which a lower halogenoalkyl group, defined below, is bonded to an oxygen atom; the lower alkanoyl group in the definition of the substituent group is a formyl group or a group in which a carbonyl group is attached to the lower alkyl group defined above; the lower halogenoalkylthio group in the definition of the substituent group a and the substituent group α, represents a group in which a lower halogenoalkyl group, defined below, is attached to a sulfur atom; the lower monoalkylamino group in the definition of the group of substituents a is a group in which a hydrogen atom of a group -NH2 is substituted with the lower alkyl group defined above; the di (lower alkyl) amino group in the definition of the group of substituents a, is a group in which the two hydrogen atoms of a group -NH2 are substituted with the lower alkyl group defined above, the two alkyl groups being the same or different; the aryloxy group and the aryloxy portion of the aryloxy group substituted by at least one group selected from the group of substituents? in the definition of the group of substituents a, is a group in which the aryl group, defined above, is linked to an oxygen atom; the heteroaryloxy group and the heteroaryloxy portion of the heteroaryloxy group substituted with at least one group selected from the group of substituents? in the definition of the group of substituents a, is a group in which the heteroaryl group, defined above, is bonded to an oxygen atom; the arylthio group and the arylthio portion of the arylthio group substituted with at least one group selected from the group of substituents? in the definition of the group of substituents a, is a group in which the aryl group, defined above, is attached to a sulfur atom; the heteroarylthio group and the heteroarylthio portion of the heteroarylthio group substituted with at least one group selected from the group of substituents? in the definition of the group of substituents a, is a group in which the heteroaryl group, defined above, is attached to a sulfur atom; and the lower halogenoalkyl group in the definition of the group of substituents β and the group of substituents α, is a group in which a lower alkyl group, defined above, is substituted by at least one halogen atom.

2. The compound according to claim 1, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R1 is a hydroxyamino group.

3. The compound according to claim 1 or 2, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R2 is an alkyl group having from 1 to 4 carbon atoms or an alkyl group having from 1 to 4 carbon atoms substituted with at least one group selected from the group of substituents defined in claim 1.

4. The compound according to claim 1 or 2, or a salt, ester or other derivative pharmacologically acceptable thereof, further characterized in that R 2 is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with at least one group selected from the group of substituents a 1; said group of substituents a1 consists of: halogen atoms, cycloalkyl groups having from 3 to 7 carbon atoms, amino groups, cyano groups and lower alkoxy groups, lower alkylthio groups, lower monoalkylamino groups, di (lower alkyl) amino groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups and heteroarylthio groups, all of them as defined in claim 1.

5. The compound according to claim 1 or 2, or a salt, ester or other derivative pharmacologically acceptable thereof, further characterized in that R2 is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with at least one group selected from the group of substituents a2; said group of a2 substituents consists of: lower alkoxy groups, lower alkylthio groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups and heteroarylthio groups, all of them as defined in claim 1.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester or other derivative thereof, further characterized in that R2 is a methyl, ethyl, propyl, isopropyl, 2-methoxyethyl, 2-methylthiophenyl, 3,3,3-trifluoropropyl, benzyl, 2-phenylethyl, benzyloxymethyl, benzylthiomethyl or 2-thienylthiomethyl group.

7. The compound according to any of claims 1 to 6, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that A is an alkylene group having from 1 to 4 carbon atoms, or a lower alkylene group interrupted by an oxygen atom or -S (0) m-.

8. The compound according to any of claims 1 to 6, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that A is a methylene, ethylene, 1, 1-dimethylethylene, trimethylene, tetramethylene group, -CH20 (CH2) 2- or - CH2S (CH2) 2-.

9. The compound according to any of claims 1 to 6, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that A is a methylene, ethylene or trimethylene group.

10. The compound according to any of claims 1 to 9, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R6 is: 58 xA H CH,

11. The compound according to any of claims 1 to 10, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R3 is a hydrogen atom, a cycloalkyl group having from 3 to 7 carbon atoms, a lower alkyl group, an alkenyl group, an alkynyl group, a lower alkyl group substituted with an aryl group, a lower alkyl group substituted with a heteroaryl group, an alkenyl group substituted with an aryl group, an alkenyl group substituted with a heteroaryl group , an alkynyl group substituted with an aryl group, or an alkynyl group substituted with a heteroaryl group, all of them as defined in claim 1; said aryl and heteroaryl portions of the above groups are optionally substituted with at least one group selected from the group of substituents a and the group of substituents defined in claim 1.

12. The compound according to claim 11, or a salt , ester or other pharmacologically acceptable derivative thereof, further characterized in that R3 is a cycloalkyl group having from 3 to 7 carbon atoms, an alkyl group as defined in claim 1, an alkenyl group as defined in claim 1, an alkynyl group as defined in claim 1, an alkyl group having from 1 to 3 carbon atoms substituted with an aryl group, an alkyl group having from 1 to 3 carbon atoms substituted with a heteroaryl group as defined in claim 1, an alkenyl group having 3 carbon atoms substituted with an aryl group as defined in claim 1, an alkenyl group having 3 carbon atoms substituted with a heteroaryl group as defined in claim 1, an alkynyl group having 3 carbon atoms substituted with an aryl group as defined in claim 1, or an alkynyl group having 3 carbon atoms. carbon substituted with a heteroaryl group as defined in claim 1.

13. The compound according to claim 12, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R3 is a methyl, ethyl group, propyl, cyclopropyl, allyl, 2-butenyl, propargyl, 2-butynyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3- (4-chlorophenyl) propyl, 3-phenyl propargyl or 3- (4-chlorophenyl) propargyl.

14. The compound according to any of claims 1 to 13, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R4 is a phenylene, naphthylene or thienylene group.

15. The compound according to any of claims 1 to 13, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R4 is a p-phenylene group.

16. The compound according to any of claims 1 to 15, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R5 is an alkyl group as defined in claim 1, a halogenoalkyl group having 1 to 4 carbon atoms, an aryl group as defined in claim 1, a heteroaryl group as defined in claim 1, an aryl group substituted with at least one group selected from the group of substituents a and the group of defined β substituents in claim 1, or a heteroaryl group substituted with at least one group selected from the group of substituents a and the group of substituents defined in claim 1.

17. The compound according to any of claims 1 to 15, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R5 is a methyl, ethyl, propyl, butyl, trifluorom group ethyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-pyridyl, 4-pyridyl, 2-thienyl or -thienyl

18. The compound according to any of claims 1 to 17, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R7 and R8 can be the same or different and each represents a hydrogen atom, a nitro group, an amino group, a cyano group, a carboxyl group, a halogen atom, a lower monoalkylamino group, a di (lower alkyl) amino group, an aryl group, a heteroaryl group, a lower alkyl group, a group lower alkanoyl, a lower alkyl group substituted by at least one group selected from the group of substituents a, a lower alkoxy group substituted by at least one group selected from the group of substituents a, a lower alkylthio group substituted by at least one group selected from the group of substituents a, a lower alkylsulfinyl group substituted by at least one group selected from the group of substituents a, or a lower alkylsulphonyl group substituted with at least one group selected from the group of substituents a, all of them as defined in claim 1, or R7 and R8 form, together with the carbon atom or atoms to which they are attached, a hydrocarbon ring not aromatic, a non-aromatic heterocyclic ring, a non-aromatic hydrocarbon ring substituted with at least one group selected from the group of substituents and the group of substituents β, a non-aromatic heterocyclic ring substituted with at least one group selected from the group of substituents and of the group of substituents β, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from the group of substituents a and the group of substituents β, or a heteroaryl ring substituted at least a group selected from the group of substituents a and the group of substituents β, all of them as defined in claim 1.

19. The compound of according to any of claims 1 to 17, or a salt, ester or other pharmacologically acceptable derivative thereof, further characterized in that R7 and R8 may be the same or different and each represents a hydrogen atom, a nitro group, a group cyano, a carboxyl group, a halogen atom, an aryl group, a heteroaryl group, a lower alkyl group, a lower alkanoyl group or a lower alkyl group substituted with at least one group selected from the group of substituents a, all of them according to is defined in claim 1, or R7 and R8 form, together with the carbon atom or atoms to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocyclic ring, a non-aromatic hydrocarbon ring substituted at less with a group selected from the group of substituents a and the group of substituents β, a non-aromatic heterocyclic ring substituted by at least one selected group of the group of substituents a and of the group of substituents β, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from the group of substituents a and the group of substituents β, or a substituted heteroaryl ring at least one group selected from the group of substituents a and the group of substituents ß, all of them as defined in claim 1.

20. The compound according to claim 1, further characterized in that it is selected from the following compounds: (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- (2-phthalimido-ethyl) glycinamide, (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (thiazolidin-2,4-dione-3-yl) ethyl] glycinamide, (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (quinazolin -2,4-dione-3-yl) ethyl] glycinamide, (±) -2- [2- (5-fluoropyrimidin-2, 4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide, (+) - N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) - 2- [2- (Thieno [3,2-d] pyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (+) - N-hydroxy-Na-methyl-2- [2- (7- methylxanthin-1-yl) ethyl] -Na- (4-phenoxy-benzenesulfonyl) glycinamide, (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2-pteridin- 2,4-dione-3-yl) ethyl] glycinamide, (±) -2- [2- (1,1-dioxo-1,2-benzoisothiazol-3-one-2-yl) ethyl] -N-hydroxy -Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide, (±) -N-hydroxy-Na-methyl-2- [2- (6-methylpyrimidin-2,4-dione-3-yl) etl] -Na- (4-phenoxybenzenesulfonyl) glycinamide, (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (5-trifluoro-methyl-pyrimidine-2,4-dione- 3-l) etl] glycinamide, N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2 (R) - (2-phthalimidoethyl) glycinamide, (±) -Na- [4- (4-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- (2-phthalimidoethyl) glycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl ] -N-hydroxy-Na-methyl- Na- (4-phenoxybenzenesulfonyl) glycinamide, (±) -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) -2- [2- (6-trifluoromethylpyrimidin-2,4-dione -3-yl) ethyl] glycinamide, (±) -N-hydroxy-Na-methyl-Na- [4- (pyridin-4-yl) oxybenzenesulfonyl] -2- [2-t-ene- [3,2- d] pyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (±) -2- [2- (6-chloro-1-methylpyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide, (+) - Na- [4- (4-chlorophenoxy) benzenesulfonyl] -2- [2- (6-chloropyrimidine-2,4-dione -3-yl) ethyl] -N-hydroxy-Na-methylglycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl-Na- [4 - (4-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methylglycinamide, (+) - Na - [4- (4-chlorophenoxy) benzenesulfonyl] - N-hydroxyl-Na-methyl-2- [2 - (6-trifluoromethylpyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (±) -Na- [4- (4-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (6-Trifluoromethylpyrimidin-2,4-dione-3-yl) etl] glycinamide, (±) -Na- [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2 - [2- (6-trifluoromethylpyrim idín-2,4-dione-3-yl) ethyl] glycinamide, (±) -Na- [4- (3-chlorophenoxy) benzenesulfonyl] -2- [2- (6-chloropyrimidin-2,4 -dione-3-yl) ethyl] -N-hydroxy-Na-methylglycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -Na-ethyl -N-hydroxy-Na- (4-phenoxybenzenesulfonyl) glycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -Na- [4- (3-fluorophenoxy ) -benzenesulfonyl] -N-hydroxy-Na-methylglycinamide, (±) -2- [2- (6-chloropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-Na-methyl- Na- [4- (pyridin-4-yl) oxybenzenesulfonyl] glycinamide, (±) -Na- [4- (3-fluorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (6-trifluoromethylpyrimidine -2,4-dione-3-yl) ethyl] glycinamide, (±) -N-hydroxy-Na-methyl-Na- [4- (pyridin-4-yl) oxybenzenesulfonyl] -2- [2- (6- trifluoromethylpyrimidin-2,4-dione-3-yl) ethyl] glycinamide, (±) -Na-ethyl-N-hydroxy-Na- (4-phenoxybenzenesulfonyl) -2- [2- (6-trifluoromethyl-pyrimidine- 2,4-dione-3-yl) ethyl] glycinamide, (±) -N-hydroxy-Na-methyl-2- [2- (1-methyl-6-trifluoromethyl-2,4-di-trifluoromethyl) ona-3-yl) ethyl] -Na- (4-phenoxybenzene) osulfonyl) glycinamide, (±) -2- [2- (5-chloropyrimidin-2,4-dione-3-yl) ethyl] -N-hydroxy-N -methyl-Na- (4-phenoxybenzenesulfonyl) glycinamide, Na- [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2-quinazolin-2,4-dione-3-yl) ethyl] glycinamide, Na- [4- ( 3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-Na-methyl-2- [2- (thieno [3,2-d] pyrimidin-2,4-dione-3-yl) ethyl] glycolimide , and Na- [4- (3-chlorophenoxy) benzenesulfonyl] -N-hydroxy-N-methyl-2- (2-phthalimidoethyl) glycinamide, or a pharmaceutically acceptable salt, ester or other derivative thereof.

21. A medicament that contains as an active ingredient the compound claimed in any of claims 1 to 20, or a salt, ester or other pharmacologically acceptable derivative thereof.

22. The compound according to any of claims 1 to 20, or a salt, ester or other pharmacologically acceptable derivative thereof, for use as a medicament.

23. The use of the compound according to any of claims 1 to 20, or a salt, ester or other pharmacologically acceptable derivative thereof, for the manufacture of a medicament for the prevention or treatment of arthritis.

24. The use of the compound according to any of claims 1 to 20, or a salt, ester or other pharmacologically acceptable derivative thereof, for the manufacture of a medicament for the prevention or treatment of osteoarthritis. The use of the compound according to any of claims 1 to 20, or a salt, ester or other pharmacologically acceptable derivative thereof, for the manufacture of a medicament for the inhibition of metastasis, invasion or development of cancer. SUMMARY OF THE INVENTION The present invention provides a compound of the following formula (I): wherein R1 is H, NHOR; R2 is H, optionally substituted alkyl, cycloalkyl, a group -AR6 - wherein A is an alkylene which may be optionally interrupted with O, -S (0) m- or -N (R9); R6 is a group (II), (III) or (IV) (ll) (lll) (IV) X is O, S, -N (R10) -. -C (R11) (R12) -; Y is O, CO, -S (0) "-, -N (R10) -, -C (R11) (R12) -; R7 and R8 are H, alkyl, COOH, optionally substituted alkyl, etc .; R9, R0, R11 and R12 are H, alkyl, etc .; m and n are 0 to 2; R3 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl; R 4 is (hetero) arylene optionally substituted; R5 is optionally substituted alkyl, optionally substituted (hetero) aryl; or a salt, ester and other pharmacologically acceptable derivative thereof; said compound has matrix metalloproteinase 13 inhibitory activity and aglyngase inhibitory activity. CR / cgt * P00-1278F LIST OF SEQUENCES < 110 > SankyoCo., Ltd. < 120 > Sulfonamide Derivatives < 130 > FP-9904 < 140 > < 141 > < 150 > JPHEI 10-91819 < 151 > 1998-04-03 < 150 > JPHEI 11-53164 < 151 > 1999-03-01 < 160 > 2 < 170 > PatentlnVer.2.0 < 21O > 1 < 211 > 33 < 212 > DNA < 213 > Artificial sequence < 220 > < 223 > Description of the artificial sequence: PCR primer to amplify a cDNA encoding human pro-MMP13 < 400 > 1 gctgagctca tgcatccagg ggtcctggct gcc 33 < 210 > 2 < 211 > 32 < 212 > DNA < 213 > Artificial sequence < 220 > < 223 > Description of the artificial sequence: PCR primer to amplify a cDNA encoding human pro-MMP13 < 400 > 2 cgaggtacca ttaccccaaa tgctcttcag ga 32