DESCRIPTION CARBAPENEM COMPOUNDS, THEIR PRODUCTION AND USE

TECHNICAL FIELD This invention relates to a novel carbapenem compound having excellent antibacterial activities and administrable not only parenterally but also orally, a method of producing the compound and an antibacterial agent. BACKGROUND ART

There have been a number of reports on carbapenem compounds, one of the typical compounds being thienamycin. While thienamycin has excellent antibacterial activities, as it is unstable to dehydropeptidase-I (DHP-I), which is a decomposing enzyme existing in a living body, it has not been practically used in the clinical field. Imipenem, which is an analogous compound to thienamycin, has been known to display clinical effects by using combinedly with cilastatin, an inhibitor of DHP-I. A number of research works have then been conducted, and it has been cleared that introduction of methyl group into lβ- position and introduction of 3-pyrrolidinylthio group into 2-position give a carbapenem compound improved both in the antibacterial activities and DHP-I stability [JPA S60 (1985)-233076 and JPA H5(1993)- 4988].

However, on the compound having an optionally hydrogenated oxazine or thiazine cyclic group bonded at 2-position of carbapenem through sulfur atom, very few study reports have been known. Only in JPA S57(1982)- 158784, there is disclosed a carbapenem compound represented by the formula:

wherein R stands for hydrogen atom or -CR ⁴ R ⁵ R ⁶ group (wherein R stands for H, hydroxyl group or a protected hydroxyl group; R and R ⁶ stand for H, alkyl group, alkenyl group, alkynyl group, aralkyl group or aryl group; or R and R form, taken together with the adjacent carbon atom, a ring) ; R stands for H or carboxyl-protective group; R stands for H, alkyl group, alkenyl group, alkynyl, aralkyl group, aryl group or -S0 ₂ R group (wherein R stands for hydroxyl group, alkyl group, alkenyl group alkynyl group, aralkyl group or aryl group) ; Z stands for 0, S or - N(R )- group (wherein R is of the same meaning as R ) ; m denotes 0 or 1; n denotes 0, 1, 2 or 3, and salts thereof, and, on such carbapenem compounds as having, at the side chain of 2-position, a condensed heterocyclic group formed by σxazine or thiazine ring and a heterocyclic ring, there has been no report at all.

While so far known carbapenem compounds show, in general, excellent antibacterial activities against gram-positive and gram-negative bacteria, the antibacterial activities are insufficient and the physico-chemical properties or the stability in a living body, especially the stability to renal dehydropeptidase-1 (DHP-1), are unsatisfactory.

Circumstances being such as above, carbapenem compounds of high safety, having excellent antibacterial activities and showing excellent stable behaviors in a living body and being, depending on cases, administrable orally, have been ardently desired.

DISCLOSURE OF INVENTION As a result of extensive studies diligently conducted, the present inventors synthesized, for the first time, a compound whose characteristic feature lies in that an optionally substituted and optionally hydrogenated condensed oxazine or thiazine ring group is bonded to 2-position of the carbapenem skeleton by the aid of a group bonded through sulfur atom, and found unexpectedly that the compound, based on this specific chemical structure, shows excellent antibacterial activities against a broad range of pathogenic bacteria from gram-positive bacteria to gram-negative bacteria including Pseudomonas aeruginosa, and shows chemical stability and stability in a living body, especially to DHP-I, and shows, depending on cases, excellent oral absorbability. Based on these findings, the present invention have been accomplished.

More specifically, the present invention relates to

(1) a carbapenem compound of the formula:

wherein R is an optionally substituted lower alkyl group, R is hydrogen or a lower alkyl group, Y is a bond or an optionally substituted lower alkylene group, and R is an optionally hydrogenated condensed oxazine or thiazine ring group, which may optionally be substituted, or its ester, or salt thereof, (2) a method of producing the compound described in (1) above, which comprises reacting a compound of the formula:

wherein L is a leaving group, and other symbols are of the same meaning as defined above, or its ester, or a salt thereof with a compound represented by the formula: H-S-Y-R wherein symbols are of the same meaning as defined above, or a salt thereof, and

(3) a pharmaceutical composition which comprises an effective amount of the compound described in (1) above.

The compound (I) of this invention shows excellent antibacterial activities against a broad spectrum of pathogenic bacteria ranging from gram-positive to gram- negative ones. Besides, it is excellent in chemical stability and the stability to DHP-1, and it shows antibacterial activities by injection or oral administration.

In the above-mentioned formulae, as lower alkyl group of the optionally substituted lower alkyl group shown by R , use is made of, for example, straight- chain or branched C^ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl and isobutyl) . Examples of the substituents include cyano group, amino group, mono- or di- Cχ. ₄ alkylamino group (e.g. methylamino and dimethylamino) , hydroxyl group, C _w alkyloxy group (e.g. methoxy and ethoxy) , carbamoyloxy group, C _U4 alkylthio group (methylthio and ethylthio), Cι_ ₄ alkyl¬ sulfonyl group (e.g. methylsulfonyl and ethylsulfonyl), halogen (e.g. fluorine, chlorine and bromine), sulfamoyl group and C ₄ alkoxy-carbonyl group (e.g. ethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and

butoxycarbonyl) . Number of these substituents ranges preferably from 1 to 3, and, when the number of these substituents is 2 or more, they may be the same as or different from one another. In the case where the lower alkyl group is substituted with amino group or hydroxyl group, these substituents may optionally be protected with a readily removable protective group, preferably exemplified by a silyl group such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl, allyloxycarbonyl, t- butoxycarbonyl, benzyloxycarbonyl or p- nitrobenzyloxycarbonyl.

More preferable examples of R include groups representable by the formula:

R ³

CH

3 wherein R stands for H, halogen, or, respectively optionally substituted hydroxyl group or amino group. As substituents of the hydroxyl group or amino group shown by R , use is made of, for example, removable protective groups mentioned as above. More preferable examples of R include hydroxyl group. Especially preferable examples of R ¹ include (IR)-hydroxyethyl group.

When carboxyl group exists at 3-position of carbapenem or exists in any other substituents, they may optionally be esterified. The esterified carboxyl group is shown by COOR . As the ester residual group of carboxyl group, i.e. R , mention is made of such ester residual groups as used in the field of β-lactam antibiotics such as cephalosporin, more specifically, ester residual groups usually employed as the group forming readily removable ester (ester convertible to so-called prodrug) at 4-position of the cephalosporin skeleton and groups commonly used as ester residual

groups of carboxylic acid in the field of pharmaceuticals. Practically, use is made of respectively optionally substituted C ₇ alkyl groups, C ₂ _ ₆ alkenyl groups, C ₆ _ι ₀ aryl groups or C ₇ . ₂₀ aralkyl group. As such respectively optionally substituted C ₇ alkyl groups, use is made of, for example, methyl, ethyl, propyl, isopropyl, butyl and t-butyl, as C ₂ _ ₆ alkenyl groups, use is made of, for example, vinyl, aryl and crotyl, as C ₆ . ₁₀ aryl groups, use is made of, for example, phenyl and naphthyl, and as C ₇ . ₂₀ aralkyl groups, use is made of, for example, benzyl, phenethyl, benzhydryl and trityl.

Further, as R*, use is advantageously made of, for example, groups represented by the formula:

wherein R ⁵ stands for H or respectively optionally substituted alkyl groups or C ₃ . ₆ cycloalkyl groups, R stands for respectively optionally substituted C _J . _JQ alkyl groups, C ₃ _ ₁₀ cycloalkyl groups, alkyloxy groups, C ₃ _ ₁₀ cycloalkyloxy groups, C ₃ _ ₁₀ cycloalkyl C _1-6 alkyl groups, C ₃ _ ₎₀ cycloalkyl, Cι_ ₆ alkyloxy groups, C ₂ . ₆ alkenyl groups, C ₆ . ₁₀ aryl groups or C ₇ . ₁₂ aralkyl groups. In the above formula, as the Cχ_ ₆ alkyl groups shown by R , use is made of, for example, methyl, ethyl, propyl, isopropyl, butyl and 2,2-dimethylpropyl, and, as the C ₃ . ₆ cycloalkyl groups, use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As alkyl groups of the C ₁ _ ₁₀ alkyl groups and Cu _o alkyloxy groups shown by R , use is made of, for example, methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, pentyl, 2,2- dimethylpropyl, hexyl, heptyl and decyl; as cycloalkyl

groups of the C ₃ . ₁₀ cycloalkyl groups, C ₃ . ₁₀ cycloalkyloxy groups, C ₃ . ₁₀ cycloalkyl C^ alkyl groups and C ₃ . ₁₀ cycloalkyl C _j .β alkyloxy groups, use is made of, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl; and, as C^g alkyl groups of the C ₃ . ₁₀ cycloalkyl C^ alkyl groups and C ₃ . ₁₀ cycloalkyl C^ alkyloxy groups, use is made of, for example, methyl, ethyl, propyl, butyl, pentyl and hexyl. As C ₂ . ₆ alkenyl groups, use is made of, for example, vinyl, allyl and crotyl; as C ₆ . ₁₀ aryl groups, use is made of, for example, phenyl and naphthyl; and, as C ₇ _ ₁₂ aralkyl groups, use is made of, for example benzyl and phenethyl.

As substituents in the respectively optionally substituted Cj_ ₇ alkyl groups, C ₂ . ₆ alkenyl groups, C ₆ . ₁₀ aryl groups or C ₇ . ₂₀ aralkyl groups shown by R , in the respectively optionally substituted C^g alkyl groups or ₃ - ₆ cycloalkyl groups shown by R , and in the respectively optionally substituted alkyl group, C ₃ . ₁₀ cycloalkyl group, C^o alkyloxy groups, C ₃ . ₁₀ cycloalkyloxy groups, C ₃ . ₁₀ cycloalkyl C _j .β alkyl groups, ^c ₃ -ιo cycloalkyl C ₆ alkyloxy groups, C ₂ . ₆ alkenyl group, Cβ-io aryl groups or C ₇ . ₁₂ aralkyl groups shown by R , mention is made of, for example, cyano group, nitro group, hydroxyl group, C^ alkyloxy groups (e.g. methoxy, ethoxy and propoxy) , carba oyloxy group, C^ alkylthio groups (e.g. methylthio) and halogen (e.g. fluorine, chlorine and bromine) . Number of such substituents as above ranges preferably from 1 to 3, and when the number is 2 or more, they may be the same as or different from one another.

Especially preferable ester residual groups shown by R include groups often used in the process of preparing pharmaceuticals [e.g. methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group,

tertiary butyl group, 2,2,2-trichloroethyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, o-nitrobenzyl group, phenethyl group, bis(methoxyphenyl)methyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, benzhydryl group, trityl group, trimethylsilyl group, 2-trimethylsilylethyl group or allyl group], or groups giving readily removable ester derivatives in a living body suitable for oral administration [e.g. acetoxymethyl group, 1- acetoxyethyl group, 1-acetoxypropyl group, pivaloyloxyraethyl group, isopropyloxycarbonyloxymethyl group, l-(isopropyloxycarbonyloxy)ethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy)ethyl group, ethoxycarbonyloxymethyl group, 1-

(ethoxycarbonyloxy)ethyl group, phthalidyl group and (2-oxo-5-methyl-l,3-dioxol-4-yl)methyl group] .

As R of the above formulae, use is made of H or a lower alkyl group. As the lower alkyl group, use is preferably made of, for example, Cj_ alkyl groups.

Examples of the Cχ. ₃ alkyl groups include methyl, ethyl, propyl or isopropyl, especially methyl being preferable.

As Y in the above formulae, use is made of a bond or an optionally substituted lower alkylene group. As the lower alkylene group, use is preferably made of C,.-, alkylene groups. As such C^ alkylene groups, mention is made of, for example, methylene, ethylene and propylene. As the substituent in the lower alkylene group, mention is made of, for example, halogen (e.g. fluorine, chlorine and bromine) , hydroxy group, C^ alkyloxy groups (e.g. methoxy and ethoxy), amino group, and mono- or di-C^ alkylamino groups (e.g. dimethylamino) . Number of such substituents is preferably 1 or 2. More preferable example of Y is a bond.

The R in the above formula is an optionally hydrogenated condensed oxazine or thiazine ring group, which may optionally have substituents. The R is preferably exemplified by a group represented by the formula:

wherein Q stands for 0 or S, ring A is optionally hydrogenated oxazine or thiazine ring, which may optionally have substituents, and ring B stands for an optionally substituted heterocyclic ring, which may optionally be oniumized. Preferable examples of ring A include dihydro-1,3- oxazine, perhydro-1,3-oxazine, dihydro-l,3-thiazine or perhydro-1,3-thiazine.

Preferable examples of the heterocyclic ring shown by ring B include 5- to 6-membered N-containing heterocyclic ring containing 1 to 4 hetero-atoms such as N, 0 and S, which is preferably condensed with the linkage bonding 2-position to 3-position of ring A. Examples of the 5-membered N-containing heterocyclic ring shown by ring B include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, variously condensed thiadiazole, variously condensed oxadiazole and their structurally possible hydrogenated groups. And, examples of the 6-membered N-containing heterocyclic group include pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, variously condensed oxazine, variously condensed thiazine, variously condensed oxadiazine, variously condensed thiadiazine and their structually possible hydrogenated groups. Preferable examples of ring B include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole and

tetrazole.

The condensed heterocyclic group form by ring A and ring B may optionally be oniumized by quaternizing the nitrogen atom therein. The oniumized condensed heterocyclic group includes groups in the following cases, namely, the case where cationic charge is localized at the bridge-head nitrogen atom of the condensed heterocyclic group, non-localized at the whole ring A, non-localized at the whole ring B or non- localized at the whole heterocyclic group formed by ring A and ring B, as shown by the following formulae:

In the case of /. is oniumized:

The condensed heterocyclic ring formed by ring A and ring B may optionally have, other than the substituent Y, substituents on a ring-forming carbon atom and substituents on a ring-forming nitrogen atom. Examples of substituents on ring A include C_ ₆ alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), C ₂ . _fl alkenyl groups (e.g. vinyl, allyl and crotyl), C ₂ . ₆ alkynyl groups (e.g. 2-propinyl), C ₆ . ₁₀ aryl groups (e.g. phenyl, tolyl and naphthyl), C ₇ . ₁₃ aralkyl groups (e.g. benzyl), 5- to 6-membered nitrogen-containing heterocyclic groups each containing 1 to 4 hetero-atoms such as N, 0 and S (e.g. 2-pyridyl). These substituents may optionally be further substituted with 1 to 3 substituents exemplified by halogen (e.g. fluorine, chlorine and bromine), hydroxy group, C ₆ alkyloxy groups (e.g. methoxy and ethoxy), amino group, mono- or di-C^ alkylamino groups (e.g. methylamino and dimethylamino) , and 5- to 6-membered N-containing

heterocyclic groups containing 1 to 4 hetero-atoms such, as N, 0 and S. Examples of substituents on ring B include, in addition to the same ones as those on ring A, hydroxyl group, amino group, mono- or di-C^g alkylamino groups (e.g. methylamino and dimethylamino) , mercapto group, C^e alkyloxy groups (e.g. methoxy and ethoxy), C _y . ₆ alkylthio groups (e.g. methylthio and ethylthio), carbamoyl group, mono- or di-Cj_ ₆ alkyl carbamoyl groups (e.g. methyl carbamoyl and dimethyl carbamoyl), carbamoyloxy group and cyano group. The ring B may have 1 to 3 substituents. The optionally hydrogenated condensed oxazine or thiazine cyclic groups shown by R may optionally be further substituted with 1 to 4 substituents exemplified above as those on ring B. When the number of those substituents is two or more, those substituents may optionally be the same as or different from one another.

The most preferable examples of R are 6,7-dihydro- 5H-imidazo[2,1-b] [1,3]thiazin-6-yl, 6,7-dihydro-5H- l,2,3-triazolo[5,l-b] [1,3]thiazin-6-yl and 2-amino-6,7- dihydro-5H-l,2,4-triazolo[5,1-b] [1,3]thiazin-6-yl.

As salts of the compounds represented by the above formulae or their esters, use is preferably made of pharmacologically or synthetically acceptable ones. As such salts, use is made of, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acid amino acid. As inorganic bases capable of producing these salts, use is made of, for example, alkali metals (e.g. sodium and potassium) and alkaline earth metals (e.g. calcium and magnesium); as organic bases, use is made of, for example, trimethylamine, triethylamine, pyridine, picoline, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, tris(hydroxymethylamino)methane and dicyclohexylamine; as inorganic acids, use is made of,

for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; as organic acids, use is made of, for example, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzensulfonic acid and p-toluenesulfonic acid; and as basic or acid amino acid, use is made of, for example, arginine, lysine, ornithine, aspartic acid and glutamic acid. Among these salts, salts with bases (i.e. salts with inorganic bases, salts with organic bases and salts with basic amino acids) mean salts which can be formed in such cases where the carboxyl group shown by COOH of the compound (I) or an acid group such as carboxyl group exists in ester residual groups or substituents of the compound (I); and salts with acids (i.e. salts with inorganic acids, salts with organic acids and salts with acid amino acids) mean salts which can be formed in such cases where a basic group such as amino group exists in the compound (I) or its ester. And, salts with acids include those in which the carboxyl group at 3-position of the compound (I) takes the form of carboxylate anion: (COO ^θ ) and those forming intramolecular salt as a pair with the cationic charge in the case where R is an oniumized condensed heterocyclic group, and salts formed when R is, for example, a group:

[wherein Y ^θ stands for anion formed by removing proton H from an inorganic acid or an organic acid.

(e.g. chloride ion, bromide ion, sulfate ion, p-toluene sulfonate ion, methanesulfonate ion and trifluoroacetate ion) ] .

The compound of the formula (I) and an ester or salt thereof may either be hydrate or a non-hydrate.

Where the compound has one or more asymetric C- atoms in the substituent at the 2-position of carbapenem skeleton, all possible diastereomers are included within the scope of the invention. Production Method 1

The compound (I) of this invention can be produced by, for example, allowing a compound represented by the formula (II) :

wherein L stands for a leaving group, and other symbols are of the same meaning as defined above or an ester thereof or a salt thereof [as the ester or salt, substantially the same one as in (I) can be used] to react with a compound represented by the formula (III): H-S-Y-R wherein symbols are of the same meaning as defined above or a salt thereof.

As the leaving group shown by L in the compound (II), use is made of a leaving group commonly employed in the field of organic synthetic chemistry [leaving groups described in, for example, Compendium of Organic Synthetic Methods, Vol.1 to Vol.7, John Wely & Sons Inc., New York (1971-1992) and R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)]. Practical examples of L include C _1-6 alkanesulfonyloxy groups optionally substituted with, e.g. 1 to 3 halogen atoms (e.g. methanesulfonyloxy and

trifluoromethanesulfonyloxy) , C ₆ . ₁₀ allene sulfonyloxy groups optionally substituted with e.g. C^ alkyl groups (e.g. benzenesulfonyloxy or toluenesulfonyloxy) , di-Ci. ₆ alkylphosphonoxy groups (e.g. dimethylphosphonoxy) , di-C ₆ . ₁₀ arylphosphonoxy group (e.g. diphenylphosphonoxy) ] , halogen (e.g. chlorine, bromine) or C^ alkanesulfinyl groups (e.g. methanesulfinyl) , or C ₆ . ₁₀ allene sulfinyl groups (e.g. benzenesulfinyl) . More preferable L is diphenylphosphonoxy group.

As salts of the compound (III), use is made of, for example, alkali metal (e.g. sodium and potassium) salts, alkaline earth metal (e.g. calcium and magnesium) salts and ammonium salt. When reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formulae of the compounds (II) and (III), these groups may optionally be protected, in accordance with a conventional method, with the protective groups mentioned below. After completion of the reaction, these protective groups can be removed in accordance with a conventional method.

The reaction between the compound (II) and the compound (III) proceeds advantageously usually in the presence of a base. Examples of the base include organic amine such as triethylamine and diisopropylethylamine and basic inorganic salts such as sodium hydrogencarbonate and potassium carbonate. The reaction can be conducted usually by stirring in an inert solvent. As the inert solvents to be employed for the reaction, any one can be used so long as it does not hamper the reaction, which is preferably exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane and chloroform,

alkyl nitriles such as acetonitrile and propionitrile, nitroalkanes such as nitromethane and nitroethane and amides such as dimethylformamide and dimethylacetamide. While the reaction temperature varies with, among others, the starting compounds (II) and (III), kinds of bases then added and kinds of solvents then employed, it ranges usually from -40°C to 100°C, preferably from -30°C to 50°C. The reaction time ranges usually from one minute to 48 hours, preferably from about 15 minutes to about 24 hours.

The method of producing the compound (II) or its esters or salts is known in the field of carbapenem (e.g. JPA S57(1982)-12318 and JPA S64( 1989)-25780) .

The compounds represented by the formula (III) can be produced by the methods described in literature references or methods analogous thereto. These methods are exemplified by those described in, for example, M. R. Grimmet et al. , Aust. J. Chem, Vol.38, p.1873 (1985), Compendium of Organic Synthetic Methods, Vol .1 to Vol.7, John Wely & Sons Inc., New York (1971-1992), Comprehensive Organic Synthesis, Vol.l-Vol.9, Pergamon Press, Oxford (1991) and R. C Larock, Comprehensive Organic Transformation, VCH, New York (1989), or analogous methods thereto. The compound represented by the formula (III) can be produced, practically, by converting X of the compound represented by the formula (III'):

wherein X stands for an optionally protected hydroxyl group or mercapto group, and other symbols are of the same meaning as defined above, when X is not mercapto group, to mercapto group by a method described in literature reference, e.g. R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989).

The compound represented by the formula (III') can be produced by, for example, subjecting alcohol or a mercaptan derivative represented by formula (IV):

wherein L 1 and Lz independently stand for a leavable group, and other symbols are of the same meaning as defined above, which can be synthesized by a method described in known literature references or an analogous method thereto, and a compound represented by the formula (V):

H-N B ] ys

H-Q wherein symbols are of the same meaning as defined above, to addition elimination reaction. Depending on cases, the hydroxyl group or mercapto group shown by H- Q or the amino group shown by H-N of the compound represented by the formula (V) may optionally be protected, and, in that case, the addition elimination reaction with the compound represented by the formula (IV) can be allowed to proceed stepwise, while conducting the deprotection of the protective group in the course of the reaction.

And, the compound represented by the formula (III') can be produced by, for example, allowing alcohol or a mercaptan derivative represented by the formula (VI):

wherein L stands for a leavable group, and other symbols are of the same meaning as defined above, which can be synthesized by a reaction described in a known

literature reference or an analogous reaction thereto, to react with a compound represented by the formula (VIII) :

wherein L stands for a leavable group, and other symbols are of the same meaning as defined above. Depending on cases, the hydroxyl group or mercapto group shown by H-Q of the compound represented by the formula (VI) or the amino group shown by H-N of the compound represented by the formula (VII) may optionally be protected, and, in that case, the addition elimination reactions of both compounds can be allowed to proceed stepwise, while conducting deprotection of the protective group in the course of the reactions.

In the compound (III'), (IV) or (VI), when X stands for respectively protected mercapto group or hydroxyl group, as those protecting groups, use can be made of, for example, such protecting groups commonly employed in the relevant field as described in Protective Groups in Organic Synthesis, Second Ed. John Wely & Sons Inc., New York (1991), T. W. Green and P.

G. M. Wuts. Preferable examples of them include alkyl- type protective groups (e.g. benzyl such as benzyl, p- methoxybenzyl and p-nitrobenzyl; substituted methyl such as diphenyl methyl, triphenyl methyl and methoxy methyl; 2-tetrahydropyranyl) , acyl-type protective groups (e.g. alkyloyl such as acetyl; aroyl such as benzoyl; t-butoxycarbonyl) or silyl-type protective groups (e.g. t-butyl dimethylsilyl) , and, among them, p-methoxybenzyl, acetyl, benzoyl, tetrahydropyran-2-yl and t-butyl dimethylsilyl, for example, are more preferable. For introduction and elimination of these

protective groups, such reaction conditions as described in the above-mentioned literature references can be employed.

As the conditions of the above reactions and the leavable groups represented by L , L , L and L employed in the reaction, use can be made of reaction conditions and removable groups commonly employed in the field of organic synthetic chemistry. [Analogous reactions are described in, for example, Compendium of Organic Synthetic Methods, Vol.l to Vol.7, John Wely & Sons Inc. New York (1971-1992) and R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)]. Practical examples of L , L and L include halogen (e.g. chloro, bromo and iodo), Cj_ ₆ alkanesulfonyloxy (e.g. methanesulfonyloxy), halogen- substituted Cj. ₆ alkanesulfonyloxy (e.g. trifluoromethanesulfonyloxy) , C ₆ _ ₁₀ allene sulfonyloxy groups (e.g. benzenesulfonyloxy and p- toluenesulfonyloxy) and hydroxyl group. And, practical examples of L include halogen (e.g. fluorine, chlorine and bromine), substituted hydroxyl group [e.g. C _L _ ₆ alkyloxy (e.g. methoxy) or C ₆ . ₁₀ aryloxy (e.g. phenoxy) or Cj. ₆ alkyloyloxy (e.g. acetoxy) or C ₆ . ₁₀ aroyloxy (e.g. benzoyloxy) ] , substituted mercapto groups [e.g. Cj. ₆ alkylthio (e.g. methylthio) or C ₆ . ₁₀ arylthio (e.g. phenylthio) or C _(t alkyloylthio (e.g. acetylthio) or C ₆ _ ₁₀ aroylthio (e.g. benzoylthio) ] .

The N-containing heterocyclic group B shown by the formulae (V) and (VII) include 5- to 6-membered N- containing heterocyclic groups containing 1 to 4 hetero-atoms, which can be produced by a conventional method. These N-containing heterocyclic groups can be described, when structually possible, as known in the field of organic chemistry, in different chemical structures as described below in accordance with

chemical equilibrium of keto-enol type or imine-enamine type.

In the above formula, N-containing heterocyclic groups shown by Bl, B2 and B3 are of tautomeric structure of ring B.

Production Method 2

The compound (I) of this invention can also be produced by subjecting a compound (VIII) of the formula

wherein M and G stand for groups which form double bond by reacting with each other, in other words, M reacts with G to form double bond by elimination, and, other symbols are of the same meaning as defined above, or an ester or salt thereof [as the ester or salt, use can be made of similar ones as those of (I)] to ring-closure reaction. Practical examples of M and G include, besides =0, =S and =Se, those described in JPA H4(1992)-179389.

As the ring-closure reaction, per se known reactions [for example, Annual Reports in Organic Synthesis, 1975-1993, Academic Press, Inc. San Diego, and Advanced Organic Chemistry Second Edition, Plenum Press New York and London (1983)] can be employed. Practically, Wittig type reaction (Wittig, Horner,

Emmons reaction) , Peterson type reaction, Aldol type reaction accompanying dehydration and McMurry type reaction using a low-electron value metal, for example, can be employed. More desirably, a Wittig type reaction employing, for example, as M,

wherein R 7 and R7' stand for a lower alkoxy group, a lower alkyl group or aryl group, is mentioned.

Examples of more practical methods include the following ones.

Production Method 2-1

The compound (I) can also be produced by allowing a compound represented by the formula (VIII-1):

wherein G ¹ stands for 0 or S, and other symbols are of the same meaning as defined above, or an ester or salt thereof [as the ester or salt, use can also be made of similar ones to those of (I)] to react with a compound represented by the formulae: P(R ⁷ ) ₃ (IX),

P(R ⁷ ) ₂ R ^7' (IX') wherein R ⁷ and R ⁷ are of the same meaning as defined above, followed by, depending on necessity, removing the protective groups.

When reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formula of the compound (VIII-1), these groups may optionally be protected with the protective groups described below in accordance with a conventional

method. After completion of the reaction, these protective groups can be removed by a conventional method.

As the lower alkoxy group shown by R or R , use is made of, for example, C^g alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; as the lower alkyl group, use is made of, for example, C^ alkyl groups such as methyl, ethyl, propyl, butyl and pentyl; and, as the aryl group, use is made of C ₆ . ₁₀ aryl groups such as phenyl.

These reactions are conducted usually under heating in the absence of solvent or in an inert solvent. While, as the inert solvent to be employed for the reaction, any one can be used so long as it does not hamper the reaction, preferable examples of such solvents include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, diethoxyethane and tetrahydrofuran, or halogenated hydrocarbons such as dichloromethane and chloroform. The amount of the compound (IX) or (IX') to be employed is 2 molar equivalents or more, preferably 2 to 10 molar equivalents, relative to the compound (VIII-1). While the reaction temperature varies with the starting compounds (VIII-1), (IX), (IX') and kinds of the solvent, it ranges usually from about 20 to 160°C, preferably from about 80 to 140°C. The reaction time ranges usually from 30 minutes to 100 hours, preferably from 1 to 72 hours. Production Method 2-2 The compound (I) can be produced by subjecting a compound represented by the formula (VIII-2):

wherein symbols are of the same meaning as defined above, or its ester or salt as the ester or salt, use can also be made of ones similar to those of (I), to ring-closure reaction, followed by, depending on necessity, removing the protecting groups. Like in the case of Production Method 2-1, when reactive groups such as amino group, hydroxyl group or carboxyl group are contained in the structural formula of the compound (VIII-2), these groups may optionally be protected, in accordance with a conventional method, with any of the protecting groups mentioned below, and these protective groups may optionally be removed in accordance with a conventional method.

The ring-closure reaction is conducted in an inert solvent. Preferable examples of the inert solvent include aromatic hydrocarbons, ethers and halogenated hydrocarbons as employed in the above Production Method 2-1. The reaction is conducted under heating at temperatures ranging from about 0 to 160°C, preferably from about 30 to 140°C. While the reaction time depends on the kinds of the compound (VIII-2) and the reaction temperature then employed, it ranges usually from about 30 minutes to 100 hours, preferably from one hour to 72 hours. As the starting materials employed in Production Method 2, 2-1 and 2-2, i.e. the compounds represented by the formulae (VIII), (VIII-1) and (VIII-2), use is made of, for example, compounds represented by the formula (III), which can be produced by conventional methods [for example, methods disclosed in JPA

S59(1984)-51286, JPA S60( 1985)-19764 , or Comprehensive

Organic Synthesis, Vol.l to Vol.9, Pergamon Press, Oxford (1991)] or methods analogous or similar thereto.

In these production steps, when an amino group is contained in the structures of the compounds represented by (II), (VIII), (VIII-1) and (VIII-2) or esters of salts thereof [as the ester or salt, use can also be made of ones similar those of (I)], or in the structures of the compounds represented by the formulae (III) and (III'), the amino group may optionally be protected with a protecting group. As the amino- protecting group, use is conveniently made of, for example, such ones as employed in the fields of β- lactam type antibiotics and peptides. Among them, for example, formyl, chloroacetyl, phenyl acetyl, phenoxy acetyl, t-butoxycarbonyl, benzyloxycarbonyl, p- methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- trimethylsilylethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, trityl and allyloxycarbonyl are preferable. And, when a hydroxyl group is contained in the structures of similar compounds, the hydroxyl group may optionally be protected. As the hydroxyl-protecting group, use is conveniently made of, for example, such one as employed in the fields of β- lactam type antibiotics and peptides. Among them, use is made of, for example, chloroacetyl, benzyl, p- nitrobenzyl, o-nitrobenzyl, methylthiomethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, 2-tetrahydropyranyl, 4-methoxy-4- tetrahydropyranyl, p-nitrobenzyloxycarbonyl, o- nitrobenzyloxycarbonyl and allyloxycarbonyl. Further, when a carboxyl group is contained in the structures of similar compounds, the carboxyl group may optionally be protected. As the carboxyl-protecting group, use is made of, for example, such ones as employed in the fields of β-lactam type antibiotics and peptides.

Among them, use is made of benzyl, benzhydryl, trityl,

p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, phenethyl, 2-trimethylsilylethyl, bis(p- methoxyphenyl)methyl, tertiary butyl and allyl.

The substituent R, i.e. the heterocyclic group formed by condensation of ring A with ring B, may optionally be converted to a chemically different group represented by R at the step of producing the compound represented by the formula (I) or (III), or at the stage of the compound represented by the formula (I) or (III).

The substituent on the substituent R may optionally be converted to a chemically different group at the step of producing the compound represented by the formula (I) or (III), or at the stage of the compound represented by the formula (I) or (III), by conducting, depending on necessity, adequate functional group conversion. For these conversion reactions, a conventional reaction can be employed [e.g. R. C. Larock, Comprehensive Organic Transformation, VCH, New York (1989)].

The carboxyl group shown by COOH of the object compound (I) may, as described above, optionally be esterified. R of the esterified carboxyl group shown by COOR* may, when desired, optionally be converted to different R* at the step of producing the compound represented by the formula (I) or (II) or at the stage of the compound represented by the formula (I) or (II). For this conversion, use can be made of a reaction commonly employed for a similar purpose in the field of β-lactam type antibiotics.

The object compound (I) thus produced can be isolated and purified by conventional means, for example, solvent-extraction, pH change, phasic transfer, salting out, crystallization, recrystallization and chromatography. And, when a

protecting group is contained in the reaction product, the compound (I) is produced by, when so desired, removing the protective group by a conventional method. So far, in the fields of β-lactam and peptide synthesis, protective groups of amino, hydroxyl or carboxyl are sufficiently studied, and the methods of protection and deprotection have been established. These methods can be utilized in the method of producing the object compound of this invention and in the method of producing intermediates for its synthesis. For example, as the method of removing the protecting group, use is made of conveniently a conventional means selected from means of using acid, means of using base, means of using 0 value palladium, means of using aluminum chloride, means of using hydrazine, means comprising reduction and means of using sodium N-methyldithiocarbamate.

The compound (I) shows excellent antibacterial activities against gram-positive and gram-negative bacteria including clinically separated strains, which is remarkably less toxic, showing, depending on cases, excellent oral absorbability and is stable physico- chemically and biochemically (especially against DHP- I), thus being a valuable antibiotic substance. The compound (I) is, therefore, utilized as drugs for man and domestic animals, which can be safely used as an antibacterial agent for the treatment and prevention of infectious diseases caused by various bacteria.

Further, the compound (I) of this invention can, for example, be added to animal feed as bactericidal agent for preservation of the feed. And, it can also be used as bactericidal agent for clearing harmful bacteria on medical and dental appliances .

The compound (I) of this invention can be used, singly or in combination with any other active components (for example, any other antibacterial

agents, anti-inflammatory agents, antipyretics and analgesics), and, depending on necessity, adding, besides pharmaceutically acceptable carriers, adjuvants e.g. a stabilizer and dispersant, as pharmaceutical preparations such as injections, capsules, tablets, liquid medicines (e.g. suspensions and emulsions) formulated by conventional methods. These preparations can be administered parenterally (e.g. intravenous or intramuscular injection) or orally. Injectable preparations can be provided in a dosage form of ampoules of vials supplemented with a preservative. These preparations may optionally be suspensions, solutions or emulsions in an oleaginous or aqueous medium, which may contain an adequate amount of conventional adjuvants such as a suspending agent, stabilizer and (or) powdery agent. The compound (I) of this invention can also be provided in a form of a pulverized or powdery agent, which can be used, by dissolving in sterilized water containing no pyrogenic substance.

The compound (I) can be formulated into tablets, capsules, powdery preparations or pulverized preparations for oral administrtion by adequately mixing with a binder (e.g. syrup, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinyl pyrrolidone and methyl cellulose), a filler (e.g. lactose, sugars, corn starch, calcium phosphate, sorbitol and glycine) , a lubricant (e.g. magnesium stearate, talc, polyethylene glycol and silica), a disintegrator (e.g. potato starch) or a wetting agent (e.g. sodium lauryl sulfate) . Tablets and powdery preparations can be film-coated by a per se known method. Orally administrable preparations may also be used as liquid preparations e.g. aqueous or oily suspensions, solutions, emulsions, syrups and elixir.

And, these preparations may be mixed with other

components, for example, a known antioxidant, preservative, binder, wetting agent, lubricant, sticking agent or flavoring agent. These preparations may further be mixed with any other active components (e.g. any other β-lactam type antibiotic substances) to give those showing a broader spectrum of antibacterial activities.

The ratio of the compound (I) in the pharmaceutical composition containing the compound (I), though variable with forms of the composition, may be that commonly employed in general antibacterial preparations. For example, in a solid preparations such as capsules, tablets and granules, the ratio of the compound (I) ranges from about 30 to 95 weight %. The compound (I) can be used for the treatment and prevention of infectious diseases from bacteria in man and any other mammalian animals (e.g. mouse, rat, rabbit, dog, cat, cow and pig), as exemplified by respiratory infectious diseases, urinary tract infection, suppurative diseases, biliary tract infection, intestinal infectious diseases, infectious diseases in the field of obsterics and gynecology, infectious diseases in the field of oto-rhino- laryngology and infectious diseases in the field of surgery. For example, in the case of respiratory infectious diseases, the dosage of the compound (I) per day, though variable with, for example, symptoms of patients, body weights and administration routes, ranges, in non-oral administration, from about 0.5 to 80 mg, preferably from about 2 to 40 mg of the active component [i.e. the compound (I)] per kg of the body weight of adult patients. The administration is preferably conducted intravenously or intramuscularly divided into 1 to 4 doses daily. And, the daily dose of oral administration ranges from about 1 to 500 mg, preferably about 5 to 100 mg, in terms of the active

component, per kg of the body weight of adult patients, divided into 1 to 3 doses.

Since the novel carbapenem compounds (I) producecd by the method of this invention have excellent properties, for example, having antibacterial activities of a broad spectrum, the present invention provides a novel antibacterial agent useful clinically.

BEST MODE FOR CARRYING OUT THE INVENTION The following Reference Examples and Working

Examples will describe the present invention in more detail. These are, however, mere examples and are not intended to limit the scope of this invention.

Elution in the column chromatography in the following Reference Examples and Working Examples was conducted under observation by TLC (thin-layer chromatography). In the TLC observation, as TLC plate, 60F ₂₅₄ manufactured by Merck & Co.,Inc. was employed, as the developing solvent, use was made of the solvent employed as the eluent in the column chromatography, and, as the detection method, a UV detector was employed. As silica gel for the column, use was made of kieselguhr 60 (70-230 or 230-400 mesh) manufactured by Merck & Co., Inc. CHP-20P resin is a product of Mitsubishi Chemical Industries, Ltd. The solvent was used, depending on necessity, after purification and drying. IR spectrum was measured by using IR-810 manufactured by Nihon Bunkosha or FT-200 manufactured by Horiba, Ltd. NMR spectrum was measured, using, as internal or external standard, tetramethyl silane or sodium 3-(trimethylsilyl)propionate, by means of GEMINI 200 (200MHz) spectrometer manufactured by Varian Co., and all the delta values were shown by ppm. The numerical values shown in parenthesis ( ) are mixture ratios of each solvent by volume. Percent (%) in the mixed solvents means volume %. Symbols in Reference

Examples and Working Examples have the following meanings. s singlet d doublet t triplet q quartet dd double doublet m multiplet br broad J coupling constant And, abbreviations in Reference Examples and Working Examples have the following meanings. THF: tetrahydrofuran DMF: dimethylformamide DMSO: dimethyl sulfoxide

PNB: p-nitrobenzyl (or 4-nitrobenzyl) hexetil: l-(cyclohexyloxycarbonyloxy)ethyl pivoxil: pivaloyloxymethyl

Reference Example 1

6-(Tetrahydropyran-2-yloxy)-6,7-dihydro-5H-imidazo[2, 1- b] [1,3]thiazine

To a DMF solution of 2-mercapto-lH-imidazole (4.0 g) was added, at 0°C, sodium hydride (purity 65%, 1.55 g) . The mixture was stirred for 30 minutes at room temperature. To this reaction mixture was added, at 0°C, 1,3-dibromo-2-[ (tetrahydropyran-2-yl)oxy]propane (12.08 g) , which was stirred for 30 hours at room temperature. To the reaction mixture was further added, at 0°C, sodium hydride (purity 65%, 1.55 g) .

The mixture was stirred for 30 minutes at 0°C, then for 2 hours at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous saline solution, which was then dried over anhydrous magnesium sulfate. The solvent was

distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica gel, 200 g, developing solvent: ethyl acetate - hexane, 3:1) to afford the title compound (4.64 g) as a colorless oily product. IR(neat): 3385, 2943, 1439 cm ^"1 .

^-NMRfCDCla) 6: 1.30-1.90(6H,m) , 3.10-3.40(2H,m) , 3.40-3.60(lH,m) , 3.70-4.30(3H,m) , 4.30-4.55( lH,m) , 4.70-4.90(lH,m) , 6.80-6.90( lH,m) , 6.99(lH,s).

Reference Example 2

6-Hydroxy-6,7-dihydro-5H-imidazo[2, 1-b] [ 1,3]thiazine

A solution of 6-(tetrahydropyran-2-yloxy)-6, 7- dihydro-5H-imidazo[2, 1-b] [ l,3]thiazine (93 mg) in a mixture of acetic acid, THF and water (4 : 2 : 1, 7 ml ) was stirred for 18 hours at 50°C. The solvent was distilled off under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate. The mixture was subjected to salting out with sodium chloride, followed by extraction with ethyl acetate - THF (1:1). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the title compound (50 mg) as a colorless solid product.

IR(KBr): 3103 1437 cm ^"1 .

¹ H-NMR(DMSO-d ₆ ) δ: 3.07( lH,dd,J=12.8,7.4Hz) , 3.25(lH,dd,J=12.8,2.6Hz) , 3.85( lH,dd,J=12.8,6.2Hz) , 4.09(lH,dd,J=12.8,4.0Hz) , 4.20- .35( lH,m) , 5.63(lH,d,J=3.2Hz) , 6.83( lH,d,J=l.2Hz) , 7.11(lH,d,J=1.2Hz) . Reference Example 3

6-Benzoylthio-6,7-dihydro-5H-imidazo[2,1- b] [ 1, 3]thiazine To a solution of triphenyl phosphine (4.26 g) in anhydrous THF (35 ml) was added, at -15°C, diisopropyl

azodicarboxylate (3.20 ml). The mixture was stirred for 30 minutes at -15°C. To the reaction mixture was then added a hexamethyl phosphoramide solution (20 ml) of 6-hydroxy-6,7-dihydro-5H-imidazo[2, 1-b] [ 1, 3]thiazine (1.30 g) and thiobenzoic acid (1.90 ml). The mixture was stirred overnight at room temperature, to which was added ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, successively, followed by drying over anhdyrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica gel, 100 g, developing solvent: ethyl acetate - hexane, 1:1 -» 2:1), followed by recrystallization from ethyl acetate to afford the title compound (710 mg) as a colorless solid product. IR(neat): 3429, 1655 cm ^"1 .

^- MRfCDCla) δ: 3.32 ( lH,dd,J=12.8,8.0Hz) , 3.54(lH,dd,J=12.8,2.8Hz) , 4.16( lH,dd,J=13.0,6.8Hz) , 4.44(lH,dd,J=13.0,3.8Hz) , 4.50-4.70( lH,m) ,

6.89(lH,d,J=1.4Hz) , 7.04 ( lH,d,J=l.4Hz) , 7.40-

7.70(3H,m), 7.90-8.00(2H,m) .

Reference Example 4

6-(Tetrahydropyran-2-yloxy)-6,7-dihydro-5H-1,2,4- triazolo[5, 1-b] [1,3]thiazine

3-Mercapto-lH-l,2,4-triazole (4.04 g) was subjected to the same reaction as in Reference Example 1 to give the title compound (4.49 g) as a colorless oily product. IR(neat): 2943, 1479, 1362, 1032 cm ^"1 . δ: 1.40-1.90(6H,m) , 3.20-3.70( 3H,m) , 3.70-4.00(lH,m) , 4.20-4.40(2H,m) , 4.40-4.60( lH,m) , 4.80-5.00(lH,m) , 7.87(lH,s). Reference Example 5 6-Hydroxy-6, 7-dihydro-5H-l, 2, -triazolo[5, 1- b] [ 1, 3]thiazine

To an ethanol solution (90 ml) of 6-

(tetrahydropyran-2-yloxy)-6,7-dihydro-5H-l,2,4- triazolo[3,2-b] [1,3]thiazine (4.51 g) was added pyridinium p-toluenesulfonate (470 mg) . The mixture was stirred for 12 hours at 60°C. The solvent was distilled off under reduced pressure. To the residue was added methylene chloride, then resulting precipitate was collected by filtration to give the title compound (2.50 g) as a colorless solid product. IR(KBr): 3101, 1487, 1358 cm ^"1 . δ:3.17(lH,ddd,J=12.8,6.2,1.2Hz) , 3.30-

4.00(lH,m) , 3.40(lH,dd,J=12.8,4.0Hz) ,

4.07(lH,ddd,J=13.2,4.8,1.2Hz) ,

4.24(lH,dd,J=13.2,3.2Hz) , 4.40-4.50(lH,m) , 7.90(lH,s). Reference Example 6

6-Benzoylthio-6,7-dihydro-5H-l,2,4-triazolo[5,1- b] [1,3]thiazine

6-Hydroxy-6,7-dihydro-5H-l,2,4-triazolo[5,1- b] [1,3]thiazine (1.57 g) was subjected to the same reaction as in Reference Example 3 to afford the title compound (2.21 g) as a pale yellow solid product.

IR(KBr): 3429, 1662, 1358, 1209 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) δ: 3.38(lH,dd,J=13.0,7.6Hz) , 3.50-

3.65(lH,m), 4.30-4.50(lH,m) , 4.55-4.75(2H,m) , 7.40- 7.70(3H,m), 7.89(lH,s), 7.90-8.00(2H,m) .

Reference Example 7

6-(Tetrahydropyran-2-yloxy)-6,7-dihydro-5H-l,2,3- triazolo[5,1-b] [1,3]thiazine

4-Mercapto-lH-l,2,3-triazole (3.03 g) was subjected to the same reaction as in Reference Example

1 to afford the title compound (2.69 g) as a colorless solid product.

IR(KBr): 2951, 1429, 1126, 989 cm ^"1 .

Η-NMRfCDCl;)) δ: 1.40-1.90(6H,m) , 3.10-3.40(2H,m) , 3.50-3.65(lH,m), 3.70-4.00(lH,m) , 4.45-4.70(3H,m) ,

4.80-4.95(lH,m), 7.43(lH,s).

Reference Example 8

6-Hydroxy-6,7-dihydro-5H-l,2, 3-triazolo[5, 1- b] [ 1, 3]thiazine

6-(Tetrahydropyran-2-yloxy)-6,7-dihydro-5H-l,2,3- triazolo[5, 1-b] [ 1, 3]thiazine (2.65 g) was subjected to the same reaction as in Reference Example 5 to afford the title compound (1.32 g) as a colorless solid product.

IR(KBr): 3169, 1232 cm ^"1 . ^-NMRfDMSO-d δ: 3.00-3.20( lH,m) , 3.20-3.40( lH,m) ,

4.25-4.55(3H,m), 5.73(lH,d,J=2.8) , 7.55(lH,s).

Reference Example 9

6-Benzoylthio-6,7-dihydro-5H-l,2,3-triazolo[5,1- b] [ 1,3]thiazine 6-Hydroxy-6,7-dihydro-5H-l,2,3-triazolo[5,1- b] [ 1,3]thiazine (1.00 g) was subjected to the same reaction as in Reference Example 3 to afford the title compound (1.35 g) as a colorless solid product.

IR(KBr): 1662, 1207 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 3.20-3.35( lH,m) ,

3.52(lH,dd,J=12.6,2.4Hz) , 4.50-4.70(2H,m) , 4.70-

4.90(lH,m), 7.40-7.70(4H,m) , 7.90-8.00(2H,m) .

Reference Example 10

6-(Tetrahydropyran-2-yloxy)-6,7-dihydro-5H- tetrazolo[5,l-b] [ 1,3Jthiazine

5-Mercapto-lH-tetrazole (2.04 g) was subjected to the same reaction as in Reference Example 1 to afford the title compound (1.54 g) as a colorless solid product. IR(KBr): 2951, 1398, 1126, 991 cm ^"1 .

^-NMRfCDCl;,) δ: 1.40-1.80(6H,m) , 3.20-4.00(4H,m) ,

4.35-4.80(3H,m) , 4.80-4.95( lH,m) .

Reference Example 11

6-Hydroxy-6,7-dihydro-5H-tetrazolo(5, 1-b] [ 1, 3]thiazine 6-(Tetrahydropyran-2-yloxy)-6 ,7-dihydro-5H- tetrazolo[5, 1-b] [ l,3]thiazine (1.45 g) was subjected to

the same reaction as in Reference Example 5 to afford the title compound (922 mg) as a colorless solid product.

IR(KBr): 3261, 1479, 1410 cm ^"1 . ¹ H-NMR(DMSO-d ₆ ) δ: 3.20-3.55(2H,m) , 4.40(2H,d,J=3.2Hz) , 4.50-4.65(lH,m), 5.83(lH,s). Reference Example 12

6-Benzoylthio-6,7-dihydro-5H-tetrazolo[5, 1- b] [ l,3]thiazine 6-Hydroxy-6,7-dihydro-5H-tetrazolo[5,1- b] [l,3]thiazine (395 mg) was subjected to the same reaction as in Reference Example 3 to afford the title compound (267 mg) as a colorless solid product. IR(KBr): 1668, 1209 cm ^"1 . ^-NMRfCDCl;,) δ: 3.35-3.50( lH,m) ,

3.64(lH,dd,J=13.0,2.6Hz) , 4.55-4.75(2H,m) , 4.75- 4.95(lH,m), 7.40-7.55(2H,m) , 7.55-7.70( lH,m) , 7.80- 8.00(2H,m) . Reference Example 13 3-[3-Bromo-2-(tetrahydropyran-2-yloxy)propylthio]-1H- 1,2,4-triazole

To a solution of 3-mercapto-lH-l,2,4-triazole (6.53 g) in DMF (50 ml) was added, at 0°C, sodium hydride (purity 65%, 2.38 g) . The mixture was stirred for 30 minutes at room temperature. This solution was added dropwise, at 0°C, to a solution of 1,3-dibromo-2- [ (tetrahydropyran-2-yl)oxy]propane (25.35 g) in DMF (50 ml). The mixture was stirred for 3 hours at room temperature, to which was added ethyl acetate. The reaction mixture was washed with water and a saturated aqueous saline solution, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a column chromatography (carrier: silica gel, 250 g, developing solvent: ethyl acetate - hexane, 2:3 → 3:2) to afford the title compound (13.0 g) as a colorless solid

product.

IR(KBr): 2941, 1022, 978 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) δ: 1.40-2.00(6H,m) , 3.30-3.80(5H,m) , 3.90-4.30(2H,m) , 4.75-4.90( lH,m) , 8.03(0.4H,s) , 8.11(0.6H,m) .

Reference Example 14

6-(Tetrahydropyran-2-yloxy)-6,7-dihydro-5H-l,2,4- triazolo[3,4-b] [ 1, 3]thiazine

To a solution of 3-[3-bromo-2-(tetrahydropyran-2- yloxy)propylthio]-lH-l,2,4-triazole (15.6 g) in toluene (150 ml) were added 1, 1, 1,3,3,3-hexamethyldisilazane (20.5 ml) and diisopropylethylamine (16.9 ml). The mixture was stirred for 20 hours at 100°C. The reaction mixture was cooled to room temperature, to which was added water (300 ml). The solution was subjected to salting out with sodium chloride, which was subjected to extraction with ethyl acetate - THF (1:1; 200 ml x 5). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (carrier: silica gel, 300 g, developing solvent: ethyl acetate - ethanol, 9:1 -» 4:1). The eluate was concentrated, and the resulting precipitate was washed with ethyl acetate to afford the title compound (6.04 g) as a colorless solid product.

IR(KBr): 2939, 1516, 1435, 1126, 1028, 989 cm ^"1 . ^-NMRfCDCl;,) δ: 1.30-1.90(6H,m) , 3.10-3.45(2H,m) , 3.45-3.65(lH,m) , 3.65-4.00(lH,m) , 4.00-4.35(2H,m) , 4.35-4.60(lH,m) , 4.80-4.90(lH,m) , 8.10(0.4H,s) , 8.11(0.6H,s) . Reference Example 15

6-Hydroxy-6,7-dihydro-5H-l,2,4-triazolo[3,4- b] [ l,3]thiazine 6-(Tetrahydropyran-2-yloxy)-6, 7-dihydro-5H-1,2,4- triazolo[3,4-b] [ 1,3]thiazine (4.28 g) was subjected to

the same reaction as in Reference Example 5 to afford the title compound (2.60 g) as a colorless solid product.

IR(KBr): 3124, 1518, 1431 cm ^"1 . ¹ H-NMR(DMSO-d ₆ ) δ: 3.13(lH,ddd,J=12.6,6.2,1.0Hz) ,

3.33(lH,dd,J=12.6,2.2Hz) ,

4.01(lH,ddd,J=13.0,5.0,0.8Hz) ,

4.12(lH,dd,J=13.0,3.4Hz), 4.30-4.40(lH,m) , 5.50-

5.80(lH,m), 8.52(lH,s). Reference Example 16

6-Benzoylthio-6,7-dihydro-5H-l,2,4-triazolo[3,4- b] [1,3]thiazine

6-Hydroxy-6,7-dihydro-5H-l,2,4-triazolo[3,4- b] [1,3]thiazine (1.57 g) was subjected to the same reaction as in Reference Example 3 to afford the title compound (1.78 g) as a pale yellow solid product.

IR(KBr): 1655, 1433, 1209, 912 cm ^"1 .

^-NMRfCDCla) δ: 3.35(lH,dd,J=13.2,7.4Hz) ,

3.56(lH,dd,J=13.2,2.8) , 4.25(lH,dd,J=12.8,4.4Hz) , 4.50(lH,dd,J=12.8,4.0Hz) , 4.50-4.65(lH,m) , 7.40-

7.55(2H,m), 7.55-7.70(lH,m) , 7.85-8.00(2H,m) ,

8.14(lH,s) .

Reference Example 17-1

2-Amino-6-hydroxy-6,7-dihydro-5H-l,2,4-triazolo[5, 1- b] [1,3]thiazine

To a solution of potassium hydroxide (3.46 g) in methanol (10 ml) was added 3-amino-lH-l,2,4-triazole-5- thiol (5.54 g) under ice cooling. The solution was added to a solution of 1,3-dichloro-2-propanol (4.55 ml) in methanol (10 ml) under ice cooling, which was heated for 30 minutes under reflux. The reaction mixture was cooled, and to the reaction mixture was added a solution of potassium hydroxide (3.46 g) in methanol (10 ml). The mixture was heated for 2 hours under reflux. The reaction mixture was cooled, and to the mixture was added a solution of potassium hydroxide

(3.46 g) in methanol (10 ml) under ice cooling. The mixture was heated for 2 hours under reflux. After the reaction mixture was cooled, insolubles were filtered off. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (carrier:silica gel, 200 g; developing solvent : ethyl acetate-ethanol, 9 : 1 - 1 : 1) to give the title compound (3.34 g) as a colorless solid product. IR (KBr): 3081, 1628, 1553, 1362, 1090 cm ^"1 .

^-NMR (DMS0-d ₆ ) δ: 3.09 (1 H, dd, J = 12.8, 6.8 Hz), 3.30 (1 H, dd, J = 12.8, 2.4 Hz), 3.77 (1 H, dd, J = 13.2, 5.2 Hz), 4.01 (1 H, dd, J = 13.2, 3.6 Hz), 4.25-4.40 (1 H, m) , 5.22 (2 H, m) , 5.69 (1 H, d, J = 3.6 Hz) .

Reference Example 17-2

2-Amino-6-benzoylthio-6,7-dihydro-5H-l,2,4-triazolo[5, 1

-b] [ 1,3]thiazine

2-Amino-6-hydroxy-6,7-dihydro-5H-l,2,4- triazolo[5, 1-b] [1,3]thiazine (1.38 g) was subjected to the same reaction and purification procedures as in Reference Example 3 to give the title compound (846 mg) as a pale yellow solid product. IR (KBr): 3330, 1665, 1541, 1362, 1209, 912, 743 cm ^"1 . *H-NMR (CDC1 ₃ ) δ: 3.32 (1 H, dd, J = 13.0, 7.8 Hz),

3.54 (1 H, dd, J = 13.0, 2.6 Hz), 4.08 (2 H, brs ) , 4.17 (1 H, dd, J = 13.2, 7.0 Hz), 4.44 (1 H, dd, J = 13.2, 2.4 Hz), 4.50-4.70 (1 H, m) , 7.35-7.70 (3 H, m), 7.90-8.00 (2 H, m) . Reference Example 18-1

3-[3-Bromo-2-(tetrahydropyran-2-yloxy)propylthio]-5- methyl-lH-1,2, 4-triazole

To a solution of 3-mercapto-5-methyl-lH-l,2 ,4- triazole (7.44 g) in DMF (50 ml) was added a sodium hydride (purity 65 %, 2.38 g) at 0 °C, which was then stirred for 30 minutes at room temperature. This

solution was added dropwise to a solution of 1,3-dibromo-2-(tetrahydropyran-2-yloxy)propane (25.35 g) in DMF (50 ml) at 0 °C, which was then stirred for 3 hours at roon temperature. To the reaction mixture was added ethyl acetate and the mixture was washed with water and saturated aqueous saline solution, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (carrier:silica gel, 250 g; developing solvent:ethyl acetate-hexane=2:3 - 3:2) to give the title compound (12.5 g) as a coloress solid product. IR (KBr): 2941, 1423, 1267, 1122, 1020 cm ^"1 . ^-NMR (CDC1 ₃ ) 6: 1.40-1.90 (6 H, m) , 2.40-2.50 (3 H, m), 3.25-3.80 (5 H, ) , 3.90-4.30 (2 H, m) , 4.75-4.90 (1 H, m) .

Reference Example 18-2

3-Methyl-6-(tetrahydropyran-2-yloxy)-6,7-dihydro-5H- 1,2,4-triazolo[3,4-b] [1,3]thiazine To a solution of 3-[3-bromo-2-(tetrahydropyran-2- yloxy)propylthio]-5-methyl-lH-l,2,4-triazole (7.66 g) in toluene (80 ml) were added 1,1,1,3,3,3- hexamethyldisilazane (9.63 ml) and diisopropylethylamine (7.94 ml), and the mixture was stirred for 24 hours at 100 °C The reaction mixture was cooled to room temperature. To the reaction mixture was added water (300 ml). The mixture was subjected to salting out and subjected to extraction with ethyl acetate-THF (1 : 4; 100 ml x 4). The extract was dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure. The obtained solid substance was washed with ethyl acetate to give the title compound (2.27 g) as a colorless solid product. IR (KBr): 2940, 1435, 1121, 1032 cm ^"1 .

^-N R (CDC1 ₃ ) δ: 1.40-1.95 (6 H, m) , 2.40 (3 H, s),

3.17 (2 H, d, J = 5.2 Hz), 3.45-3.60 (1 H, m) ,

3.65-3.85 (1 H, m) , 3.85-4.10 (2 H, m) , 4.40-4.60 (1 H, m) , 4.80-4.90 (1 H, m) .

Reference Example 18-3 6-Hydroxy-3-methyl-6,7-dihydro-5H-l,2,4-triazolo[3,4-b]

[ 1, 3]thiazine

3-Methyl-6-(tetrahydropyran-2-yloxy)-6,7-dihydro-

5H-l,2,4-triazolo[3,4-b] [ 1,3]thiazine (2.67 g) was subjected to the same reaction and purification procedures as in Reference Example 5 to give the title compound (1.29 g) as a colorless solid product.

IR (KBr): 3154, 1539, 1474, 1437, 1086 cm ^"1 .

^-NMR (DMSO-d ₆ ) δ:2.27 (3 H, s), 3.07 (1 H, dd, J =

12.6, 6.8 Hz), 3.22 (1 H, dd, J = 12.6, 2.4 Hz), 3.78 (1 H, dd, J = 12.8, 5.6 Hz), 3.97 (1 H, dd, J = 12.8,

3.8 Hz), 4.25-4.45 (1 H, m) , 5.68 (1 H, d, J = 4.0 Hz) .

Reference Example 18-4

6-Benzoylthio-3-methyl-6,7-dihydro-5H-l,2,4-triazolo[ 3,

4-b] [1,3]thiazine 6-Hydroxy-3-methyl-6,7-dihydro-5H-l,2,4- triazolof3,4-b] [1,3]thiazine (856 mg) was subjected to the same reaction and purification procedures as in

Reference Example 3 to give the title compound (930 mg) as a pale yellow solid product. IR (KBr): 1669, 1209, 912, 743 cm ^"1 .

^: H-NMR (CDC1 ₃ ) δ: 2.41 (3 H, s), 3.29 (1 H, dd, J =

13.0, 8.4 Hz), 3.48 (1 H, dd, J = 13.0, 2.8 Hz), 4.02

(1 H, dd, J = 12.8, 6.6 Hz), 4.30 (1 H, dd, J = 12.8,

4.2 Hz), 4.50-7.70 (1 H, m) , 7.40-7.70 (3 H, m) , 7.90-8.00 (2 H, m) .

Reference Example 19-1

2-Methyl-6-(tetrahydropyran-2-yloxy)-6,7-dihydro-5H- l,2,4-triazolo[5, 1-b] [1, 3]thiazine

To a solution of 3-[3-bromo-2-(tetrahydropyran-2- yloxy)propylthio]-5-methyl-lH-l,2 ,4-triazole (4.82 g) in methanol (30 ml) was added sodium methoxide (851

ml), and the mixture was stirred for 7 hours at 50 °C. The reaction mixture was cooled so that the temperature of the reaction mixture bacame to room temperature. The mixture was concentrated, and to the residue was added water (300 ml). The mixture was subjected to extraction with ethyl acetate (100 ml x 2). The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (carrier:silica gel, 60 g;developing solvent: ethyl acetate-hexane=2 : 1 - ethyl acetate) to give the title compound (2.64 g) as a colorless oily product.

IR (KBr): 2942, 1333, 1123, 1034 cm ^"1 .

^-NMR (CDC1 ₃ ) δ: 1.40-2.00 (6 H, m) , 2.34 (3 H, s), 3.20-3.45 (2 H, m) , 3.45-3.65 (1 H, m) , 3.70-4.00 (1 H, m), 4.05-4.60 (3 H, m) , 4.80-4.95 (1 H, m) . Reference Example 19-2

6-Hydroxy-2-methyl-6,7-dihydro-5H-l,2,4-triazolo[5,1-b] [l,3]thiazine To a solution of 2-methyl-6-(tetrahydropyran-2- yloxy)-6,7-dihydro-5H-l,2,4-triazolo[5,1- b] [l,3]thiazine (2.64 g) in ethanol (50 ml) was added pyridinium p-toluene sulfonate (520 mg), and the mixture was stirred for 18 hours at 70 °C. The solvent was distilled off under reduced pressure, and to the residue was added methylene chloride. The residue was collected by filtration to give the title compound (1.29 g) as a colorless solid product. IR (KBr): 3173, 1412, 1337, 1084 cm ^"1 . ^-NMR (DMSO-d ₆ ) δ: 2.17 (3 H, s), 3.13 (1 H, ddd, J = 12.8, 6.4, 1.0 Hz), 3.20-3.50 (1 H, m) , 3.96 (1 H, dd, J = 13.2, 4.4 Hz), 4.16 (1 H, dd, J = 13.2, 3.6 Hz), 4.30-4.45 (1 H, m) , 5.50-5.90 (1 H, m) . Reference Example 19-3 6-Benzoylthio-2-methyl-6,7-dihydro-5H-l,2,4-triazolo[5, 1-b] [l,3]thiazine

6-Hydroxy-2-methyl-6,7-dihydro-5H-l,2,4- triazolo[5, 1-b] [ l,3]thiazine (856 mg) was subjected to the same reaction and purification procedures as in Reference Example 3 to give the title compound (890 mg) as a pale yellow solid product.

IR (KBr): 1669, 1209, 912, 743 cm ^"1 .

^J H-NMR (CDC1 ₃ ) δ: 2.35 (3 H, s), 3.34 (1 H, dd, J = 13.2, 7.2 Hz), 3.56 (1 H, dd, J = 13.2, 2.6 Hz), 4.31 (1 H, dd, J = 13.2, 6.2 Hz), 4.45-4.70 (2 H, m) , 7.40-7.70 (3 H, m) , 7.90-8.00 (2 H, m) . Reference Example 20-1 2-(3-Chloro-2-hydroxypropylthio)-4,5-dimethylimidazole

2-Mercapto-4,5-dimethylimidazole (6.41g) was suspended in ethanol (100ml), and to the suspension were added sodium hydrogencarbonate (5.04g) and epichlorohydrin (4.00ml) in the order mentioned at room temperature. The mixture was stirred for 18 hours at the same temperature. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. To the residue were added water and diethyl ether. Insolubles were collected by filtration and dried to obtain the title compound (lO.Og). ^X H-NMR (CDCl ₃ +DMSO-d ₆ ) δ: 2.09 (6H, s), 3.14 (IH, dd, J=6.0, 14.8Hz), 3.27 (IH, dd, J=2.7, 14.8Hz), 3.65 (2H, d, J=6.4Hz), 4.1-4.25 ( IH, m) . Reference Example 20-2

6-Hydroxy-2,3-dimethyl-6,7-dihydro-5H-imidazo[2, 1-b] [ 1 , 3 ]thiazine

2-(3-Chloro-2-hydroxypropylthio)-4,5- dimethylimidazole (6.62g) was dissolved in methanol

(40ml), and to the solution was added sodium methoxide (28% methanol solution, 5.79g) at room temperature. The mixture was stirred for 20 hours at the same temperature. The reaction mixture was concentrated under resuced pressure. To the residue were added water and diethyl ether. Insolubles were collected by

filtration and fried to give the title compound (5.02g).

^X H-NMR (CDCl ₃ +DMSO-d ₆ ) δ: 2.08 (3H, s), 2.10 (3H, s), 3.12 (IH, dd, J=7.1, 12.8Hz), 3.23 (IH, dd, J=2.5, 12.8Hz), 3.76 (IH, dd, J=5.4, 12.8Hz), 3.89 (IH, dd, J=4.0, 12.8Hz), 4.4-4.55 (IH, m) . Reference Example 20-3

6-Benzoylthio-2,3-dimethyl-6,7-dihydro-5H- imidazo[2,1-b] [1,3]thiazine To a solution of triphenylphosphine (7.87g) in anhydrous tetrahydrofuran (100ml) was added diisopropyl azodicarboxylate (6.07g) at 0 °C. The mixture was stirred for 15 minutes at the same temperature. To the mixture were added, at 0°C, a solution of 6- hydroxy-2,3-dimethyl-6,7-dihydro-5H-imidazo[2,1-b] [1,3] thiazine (2.76g) in anhydrous dimethyl formamide (100ml) and thiobenzoic acid (3.53ml) in the order mentioned. The mixture was stirred for 1 hour at the same temperature and for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate, water and saturated agueous saline solution in the order mentioned. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (carrier:silica gel 150 g; developing solvent:hexane-ethyl acetate=l:l - 1:2). A fraction containing the title compound was concentrated under reduced pressure to give a mixture (5.20 g) of the title compound and triphenylphosphine. The mixture was used to the next reaction without purification. IR (KBr) : 1666 cm ^"1 . ^-NMR (CDC1 ₃ ) 6: 2.08 (3H, s), 2.13 (3H, s), 3.26 (IH, dd, J=8.2, 12.8Hz), 3.45 (IH, dd, J=2.6, 12.8Hz), 3.92

(IH, dd, J=6.8, 13.2Hz), 4.20 (IH, dd, J=4.3, 13.2Hz), 4.5-4.7 (IH, m), 7.4-7.75 (3H, m) , 7.9-8.0 (2H, m) . Reference Example 21-1

2-( 3-Chloro-2-hydroxypropylthio)-4-methylimidazole 2-Mercapto-4-methylimidazole (343mg) was suspended in ethanol (6ml), and to the suspension were added sodium hydrogencarbonate (303 mg) and epichlorohydrin (0.239ml) in the order mentioned at room temperature. The mixture was stirred for 17 hours at the same temperature. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (carrier:silica gel, 30 g;developing solvent : hexane-ethyl acetate=l:2) to give the title compound (611 mg) .

^-NMR (CDC1 ₃ ) 6: 2.20 (3H, d, J=l.lHz), 3.20 (IH, dd, J=5.8, 14.9Hz), 3.32 (IH, dd, J=2.8, 14.9Hz) , 3.55-3.8 (2H, m), 4.1-4.3 (IH, m) , 6.69 (IH, d, J=l.lHz) . Reference Example 21-2 6-Hydroxy-2-methyl-6,7-dihydro-5H-imidazo[2, 1- b] [ l,3]thiazine

2-(3-Chloro-2-hydroxypropylthio)-4-methylimidazole (8.56g) was dissolved in methanol (50ml), and to the solution was added sodium methoxide (28% methanol solution, 7.72g). The mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added 1-butanol (100ml), and the mixture was heated to 70 °C. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. To the residue were added methanol (5 ml) and diethyl ether (30ml), and insolubles were collected by filtration. To the residue were added metahnol (5 ml ) and diethyl ether (10ml), and insolubles were collected by filtration to give the title compound (1.30g) .

^-NMR (DMSO-d ₆ ) δ: 1.99 (3H, d, J=1.0Hz), 3.03 (IH,

dd, J=7.0, 12.7Hz), 3.20 (IH, dd, J=2.3, 12.7Hz), 3.74 (IH, dd, J=6.3, 12.9Hz), 4.00 (IH, dd, J=3.0, 12.9Hz), 4.15-4.35 (IH, m) , 5.60 (IH, brs) , 6.77 (IH, d, J=1.0Hz) . Reference Example 21-3

6-Benzoylthio-2-methyl-6,7-dihydro-5H-imidazo[2, 1-b] [1, 3]thiazine

To a solution of triphenylphosphine (3.67g) in anhydrous tetrahydrofuran (50ml) was added diisopropyl azodicarboxylate (2.83g) at 0 °C, and the mixture was stirred for 15 minutes at the same temperature. To the reaction mixture were added a solution of 6-hydroxy-2- methyl-6,7-dihydro-5H-imidazo[2, 1-b] [1,3]thiazine (1.19g) in anhydrous dimethylformamide (50ml) and thiobenzoic acid (1.65ml) in the order mentioned at 0 °C. The mixture was stirred for 2 hours at the same temperature and for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate, and concentrated under resuced pressure. The residue was subjected to column chromatography (carrier : silica gel 100 g; developing solvent : hexane-ethyl acetate=l:l - 1:2). A fraction containing the title compound was concentrated under reduced pressure to obtain a mixture (2.47 g, content of the title compound : 63 wt%) of the title compound and triphenylphosphine oxide. The mixture was used to the next reaction without purification. IR (KBr) : 1673 cm ^"1 . ^X H-NMR (CDCl _j ) δ: 2.18 (3H, d, J=1.0Hz), 3.29 (IH, dd, J=7.6, 13.3Hz), 3.51 (IH, dd, J=2.9, 13.3Hz), 4.08 (IH, dd, J=6.8, 13.3Hz), 4.36 (IH, dd, J=4.3, 13.3Hz),

4.5-4.65 (IH, m), 6.59 (IH, d, J=1.0Hz), 7.4-7.75 (3H, m) , 7.9-8.0 (2H, m) . Reference Example 22-1

6-Hydroxy-3-methyl-6,7-dihydro-5H-imidazo[2, 1- b] [ 1, 3]thiazine

2-(3-chloro-2-hydroxypropylthio)-4-methylimidazole (8.56 g) was dissolved in methanol (50 ml), and to the solution was added sodium methoxide (28% methnol solution, 7.72 g) at room temperature. The mixture was stirred for 24 hours at the same temperature. The reaction mixture was concentrated under reduced pressure, and to the residue was added 1-butanol (100 ml). The mixture was warmed up to 70 °C, and insolubles were filtered off. The filtrate was concentrated under reduced pressure. To the residue were added methanol (5 ml) and diethyl ether (30 ml) and insolubles were filtered off. The filtrate was concentrated under reduced pressure and to the residue was added diethyl ether (30 ml). Insolubles were collected by filtration and dried to give a mixture

(4.20 g, content of the title compound : 72 wt%) of the title compound and 6-hydroxy-2-methyl-6,7-dihydkro-5H- imidazof2, 1-b] [ 1,3]thiazine. The mixture was used to the next reaction without purification. ^X H-NMR (CDC1 ₃ ) 6: 2.15 (3H, d, J=1.0Hz), 3.15 (IH, dd,

J=6.9, 12.9Hz), 3.26 (IH, dd, J=2.5, 12.9Hz), 3.82 (IH, dd, J=5.8, 13.2Hz), 3.93 (IH, dd, J=3.9, 13.2Hz), 4.4-4.6 (IH, m) , 6.70 (IH, d, J=1.0Hz) . Reference Example 22-2 6-Benzoylthio-3-methyl-6,7-dihydro-5H-imidazo[2, 1-b] [ 1 , 3]thiazine

To a solution of triphenylphosphine (5.25 g) in anhydrous hetrahydrofuran (50 ml) was added diisopropyl azodicarboxylate (4.04 g) at 0 °C. The mixture was stirred for 15 minutes at the same temperature. To the mixture were added a solution of 6-hydroxy-3-methyl-

6,7-dihydro-5H-imidazo[2,1-b] [1,3]thiazine (1.70 g, content : 72 wt%) in anhydrous dimethylformamide (20 ml) and thiobenzoic acid (2.35 ml) in the order mentioned at 0 °C. The mixture was stirred for 1 hour at the same temperature and for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added ethyl acetate. The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (carrier : silica gel, 150g ; developing solvent : hexane-ethyl acetate=l:l - 1:2). A fraction containing the title compound was concentrated under reduced pressure to give a mixture (1.94 g, content of the title compound : 72 wt%) of the title compound and triphenylphosphine oxide. The mixture was used to the next reaction without purification. IR (KBr) : 1662 cm ^"1 .

^! H-NMR (CDC1 ₃ ) δ: 2.16 (3H, d, J=l.lHz), 3.27 (IH, dd, J=8.1, 12.9Hz), 3.46 (IH, dd, J=3.2, 12.9Hz), 3.96 (IH, dd, J=7.2, 13.1Hz), 4.24 (IH, dd, J=4.5, 13.1Hz),

4.55-4.7 (IH, m), 6.76 (IH, d, J=l.lHz), 7.4-7.7 (3H, m) , 7.9-8.0 (2H, m) .

Reference Example 23-1

(S)-2-(3-Chloro-2-hydroxypropylthio)-4,5-cyclopentenoim idazole

2-Mercapto-4,5-cyclopentenoimidazole (1.96 g) was suspended in ethanol (30 ml), and to the suspension were added sodium hydrogencarbonate (1.41 g) , (S)-epichlorohydrin (1.12 ml) in the order mentioned at room temperature. The mixture was stirred for 8 hours at the same temperature. Insolubles were filtered off

and filtrate was concentrated under reduced pressure. The residue was subjected to colomn chromatography (carrier : silica gel, 150 g; developing solvent : hexane-ethyl acetate=l:l) to give the title compound (2.86 g) .

^J H-NMR (CDC1 ₃ ) δ: 2.3-2.7 (6H, m) , 3.15 (IH, dd, J=6.2, 14.7Hz), 3.28 (IH, dd, J=2.8, 14.7Hz), 3.66 (2H, d, J=6.4Hz), 4.05-4.25 (IH, ) . Reference Example 23-2 (R)-6-Hydroxy-6,7-dihydro-5H-2,3-cyclopentenoimidazo[2, 1-b] [ 1,3]thiazine

(S)-2-(3-Chloro-2-hydroxypropylthio)-4,5- cyclopentenoimidazole (2.56 g) was dissolved in methanol (15 ml), and to the mixture was added sodium methoxide (28% methanol solution, 2.12 g) at room temperature. The mixture was stirred for 15 hours at the same temperature. The reaction mixture was concentrated under reduced pressure, and to the residue were added water and diethyl ether. Insolubles were collected by filtration and dried to give the title compound (1.71 g) .

^J H-NMR (DMSO-d ₆ ) δ: 2.2-2.7 (6H, m) , 3.03 (IH, dd, J=7.5, 12.5Hz), 3.18 (IH, dd, J=2.9, 12.5Hz), 3.69 (IH, dd, J=6.6, 12.8Hz), 3.98 (IH, dd, J=4.0, 12.8Hz), 4.15-4.35 (IH, m) , 5.61 (IH, d, J=3.2Hz). Reference Example 23-3 (S)-6-Benzoylthio-6,7-dihydro-5H-2, 3- cyclopentenoimidazo[2, 1-b] [1,3]thiazine

To a solution of triphenylphosphine (3.15 g) in anhydrous tetrahydrofuran (40 ml) was added diisopropyl azodicarboxylate (2.43 g) at 0 °C, and the mixture was stirred for 15 minutes at the same temperature. To the mixture were added a solution of (R)-6-hydroxy-6 , 7- dihydro-5H-2, 3-cyclopentenoimidazo[2, 1-b] [1,3 ]thiazine (1.18 g) in anhydrous dimethylformamide (30 ml) and thiobenzoic acid (1.41 ml) in the order mentioned at 0

°C. The mixture was stirred for 1 hour at the same temperature and for 1.5 hour at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (carrier: silica gel, 150g;developing solvent: hexane-ethylacetate=l: 1) . A fraction containing the title compound was concentrated under reduced pressure to obtain a mixture (2.50 g, content of the title compound : 66 wt%) of the title compound and triphenylphosphine.

The mixture was used to the next reaction without purification.

IR (KBr) : 1658 cm ^"1 .

^X H-NMR (CDC1 ₃ ) δ: 2.35-2.75 (6H, m) , 3.27 (IH, dd, J=8.0, 13.1Hz), 3.48 (IH, dd, J=3.0, 13.1Hz), 4.02 (IH, dd, J=7.0, 13.2Hz), 4.31 (IH, dd, J=4.4, 13.2Hz), 4.5-4.7 (IH, m) , 7.4-7.75 (3H, m) , 7.9-8.0 (2H, m) . Reference Example 24 (R)-6-benzoylthio-6,7-dihydro-5H-2,3- cyclopentenoimidazo[2, 1-b] [1,3]thiazine

Using (R)-epichlorohydrin, the same reaction and purification procedures were conducted as in Reference Example 23 to obtain a mixture (2.29 g, content of the title compound : 67 wt%) of the title compound and triphenylphosphine oxide. IR (KBr) : 1658 cm ^"1 .

^J H-NMR (CDCI ₃ ) δ: 2.35-2.7 (6H, m) , 3.27 (IH, dd, J=8.1, 13.0Hz), 3.48 (IH, dd, J=2.8, 13.0Hz), 4.02 (IH, dd, J=6.8, 13.2Hz), 4.31 (IH, dd, J=4.2, 13.2Hz), 4.5-4.65 (IH, m) , 7.35-7.75 (3H, m) , 7.9-8.0 (2H, m) . Reference Example 25-1

(S)-2-( 3-chloro-2-hydroxypropylthio)imidazole

2-Mercaptoimidazole (5.01 g) was suspended in ethanol (100 ml), and to the suspension was added sodium hydrogencarbonate (5.04 g) and (S)-epichlorohydrin (4.00 ml) in the order mentioned at room temperature. The mixture was stirred for 18 hours at the same temperature. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (carrier : silica gel, 150g; developing agent : hexane-ethyl acetate=l:2) to give the title compound (8.87 g) .

^-NMR (CDC1 ₃ ) δ: 3.24 (IH, dd, J=5.8, 15.0Hz), 3.35 (IH, dd, J=2.9, 15.0Hz), 3.65-3.7 (2H, m) , 4.15-4.3 (IH, m) , 7.02 (2H, s) . Reference Example 25-2

(R)-6-hydroxy-6,7-dihydro-5H-imidazo[2,1- b] [ l,3]thiazine

(S)-2-(3-Chlσro-2-hydroxypropylthio)imidazole (8.69 g) was dissoved in methanol (70 ml), and to the solution was added sodium methoxide (28% methanol solution, 8.70 g) at room temperature. The mixture was stirred for 17 hours at the same temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate.

Insolubles were collected by filtration and dried to obtain a mixture (8.33 g) of the title compound and sodium chloride. The mixture was used to the next reaction without purification. ^X H-NMR (DMS0-d ₆ ) δ: 3.07 (IH, dd, J=7.3, 12.5Hz), 3.24 (IH, dd, J=2.8, 12.5Hz), 3.85 (IH, dd, J=6.4, 13.0Hz), 4.08 (IH, dd, J=3.7, 13.0Hz), 4.2-4.35 (IH, ), 5.76 (IH, br s), 6.82 ( IH, d, J=1.3Hz), 7.10 (IH, d, J=1.3Hz) . Reference Example 25-3

(S)-6-benzoylthio-6, 7-dihydro-5H-imidazo[2, 1-

b] [1,3]thiazine

To a solution of triphenylphosphine (3.15 g) in anhydrous tetrahydrofuran (40 ml) was added diisopropyl azodicarboxylate (2.43 g) at 0 °C, and the mixture was stirred for 15 minutes at the same temperature. To the mixture were added a solution of the compound obtained in Reference Example 25 (1.29 g) in anhydrous dimethylformamide (50 ml) and thiobenzoic acid (1.41 ml) in the order mentioned at 0 °C. The mixture was stirred for 2.5 hours at the same temperature and for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (carrier : silica gel,150g; developing solvent : hexane-ethyl acetate=l:l - 1:2). A fraction containing the title compound was concentrated under reduced pressure to obtain a mixture (3.25 g, content of the title compound : 38 wt%) of the title compound and triphenylphosphine oxide. The mixture was used to the next reaction without purification. IR (KBr) : 1664 cm ^'1 .

^: H-NMR (CDC1 ₃ ) δ: 3.31 (IH, dd, J=7.7, 13.0Hz), 3.53 (IH, dd, J=2.8, 13.0Hz), 4.16 (IH, dd, J=6.7, 13.3Hz), 4.43 (IH, dd, J=3.9, 13.3Hz), 4.5-4.65 (IH, m) , 6.88

(IH, d, J=1.2Hz), 7.04 (IH, d, J=1.2Hz), 7.4-7.65 (3H, m) , 7.9-8.0 (2H, m) .

Reference Example 26-1

(R)-2-amino-6-hydroxy-6,7-dihydro-5H-l,2,4- triazolo[5, 1-b] [1,3]thiazine

To a suspension of 3-amino-lH-l,2,4-triazole-5-

thiol (34.8 g) in ethanol were added (S)-(+)-epichlorohydrin (27.8 g) and potassium carbonate (20.7 g) , and the mixture was stirred for 1 hour at room temperature, and heated overnight under reflux. Insolubles were filtered off, and the filtrate was concentrated so that the volume bacame to 200 ml. The filtrate was cooled and precipitated solid substance was collected by filtration to give the title compound (46.7 g) as a colorless solid product. IR (KBr): 3081, 1628, 1553, 1362, 1090 cm ^"1 .

^X H-NMR (DMS0-d ₆ ) δ: 3.09 (1 H, dd, J = 12.8, 6.8 Hz), 3.30 (1 H, dd, J = 12.8, 2.4 Hz), 3.77 (1 H, dd, J = 13.2, 5.2 Hz), 4.01 (1 H, dd, J = 13.2, 3.6 Hz), 4.25-4.40 (1 H, m) , 5.22 (2 H, m) , 5.69 (1 H, d, J = 3.6 Hz) .

Reference Example 26-2

(S)-2-amino-6-benzoylthio-6,7-dihydro-5H-l,2,4-triazolo

[5,1-b] [1,3]thiazine

To a solution of triphenylphosphine (31.2 g) in anhydrous tetrahydrofuran (420 ml) was added diisopropyl azodicarboxylate (23.4 ml) at 0 °C, and the mixture was stirred for 30 minutes at the same temperature. To the mixture were added a solution of (R)-2-amino-6-hydroxy-6,7-dihydro-5H-l,2,4-triazolo [5, 1-b] [ 1, 3]thiazine (13.7 g) in anhydrous dimethylformamide (70 ml) and thiobenzoic acid (14.0 ml) in the order mentioned at 0 °C. The mixture was stirred for 3 hours at the same temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residual solid substance was collected by filtration,

and washed with ethyl acetate-ether (1 : 1 ; 150 ml) to. give the title compound (10.8 g) as a pale yellow solid product. The filtrate was concentrated and the residue was filtered off, and washed with ethyl acetate. The filtrate was concentrated and the residue was subjected to flash-column chromatography (carrier : silica gel,200 g; developing solvent : ethyl acetate-hexane=2: 1 - ethyl acetate) to give the title compound (1.18 g) as a pale yelow solid product. IR (KBr): 3330, 1665, 1541, 1362, 1209, 912, 743 cm ^"1 . ^X H-NMR (CDC1 ₃ ) δ: 3.32 (1 H, dd, J = 13.0, 7.8 Hz), 3.54 (1 H, dd, J = 13.0, 2.6 Hz), 4.08 (2 H, brs) , 4.17 (1 H, dd, J = 13.2, 7.0 Hz), 4.44 (1 H, dd, J = 13.2, 2.4 Hz), 4.50-4.70 (1 H, m) , 7.35-7.70 (3 H, m) , 7.90-8.00 (2 H, m) .

Reference Example 27-1

(R)-6-hydroxy-6,7-dihydro-5H-[1,2,3]triazolo[5, 1-b]

[1,3]thiazine

To a suspension of sodium salt of 2-mercapto- 1,2,3-triazole (10.0 g) in ethanol (300 ml) was added (s)-epichlorohydrin (5.00 ml), and the mixture was stirred for 18 hours at room temperature. Insolubles were filtered off and filtrate was concentrated under reduced pressure. The residue was dissolved in n-butanol (about 200 ml), and to the solution was added diethyl ether. The precipitated solid substance was collected by filtration and dried under reduced pressure to give the title compound (9.00 g) . IR (KBr) : 3161, 1490, 1234, 1039, 987, 736cm ^"1 . ^- MR (DMS0-d ₆ ) δ: 3.08 (IH, dd, J=12.4, 6.2Hz), 3.29

(IH, ), 4.34-4.49 (3H, m) , 5.71 (IH, d, J=3.6Hz), 7.51 (IH, s).

Reference Example 27-2 (R)-6-methanesulfonyloxy-6,7-dihydro-5H-[ 1, 2, 3 ]triazolo [5, 1-b] [l,3]thiazine

To a solution of (R)-6-hydroxy-6 ,7-dihydro-5H-

[l,2,3]triazolo[5,l-b] [ 1,3Jthiazine (5.50 g) in DMF (100 ml) were added methanesulfonylchloride (4.00 ml) and triethylamine( 10.0 ml) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off, and to the residue was added water. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated aqueous saline solution, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether, and dried under reduced pressure to give the title compound (6.51 g) as a pale yellow solid product. IR (KBr) : 1598, 1494, 1357, 1178cm. _! . ^-NMR (CDC1 ₃ ) δ: 3.13 (3H, s), 3.42 (2H, d, J=3.8Hz), 4.57 (IH, dd, J=14.6, 3.6Hz), 4.84 (IH, dd, J=14.6, 4.8Hz), 5.57 (IH, m) , 7.50 (IH, s). Reference Example 27-3

(S)-6-acetylthio-6,7-dihydro-5H-[1,2,3]triazolo[5, 1-b] [1,3Jthiazine To a solution of (R)-6-methanesulfonyloxy-6,7- dihydro-5H-[l,2,3]triazolo[5,l-b] [ 1,3]thiazine (6.50 g) in DMF (100 ml) was added potassium thioacetate (18.0 g) , and the mixture was stirred for 2.5 hours at 80 °C. The solvent was distilled off under reduced pressure, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous saline solution, saturated aqueous solution of sodium hydrogencarbonate in the order mentioned. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (carrier : silica gel, lOOg; developing solvent : hexane-ethyl acetate=l: 1) . A fraction containing the title compound was concentrated, and recrystallization from ethyl acetate gives the title compound (2.40 g) as pale yellow needles.

IR (KBr) : 1694, 1489, 1422, 1354, 1227, 1119, 974, 627cm ^"1 .

^: H-NMR (CDC1 ₃ ) δ: 2.40 (3H, s), 3.17 (IH, dd, J=12.8, 8.4Hz), 3.40 (IH, dd, J=13.2, 2.6Hz), 4.36-4.55 (2H, m), 4.72 (IH, dd, J=13.2, 3.6Hz), 7.46 (IH, s).

Working Example 1

4-Nitrobenzyl (4R,5S,6S)-3-(6 ,7-dihydro-5H-imidazo[2,1- b] [ 1, 3]thiazin-6-ylthio)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

To a THF-methanol solution (1:1, 15 ml) of 5- benzoylthio-6,7-dihydro-5H-imidazo[2, 1-b]thiazine (350 mg) was added, at 0°C, sodium methoxide (68 mg) . The mixture was stirred for one hour at 0°C, to which were added acetic acid (0.08 ml) and acetonitrile (20 ml). The mixture was concentrated under reduced pressure until the volume of the solvent was reduced to about 5 ml. Insolubles were filtered off, and the filtrate was washed with acetonitrile (20 ml). To the filtrate thus obtained were added, at 0°C, 4-nitrobenzyl (4R,5R,6S)- 3-[ (diphenylphosphono)oxy]-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carbo- xylate (747 mg) and diisopropyl ethylamine (0.24 ml). The mixture was stirred for 2 hours at 0°C. The resulting solid matter was collected by filtration, which was washed with acetonitrile to afford diastereomer-2 (more polar) (237 mg) of the title compound as a colorless solid product. To the filtrate was added ethyl acetate, which was washed with a saturated aqueous solution of sodium hydrogencarbonate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate - ethanol, 19:1) to afford

diastereomer-1 (less polar) of the title compound (197 mg) as a colorless solid product. Diastereomer-1

IR(KBr): 3427, 1768, 1705, 1520, 1344 cm ^"1 . ^X H-NMR(DMSO-d ₆ ) δ: 1.16(3H,d,J=6.2Hz) ,

1.21(3H,d,J=7.4Hz) , 3.20-3.50(2H,m) , 3.50-3.70(2H,m) , 3.90-4.15(3H,m) , 4.32(lH,dd,J=9.4,2.8Hz) , 4.35- 4.55(lH,m), 5.13(lH,d,J=4.8Hz) , 5.39(2H,ABq,J=14.0Hz) , 6.88(lH,d,J=1.2Hz), 7.18(lH,d,J=l.2Hz) , 7.71(2H,d,J=8.8Hz), 8.24(2H,d,J=8.8Hz) . Diastereomer-2

IR(KBr): 1765, 1703, 1520, 1344 cm ^"1 . ^-NMRfDMSO-de) δ: 1.16(3H,d,J=6.6Hz) , 1.20(3H,d,J=8.4Hz) , 3.30-3.50(2H,m) , 3.50-3.80(2H,m) , 3.90-4.50(5H,m) , 5.14(lH,d,J=4.8Hz) , 5.36(2H,

ABq,J=14.2Hz) , 6.88(lH,d,J=l.2Hz) , 7.14(lH,d,J=l.2Hz) ,

7.66(2H,d,J=8.6Hz) , 8.23(2H,d,J=8.6Hz) .

Working Example 2

Sodium (4R,5S,6S)-3-(6,7-dihydro-5H-imidazo[2,1- b] [l,3]thiazin-6-ylthio)-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (diastereomer-1)

Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (192 mg) was dissolved in a mixture of THF (8 ml) and a pH 7 phosphate buffer solution (0.2M, 8 ml). To the solution was added 10% palladium- carbon (200 mg), which was subjected to hydrogenation for one hour at room temperature under atmospheric pressure. The catalyst was filtered off and washed with water sufficiently. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography (carrier: CHP-20P, 100 ml, developing solvent: water _→ 5% ethanol), followed by

freeze-drying to afford the title compound (125 mg) as a colorless solid product. IR(KBr): 3392, 1751, 1599, 1394 cm ^"1 . δ: 1.23(3H,d,J=7.0Hz) , 1.30(3H,d,J=6.6Hz) , 3.20-3.60(4H,m) , 3.90-4.20(2H,m) , 4.20-4.40(2H,m) , 4.40-4.60(lH,m), 6.99(lH,s), 7.14(lH,s). Working Example 3

1-(cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6, 7- dihydro-5H-imidazo[2, 1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- l-hydroxyethyl]-4-methyl-7-σxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (diastereomer-1)

Diastereomer-1 of sodium (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2, 1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- 1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (40 mg) was dissolved in dry N,N- dimethylacetamide (2 ml) at -15°C. To the solution was added ( 1-iodoethyl)cyclohexyl carbonate (45 mg) . The mixture was stirred for one hour at -15°C. To the reaction mixture was added ethyl acetate, which was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a flash column chromatography (carrier: silica gel, 6 g, developing solvent: ethyl acetate - ethanol, 25:1) to afford the title compound (39 mg) as a colorless solid product. IR(KBr): 3423, 1761, 1279 cm ^"1 . ^-NMRfCDCla) δ: 1.10-2.10( HH,m) , 1.30(3H,d,J=7.2Hz) , 1.35(1.5H,d,J=6.4Hz), 1.37( 1.5H,d,J=6.2Hz) , 1.60(1.5H,d,J=5.2Hz), 1.62 ( 1.5H,d,J=5.2Hz) , 3.00- 3.20(lH,m), 3.20-3.50(2H,m) , 3.29( lH,dd,J=7.0,2.8Hz) , 3.80-4.00(2H,m) , 4.15-4.45( 3H,m) , 4.50-4.80( lH,ra) , 6.80-7.00(lH,m) , 6.92( lH,d,J=l .4Hz) , 7.03(lH,d,J=1.4Hz) .

Working Example 4

Sodium (4R,5S,6S)-(6,7-dihydro-5H-imidazo[2, 1-b] [1,3] thiazin-6-ylthio)-6-[ (R)-l-hydroxyethyl]-4-methyl-7- oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (diastereomer-2)

Diastereomer-2 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2, 1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-carboxylate (235 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (153 mg) as a colorless solid product. IR(KBr): 3358, 1751, 1599, 1392 cm ^"1 .

¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.0Hz) , 1.30(3H,d,J=6.6Hz) , 3.30-3.70(4H,m) , 4.00-4.20(2H,m) , 4.20-4.50(3H,m) , 6.99(lH,s), 7.09(lH,s). Working Example 5

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2, 1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- 1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-carboxylate (diastereomer-2)

Diastereomer-2 of sodium (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2, 1-b] [l,3]thiazin-6-ylthio)-6-[ (R)- l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (39 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (42 mg) as a pale yellow solid product. IR(KBr): 3425, 1761, 1279 cm ^'1 .

¹ H-NMR(CDC1 ₃ ) δ: 1.10-2.10( HH,m) , 1.28(3H,d,J=7.2Hz) , 1.33(1.5H,d,J=6.4Hz), 1.35( 1.5H,d,J=6.2Hz) , 1.60(1.5H,d,J=5.4Hz) , 1.62( 1.5H,d,J=5.4Hz) , 3.20-

3.50(4H,m), 3.80-4.10(2H,m) , 4.10-4.40(3H,m) , 4.50- 4.80(lH,m), 6.80-6.95(2H,m), 7.02( lH,d,J=l .4Hz) . Working Example 6 (4R,5S,6S)-6-[ (R)-1-Hydroxyethyl]-4-methyl-3-( 1-methy1- 6,7-dihydro-5H-imidazo[2, 1-b] [ 1,3]thiazinium-6-ylthio) - 7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

(diastereomer-1)

Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2,1-b]1,3]thiazin-6-ylthio)-6-[ (R)- l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (46 mg) was dissolved in acetonitrile (2 ml). To the solution was added methyl iodide (0.28 mg), and the mixture was stirred for 8 hours at room temperature. The reaction mixture was concentrated, which was dissolved in a mixture of THF (2 ml) and a pH 7 phosphate buffer solution (0.2M, 2 ml). To the solution was added 10% palladium-carbon (100 mg) , which was subjected to hydrogenation for 2.5 hours at room temperature under normal pressure. The catalyst was filtered off and washed with water sufficiently. The filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, which was purified by means of a column chromatography (carrier: CHP-20P, 30 ml, developing solvent: water -» 5% ethanol), followed by freeze-drying to afford the title compound (22 mg) as a colorless solid product. IR(KBr): 3427, 1751, 1597 cm ^"1 . δ: 1.24(3H,d,J=7.0Hz) , 1.30(3H,d,J=6.2Hz) , 3.35-3.60(3H,m), 3.60-3.80(lH,m) , 3.67(3H,s), 4.05- 4.40(4H,m), 4.60(lH,dd,J=13.2,4.0Hz) , 7.39(2H,s). Working Example 7

(4R,5S,6S)-6-[ (R)-1-Hydroxyethyl]-4-methyl-3-(1-methyl- 6,7-dihydro-5H-imidazo[2,1-b] [1,3]thiazinium-6-ylthio)- 7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (diastereomer-2)

Diastereomer-2 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-imidazo[2,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)- 1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (43 mg) was subjected to the same reaction as in Working Example 6 to afford the title compound (20 rag) as a colorless solid product.

IR(KBr): 3404, 1751, 1599 cm ^"1 .

^-NMRfDzO) δ: 1.24 (3H,d,J=7.0Hz) , 1.30(3H,d,J=6.6Hz) , 3.35-3.70(3H,m) , 3.67(3H,s), 3.75-3.90(lH,m) , 4.20- 4.40(4H,m), 4.40-4.55(lH,m), 7.34(lH,s), 7.39(lH,s) . Working Example 8a

4-Nitrobenzyl (4R,5S, 6S)-3-(6,7-dihydro-5H-l,2,4- triazolo [5, 1-b] [1,3]thiazin-6-ylthio)-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate 6-Benzoylthio-6,7-dihydro-5H-l,2,4-triazolo[5, 1-b] [ 1, 3Jthiazine (710 mg) was subjected to the same reaction as in Working Example 1 to afford diastereomer-1 (less polar) (415 mg) and diastereomer-2 (more polar) (512 mg) of the title compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3423, 1772, 1713, 1522, 1348 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.33(3H,d,J=7.4Hz) , 1.38(3H,d,J=6.2Hz) , 1.62( lH,brs) , 3.15-3.50(4H,m) , 3.85-4.05(lH,m), 4.05-4.20( lH,m) , 4.20-4.40(2H,m) , 4.55-4.75(lH,m), 5.39(2H,ABq,J=13.6Hz) , 7.66(2H,d,J=9.0Hz), 7.89(lH,s), 8.24(2H,d,J=9.0Hz) . Diastereomer-2 IR(KBr): 3413, 1770, 1713, 1522, 1348 cm ^"1 . δ: 1.31(3H,d,J=7.4Hz) ,

1.36(3H,d,J=6.2Hz) , 1.63( lH,brs) , 3.25-3.50(4H,m) , 3.90-4.10(lH,m), 4.15-4.40(3H,m) , 4.40-4.60( lH,m) , 5.38(2H,ABq,J=13.8Hz) , 7.65(2H,d,J=8.6Hz) , 7.87{lH,s), 8.24(2H,d,J=8.6Hz) . Working Example 8b-l

Sodium (4R,5S,6S)-(6,7-dihydro-5H-l,2,4-triazolo[5, 1-b] [ l,3]thiazin-6-ylthio)-6-[ (R)-l-hydroxyethyl]-4-methyl- 7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (diastereomer-1) Diastereomer-1 of 4-nitrobenzyl (4R,5S, 6S)-3-( 6 , 7- dihydro-5H-l,2,4-triazolo[5, 1-b] [ 1,3]thiazin-6-ylthio) -

6- [ ( R) -l-hydroxyethyl ] -4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (260 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (154 mg) as a colorless solid product.

IR(KBr): 3423, 1751, 1601, 1392 cm ^"1 .

¹ H-NMR(D ₂ 0) δ: 1.24(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.2Hz) ,

3.30-3.60(4H,m) , 4.00-4.35(4H,m) , 4.55-4.70( lH,m) ,

7.98(lH,s) . Working Example 8c-l

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,4-triazolo[5,1-b] [ 1,3]thiazin-6-ylthio)-

6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclof3.2.0]hept-2-ene-2-carboxylate (diastereomer-1)

Diastereomer-1 of sodium (4R,5S,6S)-3-(6, 7- dihydro-5H-l,2,4-triazolo[5, 1-b] [1,3]thiazin-6-ylthio)-

6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (49 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (52 mg) as a colorless solid product.

IR(KBr): 3427, 1761, 1275 cm ^"1 .

¹ H-NMR(CDC1 ₃ ) δ: 1.10-2.10(20H,m) , 3.15-3.50(4H,m) , 3.85-4.20(2H,m), 4.20-4.35(2H,m) , 4.55-4.75(2H,m) ,

6.90(lH,q,J=5.4Hz), 7.88(lH,s).

Working Example 8b-2

Sodium (4R,5S,6S)-3-(6, 7-dihydro-5H-l,2,4-triazolo[5,1- b] [ l,3]thiazin-6-ylthio)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (diastereomer-2)

Diastereomer-2 of 4-nitrobenzyl (4R,5S,6S)-3-( 6, 7- dihydro-5H-l,2,4-triazolo[5, 1-b] [ 1,3]thiazin-6-ylthio) -

6-[ (R)-1-hydroxyethyl]-4-methy1-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (325 mg) was subjected to the same reaction as in Working Example 2

to afford the title compound (187 mg) as a colorless solid product.

IR(KBr): 3425, 1751, 1599, 1394 cm ^"1 .

¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.4Hz) , 3.35-3.60(3H,m), 3.60-3.75(lH,m) , 4.15-4.35(4H,m) , 4.45-4.60(lH,m), 7.97(lH,s). Working Example 8c-2

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6 ,7- dihydro-5H-l,2,4-triazolo[5, 1-b] [1,3]thiazin-6-ylthio)- 6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclof3.2.0]hept-2-ene-2-carboxylate (diastereomer-2)

Diastereomer-2 of sodium (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,4-triazolo[5,1-b] [1,3]thiazin-6-ylthio)- 6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-carboxylate (56 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (60 mg) as a colorless solid product. IR(KBr): 3427, 1759, 1275 cm ^"1 . 3.30(lH,dd,J=6.8,2.8Hz) , 3.25-3.50(3H,m) , 3.95- 4.35(4H,m), 4.51(lH,dd,J=13.4,4.2Hz), 4.55-4.75( lH,m) , 6.89(lH,q,J=5.4Hz) , 7.86(lH,s). Working Example 9a

4-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H-l,2,3- triazolo[5,l-b] [1,3]thiazin-6-ylthio)-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate 6-Benzoylthio-6,7-dihydro-5H-l,2, 3-triazolo[5, 1-b] [1, 3Jthiazine (710 mg) was subjected to the same reaction as in Working Example 1 to afford diastereomer-1 (less polar) (533 mg) and diastereomer-2 (more polar) (437 mg) of the title compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3423, 1770, 1711, 1522, 1348 cm ^"1 . δ: 1.16(3H,d,J=6.4Hz) ,

1.22(3H,d,J=7.0Hz) , 3.20-3.50(2H,m) , 3.50-3.65(2H,m) ,

3.90-4.25(2H,m) , 4.32(lH,dd,J=9.6,2.4Hz) , 4.45(lH,dd,J=13.0,8.4Hz) , 4.85(lH,dd,J=13.0,4.2Hz) ,

5.13(lH,d,J=5.0Hz) , 5.39(2H,ABq,J=14.0Hz) , 7.63(lH,s),

7.70(2H,d,J=8.8Hz) , 8.23(2H,d,J=8.8Hz) .

Diastereomer-2

IR(KBr): 3429, 1770, 1711, 1522, 1346 δ: 1.16(3H,d,J=7.0Hz) ,

1.20(3H,d,J=7.2Hz) , 3.20-3.50(2H,m) , 3.60-3.80(2H,m) ,

3.90-4.10(lH,m), 4.25-4.40(2H,m) , 4.55-4.80(2H,m) ,

5.13(lH,d,J=5.2Hz) , 5.33(2H,ABq,J=13.8Hz) , 7.63(lH,s),

7.63(2H,d,J=8.8Hz), 8.21(2H,d,J=8.8Hz) . Working Example 9b-1

Sodium (4R,5S,6S)-3-(6,7-dihydro-5H-l,2,3-triazolo[5,1- b] [1,3Jthiazin-6-ylthio)-6-[ (R)-1-hydroxyethylJ-4- methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2-ene-2- carboxylate (diastereomer-1) Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,3-triazolo[5,1-bJ[1,3]thiazin-6-ylthio)-

6-[ (R)-l-hydroxyethyl)-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (324 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (208 mg) as a colorless solid product.

IR(KBr): 3431, 1751, 1601, 1392 cm ^"1 . δ: 1.24(3H,d,J=7.4Hz) , 1.30(3H,d,J=6.6Hz) ,

3.27(lH,dd,J=13.2,8.8Hz) , 3.35-3.55(2H,m) , 3.51(lH,dd,J=6.0,2.8Hz) , 4.00-4.20(lH,m) , 4.20-

4.40(2H,m), 4.42(lH,dd,J=13.6,8.8Hz) , 4.80-5.00( lH,m) ,

7.58(lH,s) .

Working Example 9b-2

Sodium (4R,5S,6S)-3-(6,7-dihydro-5H-l,2,3-triazolo[5, 1- b] [ l,3]thiazin-6-ylthio)-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-

carboxylate (diastereomer-1)

Diastereomer-2 of 4-nitrobenzyl (4R,5S,6S)-3-(6, 7- dihydro-5H-l,2,3-triazolo[5, 1-bJ [ 1, 3Jthiazin-6-ylthio)-

6-[ (R)-1-hydroxyethylJ-4-methyl-7-oxo-1- azabicyclo[3.2.0Jhept-2-ene-2-carboxylate (283 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (169 mg) as a colorless solid product.

IR(KBr): 3431, 1751, 1601, 1392 cm ^"1 . ¹ H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.2Hz) , 1.31(3H,d,J=6.2Hz) ,

3.34(lH,dd,J=13.0,7.6Hz) , 3.40-3.65(3H,m) , 4.15-

4.35(3H,m) , 4.51( lH,dd,J=14.0,6.2Hz) ,

4.74{lH,dd,J=14.0,3.6Hz) , 7.58(lH,s) .

Working Example 9c-l l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,3-triazolo[5, 1-bJ [ 1,3]thiazin-6-ylthio)-

6-[ (R)-l-hydroxyethylJ-4-methyl-7-oxo-l- azabicyclo[3.2.0Jhept-2-ene-2-carboxylate

(Diastereomer-1) Diastereomer-1 of sodium (4R,5S,6S)-(6,7-dihydro-

5H-1,2,3-triazolo[5, 1-b] [1,3]thiazin-6-ylthio)-6-[ (R)-

1-hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-

2-ene-2-carboxylate (53 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (57 mg) as a colorless solid product.

IR(KBr): 3439, 1761, 1277 cm ^"1 .

^-NMRfCDCla) δ: 1.10-2.10(20H,m) , 3.10-3.45(4H,m) ,

3.85-4.00(lH,m), 4.10-4.35(3H,m) , 4.55-4.75( lH,m) ,

4.85-5.05(lH,m) , 6.90( lH,q,J=5.4Hz) , 7.48(1H,S). Working Example 9c-2

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6 ,7- dihydro-5H-l,2,3-triazolo[5, 1-b] [ 1,3]thiazin-6-ylthio) -

6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0Jhept-2-ene-2-carboxylate (diastereomer-2)

Diastereomer-2 of sodium (4R, 5S,6S)-3-(6, 7-

dihydro-5H-l,2, 3-triazolo[5, 1-b] [1,3]thiazin-6-ylthio)-

6-[ (R)-1-hydroxyethyl}-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (44 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (52 mg) as a colorless solid product.

IR(KBr): 3410, 1761, 1277 cm ^"1 .

^-NMRfCDCla) δ: 1.10-2.10(20H,m) , 3.10-3.50(4H,m) ,

3.90-4.10(lH,m), 4.15-4.40(3H,m) , 4.55-4.85(2H,m) , 6.90(lH,q,J=5.6Hz), 7.47(lH,s).

Working Example 10a

4-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H-tetrazolo

[5,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2- carboxylate

6-Benzoylthio-6,7-dihydro-5H-tetrazolo[5,1-b] [ 1, 3 ] thiazine (349 mg) was subjected to the same reaction as in Working Example 1 to afford diastereomer-1 (less polar) (267 mg) and diastereomer-2 (high polarity) (283 mg) of the title compound as colorless solid products, respectively.

Diastereomer-1

IR(KBr): 3431, 1772, 1713, 1522, 1346 cm ^"1

¹ H-NMR(DMSO-d ₆ ) 6: 1.16(3H,d,J=6.8Hz) , 1.21(3H,d,J=7.4Hz) , 3.25-3.40( lH,m) , 3.40-3.80( 3H,m) ,

3.90-4.10(lH,m), 4.15-4.40( lH,m) ,

4.32(lH,dd,J=9.6,2.6Hz) , 4.51( lH,dd,J=13.0,8.2Hz) ,

4.91(lH,dd,J=13.0,4.8Hz) , 5.1 ( lH,d,J=5.0Hz) ,

5.40(2H,ABq,J=13.8Hz) , 7.70(2H,d,J=8.8Hz) , 8.24(2H,d,J=8.8Hz) .

Diastereomer-2

IR(KBr): 3446, 1767, 1703, 1522, 1346 cm ^"1

^-NMRfDMSO-d δ: 1.16 (3H,d,J=7.2Hz) ,

1.20(3H,d,J=7.0Hz) , 3.25-3.40( lH,m) , 3.50-3.90(3H,m) , 3.90-4.10( lH,m) , 4.33( lH,dd,J=9.6,2.8Hz) , 4.30-

4.50(lH,m), 4.70-4.80(2H,m), 5.13( lH,d,J=5.2Hz) ,

5 . 33 ( 2H , ABq , J=14 . 0Hz ) , 7 . 62 ( 2H , d , J=9 . 0Hz ) ,

8 . 22 ( 2H , d , J=9 . 0Hz ) .

Working Example 10b-1

Sodium (4R,5S,6S)-3-(6,7-dihydro-5H-tetrazolo[5,1- b] [l,3]thiazin-6-ylthio)-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (diastereomer-1)

Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-tetrazolo[5,1-b] [1,3]thiazin-6-ylthio)-6- [ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (263 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (163 mg) as a colorless solid product. IR(KBr): 3429, 1751, 1601, 1394 cm ^"1 . 6: 1.24(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.2Hz) ,

3.35-3.65(4H,m), 4.00-4.20(lH,m) , 4.20-4.35(2H,m) ,

4.48(IH,dd,J=13.6,8.8Hz) , 4.96(IH,dd,J=13.6,5.0Hz) .

Working Example lOc-1 l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6,7- dihydro-5H-tetrazolo[5,1-b][1,3]thiazin-6-ylthio)-6-

[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

(diastereomer-1) Diastereomer-1 of sodium (4R,5S,6S)-(6,7-dihydro-

5H-tetrazolo[5,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate (39 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (45 mg) as a colorless solid product.

IR(KBr): 3439, 1761, 1279 cm ^"1 . δ: 1.15-2.05(20H,m) , 3.20-3.40(4H,m) ,

3.90-4.10(lH,m), 4.15-4.40(3H,m) , 4.55-4.75(lH,m) ,

4.85-5.00(lH,m) , 6.90(lH,q,J=5.4Hz) . Working Example 10b-2

Sodium (4R,5S,6S)-3-(6,7-dihydro-5H-tetrazolo[5,1-

b] [1,3]thiazin-6-ylthio)-6-[ (R)-1-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-carboxylate

(diastereomer-2)

Diastereomer-2 of 4-Nitrobenzyl (4R,5S,6S)-3-(6, 7- dihydro-5H-tetrazolo[5, 1-b] [1,3]thiazin-6-ylthio)-6-

[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (277 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (162 mg) as a colorless solid product.

IR(KBr): 3427, 1751, 1601, 1394 cm ^"1 .

^X H-NMR(D ₂ 0) δ: 1.24(3H,d,J=7.2Hz) , 1.30(3H,d,J=6.2Hz) ,

3.35-3.60(3H,m) , 3.73( lH,dd,J=13.0,3.0Hz) , 4.15-

4.35(3H,m), 4.59( lH,dd,J=14.0,6.2Hz) , 4.70-4.90( lH,m) . Working Example 10c-2 l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6, 7- dihydro-5H-tetrazolo[5, 1-b] [1,3]thiazin-6-ylthio)-6-

[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (diastereomer-2)

Diastereomer-2 of sodium (4R,5S,6S)-3-(6,7- dihydro-5H-tetrazolo[5, 1-b] [1,3]thiazin-6-ylthio)-6-

[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (41 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (49 mg) as a colorless solid product.

IR(KBr): 3427, 1761, 1279 cm ^"1 . δ: 1.20-2.10(20H,m) , 3.20-3.60(4H,m) , 4.05-4.50(4H,m) , 4.50-4.85(2H,m) , 6.88(0.5H,q,J=5.4Hz) ,

6.89(0.5H,q,J=5.4Hz) .

Working Example 11a

4-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H-l,2,4- triazolo[3,4-b] [ 1,3]thiazin-6-ylthio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[ 3.2.0]hept-2- ene-2-carboxylate

6-Benzoylthio-6,7-dihydro-5H-l,2,4-triazolo[3,4-b]. [ 1, 3 ]thiazine (710 mg) was subjected to the same reaction as in Working Example 1 to afford diastereomer-1 (low polarity) (662 mg) and diastereomer-2 (high polarity) (530 mg) of the title compound as colorless solid products, respectively. Diastereomer-1

IR(KBr): 3408, 1768, 1711, 1520, 1344 cm ^"1 . ^-NMRfDMSO-d δ: 1.16(3H,d,J=6.6Hz) , 1.21(3H,d,J=7.4Hz) , 3.20-3.50(2H,m) , 3.50-3.70(2H,m) , 3.90-4.25(3H,m) , 4.32( lH,dd,J=9.4,2.6Hz) , 4.45- 4.60(lH,m), 5.13(lH,d,J=5.0Hz) , 5.39(2H,ABq,J=14.0Hz) , 7.70(2H,d,J=8.8Hz) , 8.24(2H,d,J=8.8Hz) , 8.55(lH,s). Diastereomer-2 IR(KBr): 3250, 1767, 1709, 1518, 1344 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.16(3H,d,J=6.2Hz) ,

1.19(3H,d,J=7.8Hz) , 3.20-3.55(2H,m) , 3.55-3.80(2H,m) , 3.90-4.10(lH,m), 4.10-4.55(4H,m) , 5.14(lH,d,J=5.4Hz) , 5.35(2H,ABq,J=14.2Hz) , 7.64(2H,d,J=8.8Hz) , 8.23(2H,d,J=8.8Hz) , 8.49(lH,s). Working Example llb-1

Sodium (4R,5S,6S)-3-(6,7-dihydro-5H-l,2,4-triazolo[3,4- b] [l,3]thiazine-6-ylthio)-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (diastereomer-1)

Diastereomer-1 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,4-triazolo[3,4-b] [ 1, 3]thiazin-6-ylthio)- 6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (460 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (236 mg) as a colorless solid product.

IR(KBr): 3427, 1749, 1599, 1394 cm ^"1 . , 1.30(3H,d,J=6.2Hz) , 3.30-3.55(4H,m) , 3.90-4.35(4H,m) , 4.55-4.70( lH,m) , 8.48(lH,s) .

Working Example llc-1 l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6,7- dihydro-5H-1,2,4-triazolo[3,4-b] [1,3]thiazin-6-ylthio)-

6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

(diastereomer-1)

Diastereomer-1 of sodium (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,4-triazolo[3,4-b] [1,3]thiazin-6-ylthio)-

6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (56 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (44 mg) as a colorless solid product.

IR(KBr): 3421, 2939, 1761, 1279 cm ^"1 . ^-NMRfCDCla) δ: 1.20-2.10(HH,m) , 1.28(3H,d,J=7.4Hz) ,

1.35(1.5H,d,J=6.2Hz) , 1.37(1.5H,d,J=6.0Hz) ,

1.59(1.5H,d,J=5.6Hz) , 1.62(1.5H,d,J=5.4Hz) , 3.15-

3.45(4H,m), 3.80-4.10(2H,m) , 4.15-4.45(2H,m) , 4.45-

4.75(2H,m), 6.89(lH,q,J=5.6Hz), 8.19(0.5H,s) , 8.21(0.5H,s) .

Working Example llb-2

Sodium (4R,5S,6S)-3-(6,7-dihydro-5H-l,2,4-triazolo[3,4- b][l,3]thiazin-6-ylthio]-6-[ (R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (diastereomer-2)

Diastereomer-2 of 4-nitrobenzyl (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,4-triazolo[3,4-b][1,3]thiazin-6-ylthio)-

6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (355 mg) was subjected to the same reaction as in Working Example 2 to afford the title compound (197 mg) as a colorless solid product.

IR(KBr): 3425, 1749, 1599, 1392 cm ^"1 .

^X H-NMR(D ₂ 0) δ: 1.23(3H,d,J=7.0Hz) , 1.30(3H,d,J=6.6Hz) , 3.35-3.55(3H,m), 3.55-3.70(lH,m) , 4.05-4.35(4H,m) , 4.47(lH,d,J=13.2,3.0Hz) , 8.43(lH,s) .

Working Example llc-2

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(6,7- dihydro-5H-l,2,4-triazolo[3,4-b] [1,3]thiazin-6-ylthio)-

6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

(diastereomer-2)

Diastereomer-2 of sodium (4R,5S,6S)-3-(6,7- dihydro-5H-l , 2 ,4-triazolo[3,4-b] [1,3]thiazin-6-ylthio)-

6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (44 mg) was subjected to the same reaction as in Working Example 3 to afford the title compound (41 mg) as a colorless solid product.

IR(KBr): 3412, 2939, 1761, 1279 cm ^"1 . ¹ H-NMR(CDC1 ₃ ) δ: 1.10-2.10(20H,m) , 3.10-4.15(7H,m) ,

4.15-4.35(lH,m) , 4.50-4.90(2H,m) , 6.80-6.95(lH,m) ,

8.25-8.50(lH,m) .

Chemical structural formulae of the compounds in

Working Examples are as follows. Working Example 12a

4-Nitrobenzyl (4R,5S,6S)-3-(2-amino-6,7-dihydro-5H-

1,2,4-triazolo[5,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate 2-Amino-6-benzoylthio-6,7-dihydro-5H-l,2,4- triazolo[5,1-b][1,3]thiazine(796 mg) was subjected to the same reaction and purification procedures as in

Working Example 1 to give diastereomer-1 (low polarity) (533 mg) and diastereomer-2 (high porality) (530 mg) of the title compound as colorless solid products, respectively.

(Diastereomer-1)

IR (KBr) : 3360, 1761, 1707, 1551, 1518, 1346 cm ^"1 .

^-NMR (DMSO-d ₆ ) δ: 1.16 (3 H, d, J = 6.2 Hz), 1.21 (3 H, d, J = 7.4 Hz), 3.10-3.45 (2 H, m) , 3.45-3.70 (2 H, m), 3.85-4.20 (3 H, m) , 4.20-4.40 (2 H, m) , 5.11 (1 H,

d, J = 5.0 Hz), 5.33 (2 H, brs ) , 5.40 (2 H, ABq, J = 14.0 Hz), 7.72 (2 H, d, J = 8.8 Hz), 8.24 (2 H, d, J = 8.8 Hz) .

(Diastereomer-2) IR (KBr): 3306, 1773, 1707, 1547, 1520, 1348 cm ^"1 .

^-NMR (DMSO-d ₆ ) δ: 1.16 (3 H, d, J = 7.2 Hz), 1.20 (3 H, d, J = 7.0 Hz), 3.15-3.55 (2 H, m) , 3.55-3.75 (2 H, m), 3.90-4.10 (2 H, m) , 4.10-4.40 (3 H, m) , 5.10 (1 H, d, J = 5.2 Hz), 5.31 (2 H, brs), 5.36 (2 H, ABq, J = 14.2 Hz), 7.68 (2 H, d, J = 8.8 Hz), 8.23 (2 H, d, J = 8.8 Hz) .

Working Example 12b

Sodium (4R,5S,6S)-3-(2-amino-6,7-dihydro-5H-l,2,4- triazolo[5,l-b] [ 1,3]thiazin-6-ylthio)-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

Diastereomer-1 (350 mg) of 4-nitrobenzyl (4R,5S,6S)-3-(2-amino-6,7-dihydro-5H-l,2,4- triazolo[5,l-b] [1,3]thiazin-6-ylthio)-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate obtained in Working Example 12a was subjected to same reaction procedure as in Working Example 2 to give diastereomer-1 (208 mg) of the title compound as a colorless solid product. Diastereomer-2 (350 mg) of 4-nitrobenzyl (4R,5S,6S)-3-(2-amino-6 ,7- dihydro-5H-1,2,4-triazolo[5, 1-b] [1,3]thiazin-6-ylthio)- 6-[ (R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclof3.2.0]hept-2-ene-2-carboxylate obtained in Working Example 12a was subjected to same reaction procedure as in Working Example 2 to give diastereomer- 2 (207 mg) of the title compound as a colorless solid product.

(Diastereomer-1) IR (KBr) : 3300, 1748, 1597, 1545, 1362 cm ^"1 . Η-NMR (D ₂ 0) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30 (3 H, d, J = 6.2 Hz), 3.25-3.55 (4 H, m) , 3.90-4.15 (2 H, m) ,

4 . 15-4 . 50 ( 3 H , m) .

(Diastereomer-2)

IR (KBr) : 3328, 1752, 1590, 1547, 1366 cm ^"1 .

^! H-NMR (D ₂ 0) δ: 1.23 (3 H, d, J = 7.2 Hz), 1.30 (3 H, d, J = 6.4 Hz), 3.30-3.55 (3 H, m) , 3.63 (1 H, dd, J =

13.0, 2.6 Hz), 3.95-4.40 (5 H, m) .

Working Example 12c

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-(2- amino-6,7-dihydro-5H-l,2,4-triazolo[5, 1-b] [1,3]thiazin- 6-ylthio)-6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Diastereomer-1 (53 mg) of Sodium (4R,5S,6S)-3-(2- amino-6,7-dihydro-5H-l,2,4-triazolo[5,1-b] [1,3]thiazin-

6-ylthio)-6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained in

Working Example 12b was subjected to same reaction procedure as in Working Example 3 to give diastereomer-1 (51 mg) of the title compound as a colorless solid product. Diastereomer-2 (49 mg) of Sodium (4R,5S,6S)-3-(2-amino-6,7-dihydro-5H-l,2,4- triazolo[5,l-b][l,3]thiazin-6-ylthio)-6-[(R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate was subjected to same reaction procedure as in Working Example 3 to give diastereomer-1 (37 mg) of the title compound as a colorless solid product.

(Diastereomer-1)

IR (KBr) : 3339, 2940, 1759, 1547, 1362, 1279 cm ^"1 .

^X H-NMR (CDC1 ₃ ) δ: 1.10-2.20 (14 H, m) , 1.29 (3 H, d, J = 7.2 Hz), 1.34 (1.5 H, d, J = 6.4 Hz), 1.36 (1.5 H, d,

J = 6.2 Hz), 3.05-3.50 (4 H, m) , 3.75-4.00 (2 H, m) ,

4.11 (2 H, brs), 4.15-4.50 (3 H, m) , 4.55-4.75 (1 H, m) , 6.89 (1 H, q, J = 5.4 Hz) .

(Diastereomer-2) IR (KBr) : 3335, 2940, 1759, 1547, 1360, 1277 cm ^"1 .

^! H-NMR (CDC1 ₃ ) δ: 1.10-2.10 (14 H, m) , 1.28 (3 H, d, J

= 7.4 Hz), 1.33 (1.5 H, d, J = 6.2 Hz), 1.35 (1.5 H, d, J = 6.2 Hz), 3.20-3.50 (4 H, m) , 3.85-4.10 (2 H, m) , 4.09 (2 H, brs), 4.15-4.40 (3 H, m) , 4.55-4.75 (1 H, m) , 6.89 (1 H, q, J = 5.4 Hz) . Working Example 12d

Pivaloyloxymethyl (4R,5S,6S)-3-(2-amino-6,7-dihydro-5H- 1,2,4-triazolo[5,1-b] [1,3]thiazin-6-ylthio)-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate (Diastereomer 1)

Diastereomer-1 (37mg) of sodium (4R,5S,6S)-3-(2- amino-6,7-dihydro-5H-1,2,4-triazolo[5,1-b] [1,3]thiazin- 6-ylthio)-6-[(R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained in Working Example 12b was dissolved in dried dimethylacetamide (1 ml) at -15 °C. To the solution was added iodomethyl pivalate (32 mg), and the mixture was stirred for 1 hour at -15 °C. To the reaction mixture was added ethyl acetate, and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous saline solution in the order mentioned, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residual solution was subjected to column chromatography

(carrier : silica gel, 10 g ; developing solvent : ethyl acetate-ethanol, 14 : 1) to give the title compound (19.6 mg) as a colorless solid product. IR (KBr) : 3380, 2976, 1779, 1616, 1545, 1350 cm ^"1 . ^X H-NMR (CDC1 ₃ ) δ: 1.23 (9H, s), 1.30 (3 H, d, J = 7.4 Hz), 1.35 (3 H, d, J = 6.4 Hz), 2.36 (1 H, brs), 3.10-3.25 (1 H, m), 3.25-3.50 (3 H, m) , 3.80-4.00 (2 H, m), 4.14 (2 H, s), 4.20-4.50 (3 H, m) , 5.91 (2 H, ABq, J = 5.4 Hz) . Working Example 13a

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4-

methyl-3-(3-methyl-6, 7-dihydro-5H-l,2,4-triazolo[3,4- b] [ 1,3]thiazin-6-ylthio)-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carbonate

6-Benzoylthio-3-methyl-6,7-dihydro-5H-l,2,4- triazolo[3,4-b] [l,3]thiazine (925 mg) was subjected to the same reaction and purification procedures as in Working Example 1 to give diastereomer-1 (low polarity) (265 mg) and diastereomer-2 (high polarity) (300 mg) of the title compound as colorless solid products, respectively. (Diastereomer-1)

IR (KBr) : 3204, 1763, 1701, 1510, 1339 cm ^"1 . ^-NMR (DMS0-d ₆ ) δ: 1.16 (3 H, d, J = 6.2 Hz), 1.22 (3 H, d, J = 7.4 Hz), 2.32 (3 H, s), 3.20-3.70 (4 H, m) , 3.80-4.10 (3 H, m) , 4.25-4.45 (2 H, m) , 5.14 (1 H, d, J = 5.0 Hz), 5.40 (2 H, ABq, J = 14.0 Hz), 7.71 (2 H, d, J = 8.8 Hz), 8.24 (2 H, d, J = 8.8 Hz). (Diastereomer-2) IR (KBr) : 3248, 1763, 1701, 1522, 1343 cm ^"1 . ^! H-NMR (DMSO-d ₆ ) δ: 1.16 (3 H, d, J = 6.6 Hz) , 1.20 (3 H, d, J = 7.6 Hz), 2.30 (3 H, s), 3.20-3.65 (3 H, m) , 3.72 (1 H, dq, J = 9.4, 7.6 Hz), 3.90-4.40 (5 H, ra) , 5.12 (1 H, d, J = 5.4 Hz), 5.36 (2 H, ABq, J = 14.2 Hz), 7.67 (2 H, d, J = 8.8 Hz), 8.23 (2 H, d, J = 8.8 Hz).

Working Example 13b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-3-( 3- methyl-6,7-dihydro-5H-l,2,4-triazolo[3,4- b] [ l,3]thiazin-6-ylthio)-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate

Diastereomer-1 (260 mg) obtained in Working Example 13a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-1 (I89mg) of the title compound. Diastereomer-2 (300 mg) obtained in Working Example 13a was subjected to the same reaction and purification

procedures as in Working Example 2 to give diastereomer-2 (211 mg) of the title compound.

(Diastereomer-1)

IR (KBr) : 3370, 1732, 1599, 1397 cm ^"1 . ^! H-NMR (D ₂ 0) δ: 1.24 (3 H, d, J = 7.0 Hz), 1.30 (3 H, d, J = 6.2 Hz), 2.40 (3 H, s), 3.20-3.55 (4 H, m) ,

3.85-4.05 (2 H, m) , 4.15-4.55 (3 H, m) .

(Diastereomer-2)

IR (KBr) : 3300, 1736, 1597, 1389 era ^'1 . ^- MR (D ₂ 0) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30 (3 H, d, J = 6.6 Hz), 2.36 (3 H, s), 3.37 (1 H, dd, J = 13.2,

7.0 Hz), 3.40-3.60 (2 H, m) , 3.60 (1 H, dd, J = 13.2,

2.6 Hz) , 3.95-4.35 (5 H, m) .

Working Example 13c l-(cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-

[ (R)-1-hydroxyethyl]-4-methyl-3-(3-raethyl-6,7-dihydro-

5H-1,2,4-triazolo[3,4-b] [1,3]thiazin-6-ylthio)-7-oxo-1- azabicyclof3.2.0]hept-2-ene-2-carboxylate

Diastereomer-1 (39 mg) obtained in Working Example 13b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-1 (29 rag) of the title compound.

Diastereomer-2 (45 mg) obtained in Working Example 13b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-2 (13 mg) of the title compound.

(Diastereomer-1)

IR (KBr) : 3235, 2940, 1759, 1721, 1541, 1277 cm ^"1 . H-NMR (CDC1 ₃ ) δ: 1.10-2.10 (11 H, m) , 1.29 (3 H, d, J = 6.0 Hz), 1.36 (1.5 H, d, J = 8.4 Hz), 1.38 (1.5 H, d,

J = 7.8 Hz), 1.60 (1.5 H, d, J = 5.2 Hz), 1.63 (1.5 H, d, J = 5.2 Hz), 2.43 (3 H, s), 3.05-3.50 (4 H, m) ,

3.60-4.00 (2 H, m), 4.15-4.35 (2 H, m) , 4.41 (1 H, dd,

J = 9.8, 2.4 Hz), 4.50-4.75 (1 H, m) , 6.90 (1 H, q, J = 5.2 Hz) .

(Diastereomer-2 )

IR (KBr) : 3248, 2940, 1767, 1541, 1275 cm ^"1 . ^-NMR (CDC1 ₃ ) δ: 1.00-2.10 (20 H, m) , 2.47 (1.5 H, s), 2.49 (1.5 H, s), 3.05-3.60 (4 H, m) , 3.60-6.90 (2 H, s), 3.90-4.10 (1 H, ra), 4.10-4.35 (1 H, m) , 4.35-4.70 (2 H, m), 6.89 (0.5 H, q, J = 5.2 Hz), 6.92 (0.5 H, q, J = 5.2 Hz) . Working Example 14a

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4- methyl-3-(2-methyl-6,7-dihydro-5H-l,2,4-triazolo[5,1- b] [ 1, 3]thiazin-6-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate

6-Benzoylthio-2-methyl-6,7-dihydro-5H-l,2,4- triazolo[5, 1-b] [1,3Jthiazine (887 mg) was subjected to the same reaction and purification procedures as in Working Example 1 to give diastereomer-1 (low polarity) (470 mg) and diastereomer-2 (high polarity) (533 mg) as colorless solid products, respectively. (Diastereomer-1) IR (KBr) : 3417, 1772, 1705, 1518, 1340 cm ^"1 .

^X H-NMR (DMSO-d ₆ ) δ: 1.16 (3 H, d, J = 6.4 Hz), 1.21 (3 H, d, J = 7.2 Hz), 2.20 (3 H, s), 3.25-3.70 (4 H, m) , 3.90-4.25 (3 H, m) , 4.31 (1 H, dd, J = 9.6, 2.6 Ha), 4.40-4.60 (1 H, ra), 5.11 (1 H, d, J = 5.0 Hz), 5.39 (2 H, ABq, J = 14.0 Hz), 7.71 (2 H, d, J = 8.8 Hz), 8.23 (2 H, d, J = 8.8 Hz). (Diastereoraer-2)

IR (KBr) : 3404, 1770, 1709, 1520, 1348 cm ^"1 . ^-NMR (DMSO-d ₅ ) δ: 1.16 (3 H, d, J = 7.0 Hz), 1.20 (3 H, d, J = 7.6 Hz), 2.18 (3 H, s), 3.20-3.55 (2 H, m) ,

3.55-3.80 (2 H, m) , 3.90-4.10 (1 H, m) , 4.15-4.35 (3 H, m), 4.35-4.55 (1 H, m) , 5.10 (1 H, d, J = 5.2 Hz), 5.35 (2 H, ABq, J = 14.0 Hz), 7.66 (2 H, d, J = 8.8 Hz), 8.21 (2 H, d, J = 8.8 Hz) . Working Example 14b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-3-( 2-

methyl-6,7-dihydro-5H-l,2,4-triazolo[5,1- b] [1,3]thiazin-6-ylthio)-7-oxo-l-azabicyclo[3.2.0Jhept-

2-ene-2-carboxylate

(Diastereomer 1) Diastereomer-1 (300 mg) of 4-nitrobenzyl

(4R,5S,6S)-6-[ (R)-1-hydroxyethyl]-4-methyl-3-(2-methyl-

6,7-dihydro-5H-l,2,4-triazolo[5,1-b] [1,3]thiazin-6- ylthio)-7-oxo-l-azabicyclo[3.2.0Jhept-2-ene-2- carboxylate obtained in Working Example 14a was subjected to the same reaction and purification procedures as in Working Example 2 to give the title compound (197 mg) as a colorless solid product.

Diastereomer-2 (330 mg) of 4-nitrobenzyl

(4R,5S,6S)-6-[ (R)-1-hydroxyethylJ-4-methyl-3-(2-methyl- 6,7-dihydro-5H-l,2,4-triazolo[5,1-b] [1,3Jthiazin-6- ylthio)-7-oxo-l-azabicyclo[3.2.0Jhept-2-ene-2- carboxylate obtained in Working Example 14b was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-2 (197 mg) of the title compound as a colorless solid product.

(Diastereomer-1)

IR (KBr) : 3429, 1751, 1595, 1396 cm ^"1 .

^X H-NMR (D ₂ 0) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30 (3 H, d, J = 6.2 Hz), 2.29 (3 H, s), 3.25-3.60 (4 H, m) ,

4.00-4.35 (4 H, m) , 4.50-4.65 (1 H, m) .

( Diastereomer-2 )

IR (KBr) : 3427, 1740, 1595, 1394 cm ^"1 .

^X H-NMR (D ₂ 0) δ: 1.22 (3 H, d, J = 5.4 Hz), 1.30 (3 H, d, J = 6.4 Hz), 2.29 (3 H, s), 3.30-3.55 (3 H, m) ,

3.60-3.75 (1 H, m) , 4.10-4.35 (4 H, m) , 4.35-4.55 (1 H, ra) .

Working Example 15a

4-Nitrobenzyl (4R,5S,6S)-3-[ (2,3-dimethyl-6,7-dihydro- 5H-imidazo[2,l-b][l,3jthiazin-6-yl)thio]-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept- -

ene-2-carboxylate

To a solution of 6-benzoylthio-2, 3-dimethyl-6 , 7- dihydro-5H-imidazo[2, 1-bJ [1,3Jthiazine(2.27 g, content 67 wt%) in methanol (25 ml) was added sodium methoxide (28% methanol solution, 965 mg) at 0 °C. The mixture was stirred for 1 hour at 0 °C. To the reaction mixture were added acetic acid (0.315 ml) and acetonitrile (30 ml), and the mixture was concentrated under reduced pressure. To the residue was added acetonitrile (20 ml) and insolubles were filtered off. The filtrate was washed with acetonitrile (30 ml). To the obtained filtrate were added 4-nitrobenzyl (4R,5R,6S)-3-(diphenoxyphosphoryloxy)-6-[ (R)-1- hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate (2.97 g) and diisopropylethylamine (0.958 ml) in the order mentioned. The mixture was stirred for 2.5 hours at the same temperature, and kept standing for 63 hours at -20 °C. The residual insolubles were collected by filtration and washed with acetonitrile to give diastereomer-1 (low polarity) ( 1136 mg) . The filtrate was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with saturated sodium hydrogencarbonate, water and saturated saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resudue was subjected to column chromatography (carrier:silica gel, 80g; developing solvent:ethyl acetate-ethanol=l:0 - 15:1) to give diastereomer-2 (high polarity) (818 mg) of the title compound. (Diastereomer-1)

IR (KBr): 1768, 1699, 1509 cm ^"1 . ^[ H-NMR (CDC1 ₃ ) δ: 1.32 (3H, d, J=7.4Hz), 1.39 (3H, d, J=6.2Hz), 2.11 (6H, s), 2.95-4.0 (5H, m) , 3.32 (IH, dd, J=2.7, 7.5Hz), 4.1-4.35 (2H, m) , 4.40 (IH, dd, J=2.7,

9.4Hz), 5.24 (IH, d, J=13.9Hz), 5.52 (IH, d, J=13.9Hz),

7.66 (2H, d, J=8.8Hz), 8.24 (2H, d, J=8.8Hz).

(Diastereomer-2)

IR (KBr): 1772, 1718, 1521 cm ^"1 . ^J H-NMR (CDC1 ₃ ) δ: 1.32 (3H, d, J=7.4Hz), 1.37 (3H, d,

J=6.2Hz), 2.07 (3H, s), 2.10 (3H, s), 3.2-4.1 (6H, m) ,

3.34 (IH, dd, 3=2.1, 6.5Hz ) , 4.2-4.4 (IH, m) , 4.34 (IH, dd, J=2.7, 9.6Hz), 5.24 (IH, d, J=13.7Hz), 5.51 (IH, d,

J=13.7Hz), 7.66 (2H, d, J=8.8Hz), 8.24 (2H, d, J=8.8Hz).

Working Example 15b

Sodium (4R,5S,6S)-3-[ (2,3-dimethyl-6,7-dihydro-5H- imidazo[2,1-b] [1,3Jthiazin-6-yl)thio]-6-[ (R)-1- hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0}hept-2- ene-2-carboxylate

Diastereomer-1 (600 mg) obtained in Working

Example 15a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-1 (319 mg) . Diastereomer-2 (600 mg) obtained in Working Example 15a was subjected to the same reaction and purification procedures as in Working

Example 2 to give diastereomer-2 (319 mg) .

(Diastereomer-1)

IR (KBr): 1753, 1602 cm ^"1 . ^-NMR (D ₂ 0) δ: 1.23 (3H, d, J=7.2Hz), 1.30 (3H, d,

J=6.2Hz), 2.06 (3H, s), 2.10 (3H, s), 3.15-3.55 (4H, m), 3.75-4.05 (2H, m) , 4.15-4.35 (3H, m) .

(Diastereomer-2)

IR (KBr): 1753, 1602 cm ^"1 . ^: H-NMR (D ₂ 0) δ: 1.22 (3H, d, J=7.4Hz), 1.30 (3H, d,

J=6.6Hz), 2.06 (6H, s), 3.25-3.65 (4H, m) , 3.85-4.35

(5H, ra) .

Working Example 15c l-(cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3- [ (2,3-dimethyl-6,7-dihydro-5H-imidazo[2,l- b] [l,3]thiazin-6-yl)thio]-6-( (R)-1-hydroxyethyl]-4-

methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate

Diastereomer-1 (63 mg) obtained in Working Example 15b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-1 (63 mg) . Diastereomer-2 (80 mg) obtained in Working Example 15b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-2 (91 mg) . (Diastereomer-1)

IR (KBr) : 1762 cm ^"1 .

^X H-NMR (CDC1 ₃ ) δ: 1.1-2.15 (19H, m) , 2.11 (6H, s), 2.95-3.95 (6H, ra) , 4.1-4.4 (3H, m) , 4.55-4.75 (IH, ra) , 6.85-6.95 (IH, m) . (Diastereomer-2)

IR (KBr) : 1760 cm ^' l.

^X H-NMR (CDC1 ₃ ) δ: 1.1-2.15 (25H, m) , 3.15-3.5 (4H, m) ,

3.65-4.35 (5H, m) , 4.55-4.75 (IH, m) , 6.85-6.95 (IH, m). Working Example 16a

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-l-hydroxyethylJ-4- methyl-3-[ (2-methyl-6,7-dihydro-5H-imidazo[2,1- b] [1,3Jthiazin-6-yl)thioJ-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate To a solution of 6-benzoylthio-2-methyl-6,7- dihydro-5H-imidazo[2,1-bJ [1,3Jthiazine (2.30 g, content : 63 wt%) in methanol (25 ml) was added sodium methoxide (28% methanol solution, 965 mg) at 0 °C, and the mixture was stirred for 1 hour at 0 °C. To the reaction mixture were added acetic acid (0.315 ml) and acetonitrile (30 ml), and the mixture was concentrated under reduced pressure. To the residue was added acetonitrile (20 ml), and insolubles were filtered off. The residue was washed with acetonitrile (30 ml), and to the obtained filtrate were added 4-nitrobenzyl (4R,5R,6S)-3-(diphenoxyphosphoryloxy)-6-[ (R)-l-

hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept- 2-ene-2-carboxylate (2.97 g) and diisopropylethylamine (0.958 ml) in the order mentioned at 0 °C. The mixture was stirred for 1 hour at the same temperature, and kept standing for 14 hours at -20 °C. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate. The mixture was washed with saturated sodium hydrogencarbonate, water and saturated saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (carrier:silica gel,lOOg;developing solvent: ethyl acetate-ethanol=l:0 - 19:1) to give mixture of diastereomers of the title compound. To the mixture of diastereomers was added acetonitrile, and insolubles were collected by filtration. The insolubles were recrystallized from acetonitrile to give diastereomer-2 (high polarity) (443 mg) of the title compound. The filtrate was concentrated under reduced pressure and residue was subjected to column chromatography (carrier:silica gel,130g;developing solvent:ethyl acetate-ethanol=l:0 - 19:1) to give diastereomer-1 (low polarity) (528 mg) . (Diastereomer-1)

IR (KBr): 1768, 1700, 1521 cm ^"1 .

^-NMR (CDC1 ₃ ) δ: 1.32 (3H, d, J=7.2Hz), 1.39 (3H, d, J=6.2Hz), 2.17 (3H, d, J=1.0Hz), 3.0-3.55 (3H, ra) , 3.33 (IH, dd, J=2.7, 7.1Hz), 3.75-3.95 (2H, m) , 4.2-4.45 (2H, ra), 4.37 (IH, dd, J=2.7, 9.6Hz), 5.24 (IH, d, J=13.6Hz), 5.52 (IH, d, J=13.6Hz), 6.62 (IH, d, J=1.0Hz), 7.66 (2H, d, J=8.8Hz) , 8.24 (2H, d, J=8.8Hz) . (Diastereomer-2) IR (KBr): 1766, 1720, 1515 cm ^"1 . ^J H-NMR (CDC1 ₃ ) δ: 1.31 (3H, d, J=7.2Hz), 1.37 (3H, d,

J=6.2Hz), 2.17 (3H, d, J=1.0Hz), 3.2-3.5 (3H, m) , 3.34

81

(IH, dd, J=2.8, 6.4Hz), 3.8-4.4 (4H, m) , 4.33 (IH, dd,

J=2.8, 9.6Hz), 5.24 (IH, d, J=13.8Hz), 5.51 (IH, d,

J=13.8Hz), 6.56 (IH, d, J=1.0Hz), 7.65 (2H, d,

J=8.8Hz), 8.24 (2H, d, J=8.8Hz). Working Example 16b

Sodium (4R,5S,6S)-6-[ (R)-1-hydroxyethylJ-4-methyl-3-

[ (2-methyl-6,7-dihydro-5H-imidazo[2,1-b] [1,3]thiazin-6- yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate Diastereomer-1 (480 rag) obtained in Working

Example 16a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-1 (279 mg) of the title compound.

Diastereomer-2 (420 mg) obtained in Working Example 16a was subjected to the same reaction and purification procedures as in Working Example 2 to give diastereomer-2 (162 mg) of the title compound.

(Diastereomer-1)

IR (KBr): 1753, 1598 cm ^"1 . ^J H-NMR (D ₂ 0) δ: 1.23 (3H, d, J=7.2Hz), 1.30 (3H, d,

J=6.6Hz), 2.15 (3H, s), 3.25-3.55 (4H, m) , 3.9-4.55

(5H, ra) , 6.91 (IH, s) .

{Diastereomer-2)

IR (KBr): 1756, 1600 cm ^"1 . ^X H-NMR (D ₂ 0) δ: 1.23 (3H, d, J=7.2Hz), 1.30 (3H, d,

J=6.2Hz), 2.16 (3H, s), 3.3-3.7 (4H, m) , 3.95-4.45 (5H, ra), 6.87(1H, s).

Working Example 16c

1-(cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[(R)- l-hydroxyethyl]-4-methyl-3-[ (2-methyl-6,7-dihydro-5H- imidazo[2,1-b] [1,3]thiazin-6-yl)thio]-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Diastereomer-1 (62 mg) obtained in Working Example

16b was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-1 (66 mg) of the title compound.

Diastereomer-2 (55 mg) obtained in Working Example 16a was subjected to the same reaction and purification procedures as in Working Example 3 to give diastereomer-2 (42 mg) of the title compound. (Diastereomer-1)

IR (KBr) : 1759 cm ^"1 .

^-NMR (CDC1 ₃ ) δ: 1.1-2.1 (19H, m) , 2.17 (3H, d, J=1.0Hz), 3.0-3.5 (3H, m) , 3.28 (IH, dd, 3=2.1, 7.1Hz), 3.75-3.95 (2H, m) , 4.15-4.4 (3H, ra) , 4.55-4.75 (IH, m) . 6.62 (IH, d, J=1.0Hz), 6.85-6.95 (IH, m) .

( Diastereomer-2 ) IR (KBr) : 1759 cm ^"1 .

^X H-NMR (CDClj) δ: 1.1-2.1 (19H, m) , 2.17 (3H, d, J=1.0Hz), 3.15-3.45 (4H, m) , 3.8-4.35 (5H, ra) , 4.55-4.75 (IH, m) , 6.55-6.6 (IH, ra) , 6.85-6.95 (IH, ra) . Working Example 17a

4-Nitrobenzyl (4R,5S,6S)-6-[ (R)-1-hydroxyethylJ-4- raethyl-3-[ (3-methyl-6,7-dihydro-5H- imidazo[2,1-bJ [1,3Jthiazin-6-yl)thioj-7-oxo-l- azabicyclo[3.2.0Jhept-2-ene-2-carboxylate

6-Benzoylthio-3-methyl-6,7-dihydro-5H- imidazo[2,1-bJ [1,3Jthiazine(1.82 g, content : 72 wt%) was suspended in methanol (30 ml). To the suspension was added sodium methoxide (28% methanol solution, 868 mg) at 0 °C and the mixture was stirred for 1.5 hour at 0 °C. To the reaction mixture were added acetic acid (0.283 ml) and acetonitrile (30 ml), and the mixture was concentrated under redudced pressure. To the residue was added acetonitrile (20 ml) and insolubles were filtered off, which was washed with acetonitrile(40 ml). To the filtrate were added 4-nitrobenzyl (4R,5R,6S)-3-(diphenoxyphosphoryloxy)- 6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2. 0]hept-2-ene-2-carboxylate (2.68 g) and diidopropylethylamine (0.862 ml) at 0 °C, and the mixture was stirred for 3 hours at the same

temperature, which was kept standing at -20 °C for 64 hours. The reaction mixture was subjected to concentration under reduced pressure. To the residue was added ethyl acetate and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous saline solution in the order mentiond. The organic layer was dried over anhydrous sodium sulfate, and concentrated under resuced pressure, and the residue was subjected to column chromatography(carrier:silica gel 200g, ethyl acetate-ethanol=l:0 - 19:1) to give a diastereomer-1 (low polarity) (540 mg) and diastereomer-2 (high polarity) (355 mg) of the title compound. (Diastereomer-1) IR (KBr): 1772, 1714, 1521 cm ^"1 .

^X H-NMR (CDC1 ₃ ) δ: 1.32 (3H, d, J=7.4Hz), 1.39 (3H, d, J=6.2Hz), 2.18 (3H, d, J=1.0Hz), 2.9-4.0 (5H, m) , 3.34 (IH, dd, 3=2.1, 7.1Hz), 4.15-4.35 (2H, m) , 4.40 (IH, dd, J=2.7, 9.6Hz), 5.25 (IH, d, J=13.7Hz), 5.53 (IH, d, J=13.7Hz), 6.76 (IH, d, J=1.0Hz), 7.67 (2H, d, J=8.7Hz), 8.24 (2H, d, J=8.7Hz). (Diastereomer-2)

IR (KBr): 1760, 1697, 1521 cm ^"1 . ^-NMR (CDCl ₃ +DMSO-d ₆ ) δ: 1.31 (3H, d, J=7.4Hz), 1.33 (3H, d, J=6.2Hz), 2.15 (3H, d, J=1.0Hz), 3.15-3.55 (4H, m), 3.7-4.3 (4H, m) , 4.35 (IH, dd, J=2.6 , 9.6Hz), 4.55 (IH, d, J=5.2Hz), 5.24 (IH, d, J=l3.9Hz), 5.51 (IH, d, J=13.9Hz), 6.72 (IH, d, J=1.0Hz), 7.67 (2H, d, J=8.8Hz), 8.23 (2H, d, J=8.8Hz). Working Example 17b

Sodium (4R,5S,6S)-6-[ (R)-l-hydroxyethyl]-4-methyl-3- [ (3-methyl-6,7-dihydro-5H-imidazo[2,1-b] [1,3]thiazin- 6-yl)thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate Diastereomer-1 (530 mg) obtained in Example 17a was subjected to the same reaction and purification

procedures as in Example 2 to give diastereomer-1 (226 mg) of the title compound. Diastereomer-2 (346 mg) obtained in Example 17a was subjected to the same procedures to give diastereomer-2 (162 mg) of the title compound.

(Diastereomer-1)

IR (KBr): 1748, 1601 cm ^"1 .

'H-NMR (D ₂ 0) δ: 1.24 (3H, d, J=7.4Hz), 1.31 (3H, d,

J=6.4Hz), 2.18 (3H, s), 3.2-3.55 (4H, ra) , 3.8-4.1 (2H, m), 4.15-4.45 (3H, m) , 6.73 (IH, s).

( Diastereomer-2 ) IR (KBr): 1751, 1602 cm ^'1 .

^X H-NMR (D ₂ 0) 6: 1.23 (3H, d, J=7.2Hz), 1.31 (3H, d, J=6.4Hz), 2.14 (3H, s), 3.25-3.7 (4H, m) , 3.9-4.35 (5H, m), 6.76(1H, s).

Working Example 17c l-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-6-[(R)- 1-hydroxyethyl]-4-methyl-3-[ (3-methyl-6,7-dihydro-5H- iraidazo[2,1-b][1,3]thiazin-6-yl)thio]-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Diastereomer-1 (81 mg) obtained in Example 17b was subjected to the same reaction and purification procedures as in Example 3 to give diastereomer-1 (61 mg) of the title compound. Diastereomer-2 (67 mg) obtained in Example 17a was subjected to the same procedures to give diastereomer-2 (66 mg) of the title compound. (Diastereomer-1) IR (KBr) : 1759 cm ^"1 . ^: H-NMR (CDC1 ₃ ) δ: 1.1-2.1 (19H, m) , 2.19 (3H, d,

J=1.0Hz), 3.0-4.0 (6H, m) , 4.15-4.4 (3H, m) , 4.55-4.75 (IH, m), 6.75 (IH, d, J=1.0Hz), 6.85-6.95 (IH, m) . (Diastereomer-2) IR (KBr) : 1759 cm ^"1 . ^! H-NMR (CDC1 ₃ ) δ: 1.1-2.1 (19H, m) , 2.1-2.2 (3H, m) ,

3.15-3.5 (4H, m), 3.7-4.35 (5H, m) , 4.55-4.75 (IH, m) , 6.7-6.75 (IH, m), 6.85-6.95 ( IH, m) . Working Example 18a

4-Nitrobenzyl (4R,5S,6S)-3-[(S)-(6,7-dihydro-5H-2 ,3- cyclopentenoimidazo[2, 1-b] [ 1,3]thiazin-6-yl)thio]-6-

[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo( 3.2.0] hept-2-ene-2-carboxylate

To a solution of (S)-6-benzoylthio-6,7-dihydro-5H- 2,3-cyclopentenoimidazo[2, 1-b] [ 1,3Jthiazin (1.44 g, content : 66 wt%) in methanol (20 ml) was added sodium methoxide (28% methanol solution) at 0 °C, which was stirred for 1 hour at 0 °C. To the reaction mixture were added acetic acid (0.189 ml) and acetonitrile (30 ml) . The mixture was concentrated under reduced pressure. To the residue was added acetonitrile (20 ml) and insolubles were filterd off. The insolubles were washed with acetonitrile(50 ml). To the filtrate were added 4-nitrobenzyl (4R,5R,6S)-3- (diphenoxyphosphoryloxy)-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2- ene-2-carboxylate (1.78 g) and diisopropylethylamine (0.575 ml) at 0 °C in the order mentioned. The mixture was stirred for 1 hour at the same temperature and for 3 hours at room temperature. The reaction mixture was subjected to concentration under reduced pressure. To the residue was added ethyl acetate and the mixture was washed with saturated solution of sodium hydrogencarbonate and saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate and subjected to concentration under reduced pressure. The residue was subjected to column chromatography (carrier:silica gel lOOg; ethyl acetate-ethanol=l:0 - 19:1) to give the title compound (878 rag) . IR (KBr): 1771, 1713, 1520 cm ^"1 .

^X H-NMR (CDC1 ₃ ) δ: 1.32 (3H, d, J=7.4Hz), 1.39 (3H, d,

J=6.2Hz), 2.35-2.75 (6H, m) , 3.0-3.55 (4H, m) , 3.7-4.0

(2H, m), 4.15-4.35 (2H, m) , 4.39 (IH, dd, J=2.7 ,

9.3Hz), 5.25 (IH, d, J=13.8Hz), 5.52 (IH, d, J=13.8Hz),

7.66 (2H, d, J=8.9Hz), 8.24 (2H, d, J=8.9Hz). Working Example 18b

Sodium (4R,5S,6S)-3-[(S)-(6,7-dihydro-5H-2,3- cyclopentenoimidazo[2,1-bJ [1,3]thiazin-6-yl)thioJ-6-

[ (R)-1-hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate The compound (650 mg) obtained in Working Example

18a was subjected to the same reaction and purification procedures as in Working Example 2 to give the title compound (289 mg) .

IR (KBr): 1753, 1598 cm ^"1 . ^X H-NMR (D ₂ 0) δ: 1.23 (3H, d, J=7.4Hz), 1.30 (3H, d,

J=6.4Hz), 2.35-2.8 (6H, m) , 3.2-3.55 (4H, ra) , 3.9-4.1

(2H, m) , 4.15-4.5 (3H, m) .

Working Example 19a

4-Nitrobenzyl (4R,5S,6S)-3-[ (R)-(6,7-dihydro-5H- 2,3-cyclopentenoimidazo[2,1-bJ [1,3)thiazin-6-yl)thio]-

6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.

0Jhept-2-ene-2-carboxylate

(R)-6-Benzoylthio-2 ,3-trimethylene-6,7-dihydro-

5H-imidazo[2,l-bJ [1,3Jthiazin(1.42 g; content : 67w t%) was subjected to the same reaction and purification procedures as in Example 18a to give the title compound

(1.17 mg) .

IR (KBr): 1779, 1713, 1522 cm ^"1 .

^-NMR (CDC1 ₃ ) 6: 1.31 (3H, d, J=7.2Hz), 1.37 (3H, d, J=6.2Hz), 2.35-2.7 (6H, m) , 3.2-3.55 (3H, m) , 3.34 (IH, dd, J=2.7, 6.6Hz), 3.8-4.4 (4H, ra) , 4.33 (IH, dd,

J=2.7, 9.4Hz), 5.24 (IH, d, J=13.7Hz), 5.51 (IH, d,

J=13.7Hz), 7.65 (2H, d, J=8.7Hz), 8.23 (2H, d,

J=8.7Hz) . Working Example 19b

Sodium (4R,5S,6S)-3-[ (R)-(6,7-dihydro-5H-2,3-

cyclopentenoimidazo[2, 1-bJ [ 1,3Jthiazin-6-yl)thio]-6- [ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[ 3.2.0) hept-2-ene-2-carboxylate

The compound (650 mg) obtained in Working Example 19a was subjected to the same reaction and purification procedures as in Working Example 2 to give the title compound (319 mg) . IR (KBr): 1754, 1602 cm ^"1 . ^X H-NMR (D ₂ 0) 6: 1.22 (3H, d, J=7.2Hz), 1.31 (3H, d, J=6.2Hz), 2.35-2.75 (6H, m) , 3.25-3.7 (4H, m) , 3.95-4.35 (5H, m) . Working Example 20a

4-Nitrobenzyl (4R,5S,6S)-3-[ (S)-(6,7-dihydro-5H- imidazo[2,1-bJ [ 1,3]thiazin-6-yl)thioJ-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate

To a solution of (S)-6-benzoylthio-6,7-dihydro-5H- imidazo[2, 1-bJ [1,3Jthiazine (1.98 g, content : 38 wt%) in methanol (20 ml) was added sodium methoxide (28% methanol solution) at 0 °C, and the mixture was stirred for 1.5 hour at 0 °C. To the reaction mixture were added acetic acid (0.172 ml) and acetonitrile (30 ml), and the mixture was concentrated under reduced pressure. To the residue was added acetonitrile (20 ml), and insolubles were filterd off. The insolubles were washed with acetonitrile (40 ml) . To the filtrate were added 4-nitrobenzyl (4R,5R,6S)-3- (diphenoxyphosphoryloxy)-6-[ (R)-l-hydroxyethylJ-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (1.62 g) and diisopropylethylamine (0.523 ml) in the order mentioned at 0 ^Q C. The mixture was stirred for 3 hours at the same temperature and for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated solution of sodium hydrogencarbonate and

saturated aqueous saline solution in the order mentioned. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel lOOg, ethyl acetate-ethanol=19: 1 - 9:1) to give the title compound (900 mg) . IR spectrum and IH-NMR spectrum of this compound were the same as those of the diastereomer-1 of the compound obtained in Working Example 1. Working Example 20b

Sodium (4R,5S,6S)-3-[ (S)-(6,7-dihydro-5H-imidazo[2,1- bJ [ 1, 3Jthiazin-6-yl)thio]-6-[ (R)-1-hydroxyethylJ-4- methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2-ene-2- carboxylate The compound (850 mg) obtained in Working Example 20a was subjected to the same reaction and purification procedures as in Working Example 2 to give the title compound (457 mg) . IR spectrum and IH-NMR spectrum of this compound were the same as those of the compound obtained in Working Example 2. Working Example 20c

1-(Cyclohexyloxycarbonyloxy)ethyl (4R,5S,6S)-3-[ (S)- (6,7-dihydro-5H-imidazo[2, 1-bJ [1,3Jthiazin-6-yl)thio]- 6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2. 0]hept-2-ene-2-carboxylate

The compound (100 mg) obtained in Working Example 20b was subjected to the same reaction and purification procedures as in Working Example 3 to give the title compound (109 mg) . IR spectrum and H-NMR spectrum of this compound were the same as those of the compound obtained in Working Example 3. Working Example 20d

Pivaloyloxymethyl (4R,5S,6S)-3-[ (S)-(6,7-dihydro- 5H-imidazo[2,l-bJ [ 1,3]thiazin-6-yl)thioJ-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate

Sodium (4R,5S,6S)-3-[ (S)-(6,7-dihydro-5H- imidazo[2, 1-bJ [ 1, 3Jthiazin-6-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate (156 mg) was dissolved in dried N,N-dimethylacetamide (2 ml). To the solution was added iodomethyl pivalate (148 mg) at 0 °C, and stirred for 1 hour at the same temperature. To the reaction mixture was added ethyl acetate. The mixture was washed with water and saturated aqueous solution of sodium hydrogencarbonate in the order mentioned. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (carrier:silica gel 15g;developing solvent: ethyl acetate-ethanol=l:0 - 19:1) to give the title compound (80 mg) . IR (KBr) : 1759 cm ^"1 .

^X H-NMR (CDC1 ₃ ) δ: 1.23 (9H, s), 1.31 (3H, d, J=7.2Hz), 1.36 (3H, d, J=6.2Hz), 3.05-3.55 (4H, m) , 3.8-4.0 (2H, m), 4.15-4.45 (3H, m) , 5.84 (IH, d, J=5.6Hz), 5.98 (IH, d, J=5.6Hz), 6.91 (IH, d, J=1.6Hz), 7.03 (IH, d, J=1.6Hz) .

Working Example 21a

4-Nitrobenzyl (4R,5S,6S)-3-[ (S)-2-amino-6,7-dihydro-5H- 1,2,4-triazolo[5, 1-b] [1,3]thiazin-6-ylthio]-6-[ (R)-1- hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate

(S)-2-amino-6-benzoylthio-6,7-dihydro-5H- 1,2,4-triazolo[5, 1-bJ [ 1,3Jthiazine (11.7 g) was dissolved in the mixed solution of tetrahydrofuran and methanol (1 : 1, 400 ml). To the suspension was added sodium methoxide (2.16 g) at 0 °C, and the mixture was stirred for 30 minutes at 0 °C. To the reaction mixture were added acetic acid (2.53 ml) and acetonitrile (200 ml). The mixture was concentrated under reduced pressure until the volume became to 100 ml. To the residue was added acetonitrile (100 ml) and

insolubles were filtered off. The residue was washed with acetonitrile (300 ml). To the obtained filtrate were added 4-nitrobenzyl (4R,5R,6S)-3- (diphenoxyphosphoryloxy)-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carbonate (21.4 g) and diisopropylethylamine (7.7 ml) in the order mentioned at 0 °C, and the mixture was stirred for 3 hours at the same temperature. The resulting solid substance was recovered by filtration, and washed with acetonitrile to give the title compound (17.34 g) as an yellow solid product.

IR (KBr): 3360, 1761, 1707, 1551, 1518, 1346 cm ^"1 . ^X H-NMR (DMS0-d ₆ ) δ: 1.16 (3 H, d, J = 6.2 Hz), 1.21 (3 H, d, J = 7.4 Hz), 3.10-3.45 (2 H, m) , 3.45-3.70 (2 H, m), 3.85-4.20 (3 H, m) , 4.20-4.40 (2 H, m) , 5.11 (1 H, d, J = 5.0 Hz), 5.33 (2 H, brs), 5.40 (2 H, ABq, J = 14.0 Hz), 7.72 (2 H, d, J = 8.8 Hz), 8.24 (2 H, d, J = 8.8 Hz) . Working Example 21b Sodium (4R,5S,6S)-3-(2-amino-6,7-dihydro-5H-l,2,4- triazolo[5,l-bJ [l,3]thiazin-6-ylthio)-6-[ (R)-l- hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate

To 4-nitrobenzyl (4R,5S,6S)-3-(2-amino-6,7- dihydro-5H-l,2,4-triazolo[5,1-b] [1,3Jthiazin-6-y1thio)- 6-[ (R)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3.2.0Jhept-2-ene-2-carboxylate (7.99 g) were added THF (150 ml), phosphoric acid buffer (pH 7, 0.2 M, 300 ml) and 10 % palladium carbon (4.0 g) . The mixture was subjected to hydrogenation for 4 hours at room temperature under atomospheric pressure. The catalyst was filtered and washed with water. Tetrahydrofuran was distilled off under reduced pressure. To the residue was added ethyl acetate (300 ml), and insolubles were filtered off. The aqueous layer was concentrated under reduced pressure.

The residue was purified by column chromatography (carrier:SP-207, 800 ml;developing solvent:water - 15% ethanol) and freeze-dried to give the title compound (4.79 g) as a colorless solid product. IR (KBr): 3300, 1748, 1597, 1545, 1362 cm ^"1 .

^-NMR (D ₂ 0) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30 (3 H, d, J = 6.2 Hz), 3.25-3.55 (4 H, m) , 3.90-4.15 (2 H, ra) , 4.15-4.50 (3 H, m) . Working Example 21c Pivaloyloxymethyl (4R,5S,6S)-3-[ (S)-2-amino-6, 7- dihydro-5H-l,2,4-triazolo[5,1-bJ [1,3Jthiazin-6-ylthio]- 6-[ (R)-1-hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2. 0Jhept-2-ene-2-carboxylate

Sodium (4R,5S,6S)-3-[ (S)-2-amino-6,7-dihydro-5H- l,2,4-triazolo[5,l-bJ[l,3]thiazin-6-ylthioJ-6-[ (R)-l- hydroxyethylJ-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate (2.99 g) and sodium hydrogencarbonate (600 mg) was dissolved in water (50 ml) and freeze-dried. The obtained solid substance was dissolved in dried N,N-dimethylacetamide (42 ml) at -15 °C. To the solution was added iodomethyl pivalate (3.27 g) , and the mixture was stirred for 3 hours at -15 °C. To the reaction mixture was added ethyl acetate, and the mixture was washed with saturated solution of sodium hydrogencarbonate, water and saturated aqueous saline solution in the order mentioned, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to flash-column chromatography (carrier: silica gel, 100 g; developing solvent: ethyl acetate-ethanol, 19 : 1 - 9 : 1) to give the title compound (2.35 g) as a colorless solid product. IR (KBr): 3380, 2976, 1779, 1616, 1545, 1350 cm ^"1 . ^X H-NMR (CDC1 ₃ ) δ: 1.23 (9H, s), 1.30 (3 H, d, J = 7.4 Hz), 1.35 (3 H, d, J = 6.4 Hz), 2.36 (1 H, brs),

3.10-3.25 (1 H, m), 3.25-3.50 (3 H, m) , 3.80-4.00 (2 H, m), 4.14 (2 H, s), 4.20-4.50 (3 H, m) , 5.91 (2 H, ABq, J = 5.4 Hz) . Working Example 22a 4-Nitrobenzyl (4R, 5R, 6S)-3-[ (S)-(6,7-dihydro-5H-

[1,2,3Jtriazolo[5,1-b) [1,3Jthiazin-6-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate

To a mixed solution of (S)-6-acetylthio-6,7- dihydro-5H-[l,2,3]triazolo[5,1-b] [1,3Jthiazine (2.00 g) in THF (40 ml)-methanol (40 ml) was added sodium methoxide (0.554 g) under ice cooling, and the mixture was stirred for 40 minutes. To the mixture was added acetic acid (0.64 ml). The solvent was distilled off, and acetonitrile (40 ml) was added to the residue. Insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetonitrile (40 ml). To the solution were added diidopropylethylamine (1.90 ml) and 4-nitrobenzyl (4R,5R,6S)-3-(diphenoxyphosphoryloxy)-6- [ (R)-1-hydroxyethylJ-4-methyl-7-oxo-l- azabicyclo[3.2.0Jhept-2-ene-2-carboxylate (6.02 g) , and the mixture was stirred for 2 hours at room temperature. The resulting solid substance was collected by filtration. The solid substance was washed with acetonitrile to give the title compound (4.17 g) as a colorless solid product. IR (KBr) : 3322, 1771, 1711 cm ^"1 . ^X H-NMR (DMS0-d ₆ ) δ: 1.17 (3H, d, J=6.2Hz), 1.23 (3H, d, J=7.2Hz), 3.20-3.50 (2H, m) , 3.54-3.63 (2H, m) , 4.02 (IH, m), 4.17 (IH, m), 4.32 ( IH, dd, J=9.4, 2.6Hz) , 4.44 (IH, dd, J=13.4, 8.4Hz), 4.86 (IH, dd, J=13.4, 4.0Hz), 5.11 (IH, d, J=5.0Hz) , 5.39 (2H, Abq, J=14.2Hz), 7.59 (IH, s), 7.70 (2H, d, J=8.6Hz), 8.22 (2H, d, J=8.6Hz) .

Working Example 22b

Sodium (4R, 5R, 6S)-3-[ (S)-(6,7-dihydro-5H- [1,2,3]triazolo[5, 1-bJ [ 1,3]thiazin-6-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[ 3.2.0Jhept-2- ene-2-carboxylate 4-Nitrobenzyl (4R,5R,6S)-3-[ (S)-(6,7-dihydro-5H-

[l,2,3jtriazolo[5,l-bJ [ 1,3]thiazin-6-yl)thio]-6-[ (R)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate (4.00 g) obtained in Working Example 22a was subjected to the same reaction and purification procedures as in Working Example 2 to give the title compound (2.04 g) as a colorless solid product. IR (KBr) : 3264, 1751, 1598, 1394, 1290, 1230 cm ^"1 . ^X H-NMR (D ₂ 0) δ: 1.24 (3H, d, J=7.0Hz), 1.30 (3H, d, J=6.4Hz), 3.27 (IH, dd, J=13.0, 8.8Hz), 3.38-3.53 (3H, ra) , 4.09 (IH, m) , 4.21-4.32 (2H, m) , 4.42 (IH, dd,

J=13.7, 8.8Hz), 4.88 (IH, dd, J=13.7, 4.8Hz) , 7.58 (IH, s).

^X H-NMR and IR data were the same as those of the compound obtained in Working Example 9b-1. Working Example 22c

Pivaloyloxymethyl (4R,5R,6S)-3-[ (S)-(6,7-dihydro-5H- [1,2,3Jtriazolo[5, 1-bJ [1,3)thiazin-6-yl)thio]-6-[ (R)-1- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0Jhept-2- ene-2-carboxylate To a solution of Sodium (4R,5R,6S)-3-[ (S)-(6,7- dihydro-5H-[1,2,3Jtriazolo[5, 1-b] [1,3Jthiazin-6- y1)thioJ-6-[ (R)-1-hydroxyethyl]-4-methy1-7-oxo-1- azabicyclo[3.2.0Jhept-2-ene-2-carboxylate (0.924 g) obtained in Working Example 22b in N,N- dimethylacetamide (10 ml) was added iodomethyl pivalate (1.07 g) at -20 °C and the mixture was stirred for 30 minutes . The temperature of the mixture was elevated to 0 °C, and the mixture was further stirred for 1.5 hour. To the reaction mixture was added ethyl acetate (200 ml). The mixture was washed with saturated aqueous saline solution and dried over anhydrous sodium

sulfate and concentrated under reduced pressure. To the residue was recrystallized from ethyl acetate to give the title compound (0.73 g) as colorless needles. IR (KBr) : 3356, 2970, 1783, 1727, 1559 cm ^"1 . ^J H-NMR (CDC1 ₃ ) 6: 1.23 (9H, s), 1.31 (3H, d, J=7.2Hz), 1.35 (3H, d, J=6.2Hz), 1.85 (IH, br) , 3.19-3.23 (2H, m), 3.29-3.40 (2H, m) , 3.90 (IH, ra) , 4.24-4.34 (3H, m) , 4.95 (IH, dd, J=13.2, 4.8Hz), 5.85 (IH, d, J=5.6Hz), 5.97 (IH, d, J=5.6Hz), 7.47 (IH, s).

2 (diastereomer-1)

3 (diastereomer- 1)

4 (diastereomer-2) 5 (diastereomer-2)

(diastereomer-1) 7 (diastereomer-2)

8a (diastereomer-1 ,2) 8b (diastereomer-1 ,2)

8c (diastereomer-1 ,2)

9a (diastereomer- 1 ,2) 9b (diastereomer-1 ,2)

c (diastereomer-1 ,2)

0a (diastereomer-1 ,2) 10b (diastereomer-1 ,2)

10c (diastereomer-1 ,2)

a (diastereomer-1 ,2) ^{1 1 b} (diastereomer-1 ,2)

11 c (diastereomer-1 ,2)

12a (diastereomer- 1,2) 12b (diasteromer-1, 2)

12c (diasteromer-1, 2) 12d (diastereomer-1)

13a (diastereomer- 1, 2) 13b (diastereomer-1, 2)

3c (diastereomer-1, 2)

a (diastereomer-1, 2) 14b (diastereomer- 1, 2)

15a (diastereomer-1, 2) 15b (diastereomer-1, 2)

15c (diastereomer- 1, 2)

16a (diastereomer- 1, 2) 16b (diastereomer-1, 2)

6c (diastereomer-1, 2)

17a (diastereomer- 1, 2) 17b (diastereomer-1, 2)

c (diastereomer- 1, 2)

18b 18a

18c

19a 19b

19c

20c

21b 21a

c

[Test Example)

The compound (I) of this invention, its salts and its esters have antibacterial activities of a broad spectrum, and they can be used for the treatment and prevention of various diseases of man and other animals caused by pathogenic bacteria. [Method of Measurement] Test Example Minimum Inhibitory Concentration (MIC)

The minimum inhibitory concentration [MIC (unit: (μ/ml)] of the test compound was determined by an agar dilution method. More specifically, 0.25 ml of an aqueous solution of the test compound diluted stepwise was put into a Petri dish, which was then mixed with 9.75 ml of Muller-Hinton agar containing fildis enrichment [F-MH medium, fildis enrichment (5%)]). On thus-prepared mixed agar plate, a suspension of the test bacteria (about 10 CFU/ml) was spread, which was incubated at 37°C overnight. The minimum concentration of the test compound to completely inhibit the growth of the test bacteria was expressed as MIC. [Table 1J

MIC(μg/ml)10 ^δ CFU/ml

Straims medium imipenem W.Ex.2 W.Ex.4

E. coli NIHJ JC-2 F-MH 0.2 0.05 0.025

H. influenzae NN400 F-MH 1.56 0.025 0.05

From the above results, it is clear that the carbapenem compounds of this invention have excellent antibacterial activities against strains clinically taken seriously.