3-Pyrrolidinylthio-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid compounds

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The present invention relates to novel 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

More particularly, it relates to novel 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament and in the treatment of infectious diseases caused by pathogenic microorganisms in human being or animals.

Accordingly, one object of the present invention is to provide novel 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms and are useful as antimicrobial agents.

Another object of the present invention is to provide processes for the preparation of novel 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and salts thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a use of said 3-pyrrolidinylthio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof as a medicament and in the treatment of infectious diseases caused by pathogenic microorganisms in human being or animals.

The object 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds are novel and can be represented by the following general formula: ##STR1## wherein R.sup.1 is carboxy or protected carboxy,

R.sup.2 is hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,

R.sup.3 is hydrogen or lower alkyl,

R.sup.4 is heterocyclic group, which may have suitable substituent(s), and

R.sup.5 is hydrogen or imino-protective group, and pharmaceutically acceptable salts thereof.

In the object compounds (I) and the intermediary compounds mentioned below, it is to be understood that there may be one or more stereo-isomeric pair(s) such as optical isomers due to asymmetric carton atom(s), and such isomers are also included within the scope of the present invention.

Suitable pharmaceutically acceptable salts of the object compounds (I) are conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, dibenzylamine salt, etc.); a salt with an acid such as an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); an intermolecular quaternary salt; and the like.

According to the present invention, the object compounds (I) and pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes. ##STR2## in which:

R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each as defined above,

R.sub.a.sup.1 is protected carboxy,

R.sub.a.sup.2 is protected hydroxy(lower)alkyl,

R.sub.b.sup.2 is hydroxy(lower)alkyl,

R.sub.a.sup.4 is heterocyclic group having protected amino or protected amino(lower)alkyl,

R.sub.b.sup.4 is heterocyclic group having amino or amino(lower)alkyl,

R.sub.c.sup.4 is heterocyclic group having azido(lower)alkyl,

R.sub.d.sup.4 is heterocyclic group having amino(lower)alkyl,

R.sub.a.sup.5 is imino-protective group, and

R.sup.10 is imino-protective group.

The compound (III) used in the Process 1 is new and can be prepared, for example, by the following methods or a conventional manner. ##STR3## in which

R.sup.4, R.sub.c.sup.4 and R.sup.5 are each as defined above,

R.sub.e.sup.4 is optionally substituted 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl, or optionally substituted 1,3-dithiolan-2-yl or 1,3-dithian-2-yl,

R.sub.f.sup.4 is heterocyclic group having halo(lower)alkyl,

R.sup.6 is mercapto-protective group, and

R.sup.7 is lower alkyl.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.

Suitable "protected carboxy" may include esterified carboxy wherein esterified carboxy can be referred to the ones as mentioned below.

Suitable examples of the ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy(lower)alkyl ester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.]phthalidylidene(lower)alkyl ester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.

More preferable example of the protected carboxy thus defined may be phenyl(C.sub.1 -C.sub.4)alkoxycarbonyl which may have a nitro group and (C.sub.2 -C.sub.4)alkenyloxycarbonyl, and the most preferable one may be 4-nitrobenzylcarbonyl.

Suitable "hydroxy(lower)alkyl" may include straight or branched lower alkyl having hydroxy group such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 1-(hydroxymethyl)ethyl, 1-hydroxy-1-methylethyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like, in which more preferable example may be hydroxy(C.sub.1 -C.sub.4)alkyl and the most preferable one may be 1-hydroxyethyl.

Suitable "protected hydroxy(lower)alkyl" means aforementioned hydroxy(lower)alkyl, in which the hydroxy group is protected by a conventional hydroxy-protective group such as those mentioned in the explanation of imino-protective group as mentioned below: and further ar(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.), etc.; trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, diisopropylmethylsilyl, etc.), triarylsilyl (e.g. triphenylsilyl, etc.), triar(lower)alkylsilyl (e.g. tribenzylsilyl, etc.), etc.; and the like.

More preferable example of "protected hydroxy(lower)alkyl" thus defined may be phenyl(C.sub.1 -C.sub.4)alkoxycarbonyloxy(C.sub.1 -C.sub.4)alkyl which may have a nitro group, triphenyl(C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl and tri(C.sub.1 -C.sub.4)alkylsilyloxy(C.sub.1 -C.sub.4)alkyl.

Suitable "lower alkyl" may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which more preferable example may be C.sub.1 -C.sub.4 alkyl and the most preferable one may be methyl.

Suitable "heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as oxygen, sulfur and nitrogen atom.

Preferable heterocyclic group may be unsaturated, 3 to 8-membered, more preferably 5 or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl (e.g. 2-imidazolinyl, etc.), pyrazolyl, pyrazolinyl, pyridyl, pyridyl N-oxide, pyridinio, dihydropyridyl, tetrahydropyridyl [e.g. 1,2,3,6-tetrahydropyridyl, etc.], pyrimidinyl, pyrimidinio, pyrazinyl, pyrazinio, pyridazinyl, pyridazinio, triazinyl [e.g. 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl], tetrahydrotriazinyl [e.g. 1,2,5,6-tetrahydro-1,2,4-triazinyl, 1,4,5,6-tetrahydro-1,2,4-triazinyl, etc.], triazinio, triazolyl [e.g. 1H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], triazolio, tetrazinyl, tetrazinio, tetrazolyl [e.g. 1H-tetrazolyl and 2H-tetrazolyl], tetrazolio, etc.;

unsaturated, 3 to 8-membered, more preferably 5 or 6-membered, heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, thiazolio, isothiazolyl, thiadiazolyl [e.g. 1,2,3-thiadiazolyl, [1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl], thiadiazolio, thiazolinyl (e.g. 2-thiazolinyl, etc.), dihydrothiazinyl, etc.;

unsaturated, 3- to 8-membered, more preferably 5 or 6-membered, heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated, 3 to 8-membered, more preferably 5 or 6-membered, heteromonocyclic group containing 1 to 4 oxygen atom(s), for example, dioxolanyl (e.g. 1,3-dioxolanyl, etc.), dioxanyl (e.g. 1,3-dioxanyl, 1,4-dioxanyl, etc.), etc.;

saturated, 3 to 8-membered, more preferably 5 or 6-membered, heteromonocyclic group containing 1 to 4 sulfur atom(s), for example, dithiolanyl (e.g. 1,3-dithiolanyl, etc.), dithianyl (e.g. 1,3-dithianyl, 1,4-dithianyl, etc.), etc.; or the like.

wherein said heterocyclic group may have one or more, preferably one to three suitable substituent(s) such as amino; protected amino in which the amino-protective group may be the same as those for the imino-protective group as mentioned below; lower alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, etc.); ureido(lower)alkyl (e.g. ureidomethyl, ureidoethyl, ureidopropyl, ureidohexyl, etc.); carbamoyl; lower alkyl as mentioned above; amino(lower)alkyl (e.g. aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminohexyl, etc.); protected amino(lower)alkyl, which is the amino(lower)alkyl group as mentioned above, in which the amino group is protected by a conventional amino-protective group such as those for the imino-protective group as mentioned below; hydroxy(lower)alkyl and protected hydroxy(lower)alkyl as mentioned above; azido(lower)alkyl e.g. azidomethyl, azidoethyl, azidopropyl, azidohexyl, etc.); halo(lower)alkyl (e.g. chloromethyl, bromomethyl, iodoethyl, bromopropyl, bromohexyl, etc.); and the like. And further in case that said heterocyclic group is imidazolinyl, the imino-moiety of imidazoline ring may be protected by a conventional imino-protective group as mentioned below.

Preferable example of "heterocyclic group, which may have suitable substituent(s)" may be:

imidazolinyl (e.g. 2-imidazolin-2-yl, etc.);

N-protected imidazolinyl such as N-acylimidazolinyl, more preferably N-phenyl(or nitrophenyl)(C.sub.1 -C.sub.4)-alkoxycarbonylimidazolinyl [e.g. 1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl, etc.];

triazolyl (e.g. 1H-1,2,4-triazol-3-yl, etc.);

amino(lower)alkyltriazolyl, more preferably amino(C.sub.1 -C.sub.4)alkyltriazolyl (e.g. 3-aminomethyl-1H-1,2,4-triazol-5-yl, etc.);

protected amino(lower)alkyltriazolyl such as acylamino(lower)alkyltriazolyl, more preferably phenyl(or nitrophenyl)(C.sub.1 -C.sub.4)alkoxycarbonylamino(C.sub.1 -C.sub.4)alkyltriazolyl [e.g. 3-(4-nitrobenzyloxycarbonylaminomethyl)-1H-1,2,4-triazol-5-yl, etc.];

tetrazolyl (e.g. 1H-tetrazol-5-yl, etc.);

lower alkyltetrazolyl, more preferably C.sub.1 -C.sub.4 alkyltetrazolyl (e.g. 1-methyl-1H-tetrazol-5-yl, 2-methyl-2H-tetrazol-5-yl, etc.);

thiazolyl (e.g. thiazol-4-yl, etc.);

aminothiazolyl (e.g. 2-aminothiazol-4-yl, etc.);

lower alkylthiazolyl, more preferably C.sub.1 -C.sub.4 alkylthiazolyl (e.g. 2-methylthiazol-4-yl, etc.);

carbamoylthiazolyl (e.g. 4-carbamoylthiazol-2-yl, etc.);

lower alkylaminothiazolyl, more preferably C.sub.1 -C.sub.4 alkylaminothiazolyl (e.g. 2-methylaminothiazol-4-yl, etc.);

amino(lower)alkylthiazolyl, more preferably amino(C.sub.1 -C.sub.4)alkylthiazolyl [e.g. 2-aminomethylthiazol-4-yl, 2-(2-aminoethyl)thiazol-4-yl, etc.];

protected amino(lower)alkylthiazolyl such as acylamino(lower)alkylthiazolyl, more preferably phenyl(or nitrophenyl)(C.sub.1 -C.sub.4)alkoxycarbonylamino(C.sub.1 -C.sub.4)alkylthiazolyl [e.g. 2-(4-nitrobenzyloxycarbonylaminomethyl)thiazol-4-yl, 2-[2-(4-nitrobenzyloxycarbonylamino)ethyl]thiazol-4-yl, etc.];

protected hydroxy(lower)alkylthiazolyl such as acyloxy(lower)alkylthiazolyl, more preferably carbamoyloxy(C.sub.1 -C.sub.4)alkylthiazolyl (e.g. 2-carbamoyloxymethylthiazol-4-yl, etc.);

thiadiazolyl (e.g. 1,2,4-thiadiazol-5-yl, etc.);

lower alkylaminothiadiazolyl, more preferably C.sub.1 -C.sub.4 alkylaminothiadiazolyl (e.g. 5-methylamino-1,3,4-thiadiazol-2-yl, etc.);

thiazolinyl (e.g. 2-thiazolin-2-yl , etc.);

aminooxadiazolyl (e.g. 3-amino-1,2,4-oxadiazol-5-yl, etc.);

amino(lower)alkyloxadiazolyl, more preferably amino(C.sub.1 -C.sub.4)alkyloxadiazolyl, (e g. 3-aminomethyl-1,2,4-oxadiazol-5-yl, etc.);

oxadiazolyl (e.g. 1,2,4-oxadiazol-5-yl, etc.);

ureido(lower)alkylthiazolyl, more preferably ureido(C.sub.1 -C.sub.4)alkylthiazolyl (e.g. 2-ureidomethylthiazol-4-yl, etc.);

azido(lower)alkylthiazolyl, more preferably azido(C.sub.1 -C.sub.4)alkylthiazolyl (e.g. 4-azidomethylthiazol-2-yl, etc.);

amino(lower)alkylthiazolyl, more preferably amino(C.sub.1 -C.sub.4)alkylthiazolyl (e.g. 4-aminomethylthiazol-2-yl, etc.);

imidazolyl (e.g. imidazol-2-yl, etc:.);

protected amino(lower)alkyloxadiazolyl such as acylamino(lower)alkyloxadiazolyl, more preferably phenyl(or nitrophenyl)(C.sub.1 -C.sub.4)alkoxycarbonylamino(C.sub.1 -C.sub.4)alkyloxadiazolyl [e.g. 3-(4-nitrobenzyloxycarbonylaminomethyl)-1,2,4-oxadiazol-5-yl, etc.);

dioxolanyl (e.g. 1,3-dioxolan-2-yl, etc.];

amino(lower)alkyldioxolanyl, more preferably amino(C.sub.1 -C.sub.4)alkyldioxolanyl (e.g. 4-aminomethyl-1,3-dioxolan-2-yl, etc.);

azido(lower)alkyldioxolanyl, more preferably azido(C.sub.1 -C.sub.4)alkyldioxolanyl (e.g. 4-azidomethyl-1,3-dioxolan-2-yl, etc.);

hydroxy(lower)alkyldioxolanyl, more preferably hydroxy(C.sub.1 -C.sub.4)alkyldioxolanyl (e.g. 4-hydroxymethyl-1,3-dioxolan-2-yl, etc.);

aminodioxanyl (e.g. 5-amino-1,3-dioxan-2-yl, etc.);

protected aminodioxanyl such as acylaminodioxanyl, more preferably phenyl(or nitrophenyl)(C.sub.1 -C.sub.4)alkoxycarbonylaminodioxanyl [e.g. 5-(4-nitrobenzyloxycarbonylamino)-1,3-dioxan-2-yl, etc.];

dithiolanyl (e.g. 1,3-dithiolan-2-yl, etc.); and

dithianyl (e.g. 1,3-dithian-2-yl, etc.);

Furthermore, when the heterocyclic group as stated above is, for example, thiazolyl having amino or protected amino group at 2-position, or 1,2,4-oxadiazolyl having amino or protected amino group at 3-position, there are tautomeric isomers as shown by the following equilibriums: ##STR4## (wherein R.sup.8 is amino or protected amino, and

R.sup.8' is imino or protected imino).

All of the above tautomeric isomers are included within the scope of the present invention, and in the present specification, however, the object and intermediary compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, i.e. 2-amino (or protected amino)thiazolyl and the formula: ##STR5## or 3-amino(or protected amino)-1,2,4-oxadiazolyl and the formula: ##STR6## only for the convenient sake.

And further, when the heterocyclic group as stated above is, for example, 1,2,4-triazolyl or tetrazolyl group, there are tautomeric isomers as shown by the following equilibriums: ##STR7##

All of the above tautomeric isomers are included within the scope of the present invention and in the present specification, however, the object and intermediary compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor , i.e. 1H-1,2,4-triazolyl and the formula: ##STR8## or 1H-tetrazolyl and the formula: ##STR9## only for the convenient sake.

Suitable "imino-protective group" may include acyl such as carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.

The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfony, such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.

The aromatic acyl may include aroyl (e.g. benzoyl, toluoyl, xyloyl, etc.), N-arylcarbamoyl (e.g. N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like.

The heterocyclic acyl may include heterocycliccarbonyl (e.g. furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may include aralkanoyl such as phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), aryloxyalkanoyl such as phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.), and the like.

The aliphatic acyl substituted with heterocyclic group(s) may include heterocyclic-alkanoyl such as heterocyclic(lower)alkanoyl (e.g. thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, etc.), and the like.

These acyl groups may be further substituted with one or more suitable substituents such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), halogen (e.g. chlorine, bromine, iodine, fluorine), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), lower alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), nitro, and the like, and preferable acyl having such substituent(s) may be mono(or di or tri)haloalkanoyl (e.g. chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc.), mono(or di or tri)haloalkoxycarbonyl (e.g. chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), nitro- (or halo or lower alkoxy)aralkoxycarbonyl (e.g. nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxybenzyloxycarbonyl, etc.), mono(or di or tri)- halo(lower)alkylsulfonyl (e.g. fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, etc.), and the like.

More preferable example of "imino-protective group" thus defined may be (C.sub.2 -C.sub.4)alkenyloxycarbonyl and phenyl(C.sub.1 -C.sub.4)alkoxycarbonyl which may have a nitro group, and the most preferable one may be 4-nitrobenzyloxycarbonyl.

Suitable "mercapto-protective group" may include acyl as mentioned above, ar(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl (e.g. benzyl, phenethyl, benzhydryl, trityl, etc.), and the like, in which more preferable example may be C.sub.1 -C.sub.4 alkanoyl, aroyl and triphenyl(C.sub.1 -C.sub.4)alkyl, and the most preferable one may be benzoyl.

Suitable heterocyclic moieties of "heterocyclic group having amino or amino(lower)alkyl", "heterocyclic group having protected amino or protected amino(lower)alkyl", "heterocyclic group having azido(lower)alkyl", "heterocyclic group having amino(lower)alkyl" and "heterocyclic group having halo(lower)alkyl" are the same as those for the heterocyclic group as exemplified above.

Suitable "amino(lower)alkyl", "protected amino", "protected amino(lower)alkyl", "azido(lower)alkyl" and "halo(lower)alkyl" as the substituents of the heterocyclic moiety mentioned above are the same as those exemplified as the substituent of the heterocyclic group mentioned above.

Suitable substituent of "optionally substituted 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl" and "optionally substituted 1,3-dithiolan-2-yl or 1,3-dithian-2-yl" are the same as those exemplified as the substituents of the heterocyclic group mentioned above.

The processes for the preparation of the object compound (I) of the present invention are explained in detail in the following.

(1) Process 1:

The compounds (I) or salts thereof can be prepared by reacting the compound (II) or a reactive derivative at the oxo group thereof or salts thereof with the compound (III) or salts thereof.

Suitable salts of the compound (II may be salts with bases such as those given for the compounds (I).

The reactive derivative at the oxo group of the compound (II) can be represented by the following formula (II'), which is preferably used in this reaction and can be prepared by reacting the compound (II) or salts thereof with an acylating agent. ##STR10## in which R.sup.1, R.sup.2 and R.sup.3 are each as defined above, and

R.sup.9 is acyl as exemplified for the imino-protective group and further O,O-substituted phosphono derived from, for example, organic phosphoric acid mentioned hereinbelow.

Suitable acylating agents may include conventional ones which can introduce the acyl group as mentioned above into the compound (II), and preferable acylating agents may be organic sulfonic or phosphoric acid or its reactive derivative such as acid halide, acid anhydride, and the like, for example, arenesulfonyl halide (e.g. benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc.), arenesulfonic anhydride (e.g. benzenesulfonic anhydride, p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, etc.), lower alkanesulfonyl halide which may have additional halogen (e.g. methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.), lower alkanesulfonic anhydride which may have halogen (e.g. methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.), di(lower)alkyl phosphorohaloridate (e.g. diethyl phosphorochloridate, etc.), diaryl phosphorohaloridate (e.g. diphenyl phosphorochloridate, etc.), and the like.

This acylation reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine, etc., or a mixture thereof.

When the acylating agent is used in a free acid form or its salt form in this reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as carbodiimide compounds (e.g. N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylami nocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.); N,N'-carbonyldiimidazole, N,N'-carbonylbis(2-methylimidazole); keteneimine compounds (e.g. pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine); ethoxyacetylene; 1-alkoxy-1-chloroethylene; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl chloride; a combination of triphenylphosphine with carbon tetrachloride or diazenedicarboxylate; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

This acylation reaction may be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), tri(lower)alkylamine (e.g. trimethylamine, triethylamine, N,N-diisopropyl-N-ethylamine, etc.), pyridine compound [e.g. pyridine, picoline, lutidine, N,N-di(lower)alkylaminopyridine such as N,N-dimethylaminopyridine, etc ], quinoline, N-lower alkylmorphorine (e.g. N-methylmorphorine, etc.), N,N-di(lower)alkylbenzylamine (e.g. N,N-dimethylbenzylamine, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium butoxide, etc.), and the like.

The reaction temperature of this acylation reaction is not critical and the reaction is usually carried out under from cooling to warming.

With regard to the compound (II), it is to be noted that the 3,7-dioxo-1-azabicyclo[3.2.0]heptane ring system of the following formula (IIA) is well known to lie to tautomeric relation with the 3-hydroxy-7-oxo-1-azabicyclo[3.2.0]hept-2-ene ring system of the following formula (IIB), and accordingly, it is to be understood that both of these ring systems are substantially the same. ##STR11##

The compound (II') or salts thereof can be used with or without isolation for the subsequent reaction with the compound (III) or salts thereof.

Suitable salts of the compound (III) may be the same as those for the compound (I) and silver salt.

The reaction of the compound (II) or its reactive derivative or salts thereof with the compound (III) or salt thereof can be carried out in the presence of an organic or inorganic base such as those given in the explanation of the acylation reaction as stated above.

This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as those given in the explanation of the acylation reaction.

The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.

(2) Process 2:

The compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to elimination reaction of the carboxy-protective group on R.sub.a.sup.1.

Suitable salts of the compounds (I-a) and (I-b) may be the same as those for the compounds (I).

The present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.

(i) Hydrolysis:

Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), and the like.

Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g. phenol, anisole, etc.).

In case that the hydroxy-protective group is tri(lower)alkylsilyl, the hydrolysis can be carried out in the presence of tri(lower)alkylammonium halide (e.g. tributylammonium fluoride, etc.).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquid base or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.

(ii) Reduction:

The reduction method applicable for this elimination reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), and the like.

In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral condition.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.

In case that the carboxy-protective group is allyl group, it can be deprotected by hydrogenolysis using a palladium compound.

Suitable palladium compound used in this reaction may be palladium on carbon, palladium hydroxide on carbon, palladium chloride, a palladium-ligand complex such as tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), di[1,2-bis(diphenyl phosphino)ethane]palladium(0), tetrakis(triphenyl phosphite)palladium(0), tetrakis(triethyl phosphite)palladium(0), and the like.

This reaction can preferably be carried out in the presence of a scavenger of allyl group generated in situ, such as amine (e.g. morpholine, N-methylaniline, etc.), an activated methylene compound (e.g. dimedone, benzoylacetate, 2-methyl-3-oxovaleric acid, etc.), a cyanohydrin compound (e.g. .alpha.-tetrahydropyranyloxybenzyl cyanide, etc.), lower alkanoic acid or a salt thereof (e.g. formic acid, acetic acid, ammonium formate, sodium acetate, etc.), N-hydroxysuccinimide, and the like.

This reaction can be carried out in the presence of a base such as lower alkylamine (e.g. butylamine, triethylamine, etc.), pyridine, and the like.

When palladium-ligand complex is used in this reaction, the reaction can preferably be carried out in the presence of the corresponding ligand (e.g. triphenylphosphine, triphenyl phosphite,, triethyl phosphite,, etc.).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate, etc.,

The elimination reaction can be selected according to the kind of carboxy-protective group to be eliminated.

The present process includes within the scope thereof a case that the hydroxy- and/or imino-protective group(s) for R.sup.2 and R.sup.5, and amino- and/or imino-protective group(s) on R.sup.4 are removed or azido group on R.sup.4 is reduced to amino group at the same time during the reaction.

(3) Process 3:

The compound (I-d) or salts thereof can be prepared by subjecting the compound (I-c) or salts thereof to elimination reaction of the imino-protective group of R.sub.a.sup.5.

Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compounds (I).

This reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantitally the same as those illustrated for elimination reaction of the carboxy-protective group of the compound (I-a) in Process 2, and therefore are to be referred to said explanation.

The present process includes within the scope thereof a case that the carboxy- and/or hydroxy-protective group(s) for R.sup.1 and R.sup.2, and amino- and/or imino-protective group(s) on R.sup.4 are eliminated or azido group on R.sup.4 is reduced to amino group at the same time during the reaction.

(4) Process 4:

The compound (I-f) or salts thereof can be prepared by subjecting the compound (I-e) or salts thereof to elimination reaction of the hydroxy-protective group on R.sub.a.sup.2.

Suitable salts of the compounds (I-e) and (I-f) may be the same as those for the compound (I).

This reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated for elimination reaction of the carboxy-protective group of the compound (I-a) in Process 2, and therefore are to be referred to said explanation.

The present process includes within the scope thereof a case that the carboxy- and/or imino-protective group(s) for R.sup.1 and R.sup.5, and amino- and/or imino-protective group(s) on R.sup.4 are removed or azide group on R.sup.4 is reduced to amino group at the same time during the reaction.

(5) Process 5:

The compound (I-h) or salts thereof can be prepared by subjecting the compound (I-g) or salts thereof to elimination reaction of the amino-protective group on R.sub.a.sup.4.

Suitable salts of the compound (I-g) and (I-h) may be the same as those for the compound (I).

This reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated for elimination reaction of the carboxy-protective group of the compound (I-a) in Process 2, and therefore are to be referred to said explanation.

The present process includes within the scope thereof a case that the carboxy-protective group for R.sup.1, the hydroxy-protective group for R.sup.2 and/or the imino-protective group for R.sup.5 are removed at the same time during the reaction.

This reaction can be carried out in the presence of an organic or inorganic base such as those given in the explanation of Process 1.

(6) Process 6:

The compound (I-j) or salts thereof can be prepared by subjecting the compound (I-i) or salts thereof to reduction of the azido group on R.sub.c.sup.4.

Suitable salts of the compounds (I-i) and (I-j) may be the same as those for the compound (I).

This r