HK1005733B - 2-(heterocyclylthio)carbapenem derivatives their preparation and their use as antibiotics - Google Patents
2-(heterocyclylthio)carbapenem derivatives their preparation and their use as antibiotics Download PDFInfo
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Description
The present invention relates to a series of new carbapenem compounds, to methods using these compounds and to compositions containing these compounds, and provides processes for preparing these compounds.
The penicillins form a well known class of antibiotics, which have found considerable use in human and animal therapy for many years. Chemically, the penicillins have in common a β-lactam structure, commonly referred to as "penam", which may be represented by the following formula:
However, although the penicillins still form a valuable weapon in the pharmaceutical armory, the development of new, and often penicillin-resistant, strains of pathogenic bacteria has increasingly made it necessary to search for new types of antibiotic.
In recent years, great interest has been shown in compounds having a carbapenem structure, that is compounds having a carbon atom in place of the sulphur atom at the 1-position and having a double bond between the carbon atoms in the 2- and 3-positions of the basic penam structure. The carbapenem structure may be represented by the following formula:
These penam and carbapenem structures form the basis for the semi-systematic nomenclature of the penicillin derivatives in accordance with the recommendations of the International Union of Pure and Applied Chemistry (IUPAC), and this nomenclature is generally accepted by those skilled in the art throughout the world and is used herein. The numbering system employed herein is that illustrated on the above formula (B).
Of the known carbapenem derivatives, the best known is a compound called "thienamycin", whose semi-systematic name is 2-(2-aminoethylthio)-6-(1-hydroxyethyl)carbapen-2-em-3-carboxylic acid. Although thienamycin is known to have remarkably potent and broad antibacterial activity, its chemical stability in the human body is poor, which restricts its practical use. Various attempts have, therefore, been made to modify the chemical structure of thienamycin in order to improve its chemical stability whilst maintaining or improving its superior activity, but there is still a continuing need to develop further carbapenem antibiotics with improved properties.
The present invention provides a new group of carbapenem derivatives which possess superior absorption and metabolic stability (as evidenced by improved recovery rates in the urine), as well as a broad antibacterial spectrum and low toxicity. The invention also provides synthetic processes for the preparation of the new carbapenem derivatives, as well as pharmaceutical compositions comprising the said derivatives suitable for human and animal administration.
Of the prior art known to us, the following are believed to be the closest:
US Patent Specifications No. 4 640 799 and No. 4 665 170 disclose carbapenem compounds in which there is a group -S-A-N⁺ at the 2-position. "A" can be various groups, and N⁺ represents a quaternized nitrogen-containing heterocyclic group attached to A through its quaternary nitrogen atom. These compounds differ from those of the present invention in that, where the compounds of the present invention contain a quaternized nitrogen-containing heterocyclic group having a quaternary nitrogen atom, this is not attached to the rest of the molecule via the quaternary nitrogen atom, but is attached via a carbon atom of the heterocyclic group.
European Patent Specification No. 126 587 discloses a series of carbapenem compounds having a pyrrolidinylthio group at the 2-position. These differ from the compounds of the present invention which are quaternary nitrogen compounds in that these prior art compounds are not quaternary nitrogen compounds and they differ from the non-quaternized compounds of the present invention in the nature of the substituents on the heterocyclic ring. Certain of the compounds disclosed in this prior art may have good activity, but they are believed to be less well absorbed in vivo than are the compounds of the present invention.
European Patent Publications Nos. 72,710 and 235,823 also disclose carbapenem compounds structurally similar to those of the present application. Certain compounds of EP 72,710 have a non-aromatic heterocyclylthio group at the 2-position of the carbapenem structure. Certain compounds in EP 235,823 include a 2-position non-aromatic heterocycle containing a quaternised nitrogen atom. Similarly to the compounds of US 4,665,170 and US 4,640,799, however, this ring is attached to the remainder of the compound via its quaternised nitrogen atom.
The compounds of the present invention may be represented by the formula (I):
in which:
Ra represents a group of formula (III):
and in which:
one of the symbols R' represents a bond to the remainder of the compound of formula (I), in said group of formula (III) the others of the symbols R' all represent hydrogen atoms;
R¹ represents a methyl group;
R2a represents a hydrogen atom, a C₁ - C₆ alkyl group or a C₁ - C₆ alkanoyl group; and
-COOR⁵ represents a carboxy group, a group of formula -COO⁻, a group of formula -COOMx, where M is a cation and x is the reciprocal of the valence of the cation M, or a protected carboxy group and, where -COOR⁵ represents a carboxy group, a group of formula -COOMx or a protected carboxy group, the compound of formula (I) also contains an anion;
ℓ is zero, or an integer from 1 to 3;
p is zero or the integer 1 or 2;
and pharmaceutically acceptable salts and esters thereof.
For the following description, the definition of substituents (a) and substituents (c) is relevant:
substituents (a):
hydroxy groups, cyano groups, carbamoyloxy groups, azido groups, carboxy groups, nitro groups, oxo groups, halogen atoms, C₁ - C₆ alkoxy groups, C₁ - C₆ alkanoyl groups, C₁ - C₆ alkanoyloxy groups, C₁ - C₆ alkanoylamino groups, C₂ - C₇ alkoxycarbonyl groups, groups of formula -NR¹⁰R¹¹ and -CONR¹²R¹³
in which R¹⁰, R¹¹, R¹² and R¹³ are the same or different and each represents a hydrogen atom, a C₁ - C₆ alkyl group or a C₁ - C₆ alkanoyl group,
groups of formula -SO₂NR¹⁴R¹⁵ and -S(O)kR¹⁶
wherein R¹⁴, R¹⁵ and R¹⁶ are the same or different and each represents a C₁ - C₆ alkyl group and k is zero or an integer 1 or 2, and
groups of formula -NHSO₂R¹⁷, -N=CR¹⁸NR¹⁹R²⁰, -N=CR²¹CR²²=NR²³ and -C(=NH)NR²⁴R²⁵
wherein R¹⁷ to R²⁵ are the same or different and each represents a hydrogen atom or a C₁ - C₆ alkyl group;
substituents (c):
C₁ - C₄ alkyl groups, C₁ - C₄ alkoxy groups, C₁ - C₄ haloalkyl groups, C₁ -C₃ alkylenedioxy groups, halogen atoms, cyano groups and nitro groups.
The invention also provides a pharmaceutical composition comprising an effective amount of an antibiotic in admixture with a pharmaceutically acceptable carrier or diluent, wherein the antibiotic is at least one compound selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts and esters thereof.
The invention still further provides the use for the manufacture of a medicament for the treatment or prevention of microbial infection (e.g. in a mammal, which may be human) of an antibiotic, wherein the antibiotic is at least one compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.
The invention also provides processes for preparing the compounds of the present invention, which are described in more detail hereinafter.
In the compounds of the present invention, where R2a represents an alkyl group, this may be a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, hexyl, isohexyl and 2-methylpentyl groups, of which the methyl, ethyl, propyl and butyl groups are preferred, the methyl group generally being most preferred.
Where R2a or substituent (a) represents an alkanoyl group, this may be a straight or branched chain alkanoyl group containing from 1 to 6 carbon atoms, and examples include the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups, of which the formyl and acetyl groups are more preferred.
Where substituent (a) represents an alkanoylamino group, this may be a straight or branched chain alkanoylamino group containing from 1 to 6 carbon atoms, and examples include the formamido, acetamido, propionamido, butyramido, isobutyramido, valerylamino, isovalerylamino, pivaloylamino and hexanoylamino groups, of which the acetamido group is more preferred.
Where substituent (a) represents an alkanoyloxy group, this may be a straight or branched chain alkanoyloxy group containing from 1 to 6 carbon atoms, and examples include the formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and hexanoyloxy groups, of which the acetoxy, propionyloxy, butyryloxy, isobutyryloxy and pivaloyloxy groups are more preferred, and the acetoxy group is most preferred.
Where substituent (a) represents a halogen atom, this may be a fluorine, chlorine, iodine or bromine atom, of which the fluorine, chlorine and bromine atoms are preferred, the fluorine and chlorine atoms being most preferred.
Where substituent (a) represents an alkoxy group, this may be a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, and examples include the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, hexyloxy, isohexyloxy and 2-methylpentyloxy groups, of which the methoxy, ethoxy, propoxy and butoxy groups are preferred, the methoxy group generally being most preferred.
Where substituent (a) represents an alkoxycarbonyl group, this may be a straight or branched chain alkoxy group containing, in total, from 2 to 7 carbon atoms, including the carbon atom of the carbonyl group (i.e. the alkoxy part contains from 1 to 6 carbon atoms), and examples include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl and 2-methylpentyloxycarbonyl groups, of which the methoxycarbonyl and ethoxycarbonyl groups are most preferred.
Specific examples of atoms and groups which are included within substituents (a) include:
hydroxy groups, cyano groups, carbamoyloxy groups, azido groups, carboxy groups, nitro groups and oxo groups;
halogen atoms, such as the chlorine, fluorine, bromine and iodine atoms, especially the chlorine and fluorine atoms;
C₁ - C₆ alkoxy groups, C₁ - C₆ alkanoyl groups, C₁ - C₆ alkanoyloxy groups, C₁ - C₆ alkanoylamino groups and C₂ - C₇ alkoxycarbonyl groups, as exemplified above;
groups of formula -NR¹⁰R¹¹ and -CONR¹²R¹³, i.e. amino and carbamoyl groups and alkyl-substituted and alkanoyl-substituted derivatives thereof, such as the amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, t-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, t-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, formamido, acetamido, propionamido, butyramido, isobutyramido, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino formylcarbamoyl, acetylcarbamoyl, propionylcarbamoyl, butyrylcarbamoyl, isobutyrylcarbamoyl, valerylamino, isovalerylamino, pivaloylcarbamoyl and hexanoylcarbamoyl groups;
groups of formula SO₂NR¹⁴R¹⁵ and -S(O)kR¹⁶, i.e. sulphamoyl, thio, sulphinyl and sulphonyl groups, for example the methylsulphamoyl, ethylsulphamoyl, propylsulphamoyl, isopropylsulphamoyl, butylsulphamoyl, isobutylsulphamoyl, sec-butylsulphamoyl, t-butylsulphamoyl, dimethylsulphamoyl, diethylsulphamoyl, dipropylsulphamoyl, diisopropylsulphamoyl, dibutylsulphamoyl, and the thio, sulphinyl and sulphonyl groups exemplified for R² where R² represents a group of formula -S(O)jR⁹;
groups of formula -NHSO₂R¹⁷, -N=CR¹⁸NR¹⁹R²⁰, -N=CR²¹CR²²=NR²³ and -C(=NH)NR²⁴R²⁵, in which R¹⁷ to R²⁵ are as defined and exemplified above.
R⁵ represents a hydrogen atom or a protecting group, which is capable of removal under chemically moderate conditions such as by means of a chemical reducing reagent or by catalytic reduction, or which is capable of removal by means of biological reactions, e.g. in vivo, to produce a carboxy group. There is no limitation upon the nature of such a protecting group, provided that, where the resulting compound is to be used for therapeutic purposes, it is pharmaceutically acceptable, which, as is well-known in the art, means that the compound does not have reduced activity (or unacceptably reduced activity) or increased toxicity (or unacceptably increased toxicity) compared with the corresponding compound of formula (I) where R⁵ represents a hydrogen atom. Where, however, the compound is to be used for non-therapeutic purposes, e.g. as an intermediate in the preparation of other compounds, even this limitation does not apply, and the protecting group may be chosen having regard simply to process criteria. Examples of groups which may be represented by R⁵ include:
C₁ - C₂₀ alkyl groups, more preferably C₁ - C₆ alkyl groups, such as those exemplified in relation to R² etc. and higher alkyl groups as are well known in the art, such as the heptyl, octyl, nonyl and decyl groups, but most preferably the methyl, ethyl and t-butyl groups;
C₃ - C₇ cycloalkyl groups, for example where the cycloalkyl group is any one of those C₃ - C₆ cycloalkyl groups described herein in relation to R⁶ and R⁷ or the cycloheptyl group;
aralkyl groups, as defined and exemplified above in relation to R³ and R⁴ but in which the aromatic group is C₆ - C₁₄, which may be substituted or unsubstituted, and, if substituted may have at least one of substituents (c), defined above and exemplified below; examples of such aralkyl groups include the benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, benzhydryl (i.e. diphenylmethyl), triphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2,4,6-trimethylbenzyl, 4-bromobenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl and piperonyl groups;
alkenyl groups such as those defined and exemplified above in relation to R³ and R⁴, but which may be substituted or unsubstituted and, if substituted have at least one of substituents (a) defined above; examples of the unsubstituted groups are given above in relation to R³ and R⁴, and preferred groups include the allyl, 2-chloroallyl and 2-methylallyl groups;
halogenated C₁ - C₆, preferably C₁ - C₄, alkyl groups in which the alkyl part is as defined and exemplified in relation to the alkyl groups which may be represented by R² etc, and the halogen atom is chlorine, fluorine, bromine or iodine, such as the 2,2,2-trichloroethyl, 2-haloethyl (e.g. 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl or 2-iodoethyl), 2,2-dibromoethyl and 2,2,2-tribromoethyl group;
substituted silylalkyl groups, in which the alkyl part is as defined and exemplified in relation to the alkyl groups which may be represented by R² etc, and the silyl group has up to 3 substituents selected from the group consisting of C₁ - C₆ alkyl groups and phenyl groups which are unsubstituted or have at least one of substituents (a) defined and exemplified above, for example a 2-trimethylsilylethyl group;
phenyl groups, in which the phenyl group is unsubstituted or substituted, preferably with at least one C₁-C₄ alkyl or acylamino group, for example the phenyl, tolyl and benzamidophenyl groups;
phenacyl groups, which may be unsubstituted or have at least one of substituents (a) defined and exemplified above, for example the phenacyl group itself or the p-bromophenacyl group;
cyclic and acyclic terpenyl groups, for example the geranyl, neryl, linalyl, phytyl, menthyl (especially m- and p- menthyl), thujyl, caryl, pinanyl, bornyl, notcaryl, norpinanyl, norbornyl, menthenyl, camphenyl and norbornenyl groups;
alkoxymethyl groups, in which the alkoxy part is C₁ - C₆, preferably C₁ - C₄, and may itself be substituted by a single unsubstituted alkoxy group, such as the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and methoxyethoxymethyl groups;
aliphatic acyloxymethyl groups, in which the acyl group is preferably an alkanoyl group and is more preferably a C₂ - C₆ alkanoyl group, such as the acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl and pivaloyloxymethyl groups;
higher aliphatic acyloxyalkyl groups in which the acyl group is preferably an alkanoyl group and is more preferably a C₂ - C₆ alkanoyl group, and the alkyl part is C₂ - C₆, and preferably C₂ - C₄, such as the 1-pivaloyloxyethyl, 1-acetoxyethyl, 1-isobutyryloxyethyl, 1-pivaloyloxypropyl, 2-methyl-1-pivaloyloxypropyl, 2-pivaloyloxypropyl, 1-isobutyryloxyethyl, 1-isobutyryloxypropyl, 1-acetoxypropyl, 1-acetoxy-2-methylpropyl, 1-propionyloxyethyl, 1-propionyloxypropyl, 2-acetoxypropyl and 1-butyryloxyethyl groups;
cycloalkyl-substituted aliphatic acyloxyalkyl groups, in which the acyl group is preferably an alkanoyl group and is more preferably a C₂ - C₆ alkanoyl group, the cycloalkyl substituent is C₃ - C₇, and the alkyl part is a C₁ - C₆ alkyl group, preferably a C₁ - C₄ alkyl group, such as the (cyclohexylacetoxy)methyl, 1-(cyclohexylacetoxy)ethyl, 1-(cyclohexylacetoxy)propyl, 2-methyl-1-(cyclohexylacetoxy)propyl, (cyclopentylacetoxy)methyl, 1-(cyclopentylacetoxy)ethyl, 1-(cyclopentylacetoxy)propyl and 2-methyl-1-(cyclopentylacetoxy)propyl, groups;
alkoxycarbonyloxyalkyl groups, especially 1-(alkoxycarbonyloxy)ethyl groups, in which the alkoxy part is C₁ - C₁₀, preferably C₁ - C₆, and more preferably C₁ - C₄, and the alkyl part is C₁ - C₆, preferably C₁ - C₄, such as the 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1-sec-butoxycarbonyloxyethyl, 1-t-butoxycarbonyloxyethyl, 1-(1-ethylpropoxycarbonyloxy)ethyl and 1-(1,1-dipropylbutoxycarbonyloxy)ethyl groups, and other alkoxycarbonylalkyl groups, in which both the alkoxy and alkyl groups are C₁ - C₆, preferably C₁ - C₄, such as the 2-methyl-1-(isopropoxycarbonyloxy)propyl, 2-(isopropoxycarbonyloxy)propyl, isopropoxycarbonyloxymethyl, t-butoxycarbonyloxymethyl, methoxycarbonyloxymethyl and ethoxycarbonyloxymethyl groups;
cycloalkylcarbonyloxyalkyl and cycloalkyloxycarbonyloxyalkyl groups, in which the cycloalkyl group is C₃ - C₁₀, preferably C₃ - C₇, is mono- or poly- cyclic and is optionally substituted by at least one (and preferably only one) C₁ - C₄ alkyl group (e.g. selected from those alkyl groups exemplified above) and the alkyl group is a C₁ - C₆, more preferably C₁ - C₄, alkyl group (e.g. selected from those alkyl groups exemplified above) and is most preferably methyl, ethyl or propyl, for example the 1-methylcyclohexylcarbonyloxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, cyclopentylcarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentyloxycarbonyloxyethyl, 1-cyclopentylcarbonyloxyethyl, 1-cycloheptyloxycarbonyloxyethyl, 1-cycloheptylcarbonyloxyethyl, 1-methylcyclopentylcarbonyloxymethyl, 1-methylcyclopentyloxycarbonyloxymethyl, 2-methyl-1-(1-methylcyclohexylcarbonyloxy)propyl, 1-(1-methylcyclohexylcarbonyloxy)propyl, 2-(1-methylcyclohexylcarbonyloxy)propyl, 1-(cyclohexylcarbonyloxy)propyl, 2-(cyclohexylcarbonyloxy)propyl, 2-methyl-1-(1-methylcyclopentylcarbonyloxy)propyl, 1-(1-methylcyclopentylcarbonyloxy)propyl, 2-(1-methylcyclopentylcarbonyloxy)propyl, 1-(cyclopentylcarbonyloxy)propyl, 2-(cyclopentylcarbonyloxy)propyl, 1-(1-methylcyclopentylcarbonyloxy)ethyl, 1-(1-methylcyclopentylcarbonyloxy)propyl, adamantyloxycarbonyloxymethyl, adamantylcarbonyloxymethyl, 1-adamantyloxycarbonyloxyethyl and 1-adamantylcarbonyloxyethyl groups;
cycloalkylalkoxycarbonyloxyalkyl groups in which the alkoxy group has a single cycloalkyl substituent, the cycloalkyl substituent being C₃ - C₁₀, preferably C₃ - C₇, and mono- or poly- cyclic, for example the cyclopropylmethoxycarbonyloxymethyl, cyclobutylmethoxycarbonyloxymethyl, cyclopentylmethoxycarbonyloxymethyl, cyclohexylmethoxycarbonyloxymethyl, 1-(cyclopropylmethoxycarbonyloxy)ethyl, 1-(cyclobutylmethoxycarbonyloxy)ethyl, 1-(cyclopentylmethoxycarbonyloxy)ethyl and 1-(cyclohexylmethoxycarbonyloxy)ethyl groups;
terpenylcarbonyloxyalkyl and terpenyloxycarbonyloxyalkyl groups, in which the terpenyl group is as exemplified above in relation to the terpenyl groups which may be represented by R⁵, and is preferably a cyclic terpenyl group, for example the 1-(menthyloxycarbonyloxy)ethyl, 1-(menthylcarbonyloxy)ethyl, menthyloxycarbonyloxymethyl, menthylcarbonyloxymethyl, 1-(3-pinanyloxycarbonyloxy)ethyl, 1-(3-pinanylcarbonyloxy)ethyl, 3-pinanyloxycarbonyloxymethyl and 3-pinanylcarbonyloxymethyl groups;
5-alkyl or 5-phenyl [which may be substituted by at least one of substituents (c)] (2-oxo-1,3-dioxolen-4-yl)alkyl groups in which each alkyl group (which may be the same or different) is C₁ - C₆, preferably C₁ - C₄, for example the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and 1-(5-methyl-2-oxo-1,3-dioxolen-4-yl)ethyl groups; and
other groups, especially groups which are easily removed in vivo such as the phthalidyl, indanyl and 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxolen-4-yl groups.
Of the above groups, we especially prefer those groups which can be removed easily in vivo, and most preferably the aliphatic acyloxymethyl groups, higher aliphatic acyloxyalkyl groups, cycloalkyl-aliphatic acyloxyalkyl groups, alkoxycarbonyloxyalkyl groups, cycloalkylcarbonyloxyalkyl groups, and cycloalkylalkoxycarbonyloxyalkyl groups.
The compounds of the present invention can contain a basic group and can, therefore, form acid addition salts. The nature of such salts and such acids is not critical to the invention, provided that, where the compound is intended for use therapeutically, the salt is pharmaceutically acceptable, which, as is well known, means that it does not have a lower (or significantly lower) activity or a higher (or significantly higher) toxicity than the free base. However, where the compound is intended for other uses, e.g. as an intermediate in the preparation of other compounds, even this limitation does not apply.
Examples of acids which can form such salts or can provide the balancing anion include: inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulphuric acid or nitric acid; organic sulphonic acids, such as methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid; and organic carboxylic acids, such as oxalic acid, tartaric acid, citric acid, maleic acid, succinic acid, acetic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid.
Examples of cations which may be represented M in the compounds of the present invention include: metal atoms, especially alkali metal atoms, such as the sodium and potassium atoms, and alkaline earth metal atoms, such as the calcium atom; the ammonium group; and cations derived from a trialkylamine, such as triethylamine, or from another organic base, such as procaine, dibenzylamine or phenethylamine.
Where the compound of the invention is an ester, i.e. R⁵ represents a protecting group, we prefer those in which:
R⁵ represents: a C₁ - C₂₀ alkyl group, more preferably a C₁ - C₆ alkyl group; a C₃ - C₇ cycloalkyl group; an aralkyl group in which the alkyl part is C₁ - C₃ and the aromatic group is C₆ - C₁₄ and is unsubstituted or has at least one of substituents (c), defined above; a C₂ - C₆ alkenyl group which is unsubstituted or has at least one of substituents (a) defined above; a halogenated C₁ - C₆, preferably C₁ - C₄, alkyl group; a substituted silylalkyl group in which each alkyl part is C₁ - C₆ and the silyl group has up to 3 substituents selected from the group consisting of C₁ - C₆ alkyl groups and phenyl groups which are unsubstituted or have at least one of substituents (a) defined above; a phenyl group which is unsubstituted or has at least one C₁ - C₄ alkyl or acylamino substituent; a phenacyl group which is unsubstituted or has at least one of substituents (a) defined above; a cyclic or acyclic terpenyl group; an alkoxymethyl group, in which the alkoxy part is C₁ - C₆, preferably C₁ - C₄, which is unsubstituted or is itself substituted by a single unsubstituted alkoxy group; an aliphatic acyloxymethyl group, in which the acyl group is preferably an alkanoyl group and is more preferably a C₂ - C₆ alkanoyl group; a higher aliphatic acyloxyalkyl group in which the acyl group is preferably an alkanoyl group and is more preferably a C₂ - C₆ alkanoyl group, and the alkyl part is C₂ - C₆, and preferably C₂ - C₄; a cycloalkyl-substituted aliphatic acyloxyalkyl group, in which the acyl group is preferably an alkanoyl group and is more preferably a C₂ - C₆ alkanoyl group, the cycloalkyl substituent is C₃ - C₇, and the alkyl part is a C₁ - C₆ alkyl group, preferably a C₁ - C₄ alkyl group; an alkoxycarbonyloxyalkyl group, especially a 1-(alkoxycarbonyloxy)ethyl group, in which the alkoxy part is C₁ - C₁₀, preferably C₁ - C₆, and more preferably C₁ - C₄, and the alkyl part is C₁ - C₆, preferably C₁ - C₄; a cycloalkylcarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl group, in which the cycloalkyl group is C₃ - C₁₀, preferably C₃ - C₇, is mono- or poly- cyclic and is optionally substituted by at least one C₁ - C₄ alkyl group, and the alkyl group is a C₁ - C₆, more preferably C₁ - C₄, alkyl group; a cycloalkylalkoxycarbonyloxyalkyl group in which the alkoxy group has a single cycloalkyl substituent, the cycloalkyl substituent being C₃ - C₁₀, preferably C₃ - C₇, and mono- or poly- cyclic; a terpenylcarbonyloxyalkyl or terpenyloxycarbonyloxyalkyl group; a 5-alkyl- or 5-phenyl- substituted (2-oxo-1,3-dioxolen-4-yl)alkyl group in which each alkyl group is C₁ - C₆, preferably C₁ - C₄, and in which the phenyl group is unsubstituted or has at least one of substituents (c); a phthalidyl group; an indanyl group; or a 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxolen-4-yl group.
Of the compounds of the present invention where Ra represents a group of formula (III), we prefer:
p is 1, and particularly where the group of formula (III) is a pyrrolidin-2-one-4-yl group, which has the group R2a at its nitrogen atom; and
R2a is a hydrogen atom, a C₁ - C₄ alkyl group, more preferably a methyl, ethyl, propyl or butyl group, or a C₁ - C₄ alkanoyl group, more preferably a formyl, acetyl, propionyl or butyryl group, and is most preferably a hydrogen atom, i.e. the pyrrolidin-2-one-4-yl group is unsubstituted.
The compounds of formula (I) can exist in the form of various isomers because of the presence of asymmetric carbon atoms. Both the individual isomers and mixtures of two or more isomers are included in the present invention. Such mixtures may be prepared as a result of the synthesis reactions or by mixing. Where an individual isomer is required, this may be prepared by a stereo-specific synthesis route or it may be prepared by separating a mixture of isomers, using separation techniques well known in the art. We particularly prefer those compounds in which the 1-hydroxyethyl group at the 6-penem position is in the same configuration as thienamycin, i.e. it is 1(R)-hydroxyethyl. Also, when R¹ represents a hydrogen atom, the (5R, 6S) configuration is preferred, and, when R¹ represents a methyl group, the (1R, 5S, 6S) configuration is preferred.
Specific Examples of compounds of the invention are given in the following formulae (I-8) and (I-9), in which the substituents are as defined in the corresponding one of Tables 8 and 9 [i.e. Table 8 relates to formula (I-8), Table 9 relates to formula (I-9)].
In the Tables, the following abbreviations are used:
- Ac
- acetyl
- Ada
- adamantyl
- All
- allyl
- Azr
- aziridinyl
- Azt
- azetidinyl
- Bu
- butyl
- cBu
- cyclobutyl
- sBu
- sec-butyl
- tBu
- t-butyl
- Byr
- butyryl
- iByr
- isobutyryl
- Bz
- benzyl
- Car
- carbamoyl
- Dix
- 2-oxo-1,3-dioxolen-4-yl
- Dox
- (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl
- Et
- ethyl
- Etc
- ethoxycarbonyl
- cHp
- cycloheptyl
- cHx
- cyclohexyl
- Me
- methyl
- Mec
- methoxycarbonyl
- Men
- menthyl
- Mor
- morpholino
- Pdox
- (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl
- Ph
- phenyl
- Phth
- phthalidyl
- Pip
- piperidyl
- Piv
- pivaloyl
- Piz
- piperazinyl
- cPn
- cyclopentyl
- Pr
- propyl
- cPr
- cyclopropyl
- iPr
- isopropyl
- Prg
- propargyl (= 2-propynyl)
- Prn
- propionyl
- Pyrd
- pyrrolidinyl
- Tfm
- trifluoromethyl
- Thz
- perhydro-1,4-thiazin-4-yl (= thiomorpholino)
Of the compounds listed above, the following are preferred, that is to say Compounds No. 9-2, 9-3, 9-5, 9-6 and 9-8, of which the following are most preferred:
- 9-2. Pivaloyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate, especially its pivaloyloxymethyl (1R, 5S, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate isomer;
- 9-3. (1-Methylcyclohexan-1-yl)carbonyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate, especially its (1-methylcyclohexan-1-yl)carbonyloxymethyl (1R, 5S, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate isomer;
- 9-5. 1-(Cyclopentyloxycarbonyloxy)ethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate, especially its 1-(cyclopentyloxycarbonyloxy)ethyl (1R, 5S, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate isomer;
The compounds of the present invention can be prepared by a variety of methods well known for preparing this type of compound. For example, in general terms, the compounds may be prepared by reacting a compound of formula (IV):
(in which R¹ is as defined above, R²⁷ represents a group of formula -OR²⁹ or -SO-R³⁰, in which:
R²⁹ represents an alkanesulphonyl group, an arylsulphonyl group, a dialkylphosphoryl group, or a diarylphosphoryl group; and
R³⁰ represents an alkyl group, a haloalkyl group, a 2-acetylaminoethyl group, a 2-acetylaminovinyl group; an aryl group or a heteroaryl group (i.e. an aromatic heterocyclic group); and
R²⁸ represents a protecting group for a carboxylic acid);
with a compound of formula (Vb):
HS-(CH₂)ℓ-RIII (Vb)
[in which RIII represents said group of formula (III), in which, if required any active groups are protected, ℓ is as defined above, and X⁻ is a balancing anion],
to give a compound of formula (VI):
[in which R¹, R²⁸ and ℓ are as defined above, and Rb represents said group of formula (III), in which, if required any active groups are protected, and which, if necessary contains a balancing anion], and then, if necessary, removing protecting groups and/or esterifying and/or salifying the resulting compound to give a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.
In the above formulae, R²⁹ represents: an alkanesulphonyl group, such as a methanesulphonyl, ethanesulphonyl, propanesulphonyl, isopropanesulphonyl or butanesulphonyl group; an arylsulphonyl group, such as a phenylsulphonyl, tolylsulphonyl, especially p-tolylsulphonyl, or naphthylsulphonyl group; a dialkylphosphoryl group, such as a dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl or dipentylphosphoryl group; or a diarylphosphoryl group, such as a diphenylphosphoryl or ditolylphosphoryl group;
R³⁰ represents an alkyl group, such as a methyl, ethyl, propyl or isopropyl group; a haloalkyl group, such as a fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl group; a 2-acetylaminoethyl group; a 2-acetylaminovinyl group; an aryl group, such as a phenyl or naphthyl group which may optionally be substituted with from 1 to 3 substituents, which may be the same or different and examples of the substituent include the fluorine, chlorine and bromine atoms, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, nitro, hydroxy and cyano groups; a heteroaryl group such as a pyridyl or pyrimidinyl group which may optionally be substituted with from 1 to 3 substituents, which may be the same or different and examples of the substituent include the fluorine, chlorine and bromine atoms and the methyl, ethyl, propyl and isopropyl groups; and
R²⁸ represents a protecting group for a carboxylic acid, examples of the protecting group include, for example an alkyl group such as a methyl, ethyl or t-butyl group; an aralkyl group such as a benzyl, diphenylmethyl, 4-nitrobenzyl or 2-nitrobenzyl group; an alkenyl group such as an allyl, 2-chloroallyl or 2-methylally group; a haloalkyl group such as a 2,2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-tribromoethyl group or a 2-trimethylsilylethyl group.
In more detail, the compounds may be prepared as illustrated in the following Methods A and B.
This is as shown in the following Reaction Scheme A:
In the above formulae:
R¹, R⁵, Ra, Rb, R²⁸, R²⁹ and ℓ are as defined above.
In Step A1 of this reaction scheme, the compound of formula (VII), which is the starting material, is reacted with an active derivative of an alkanesulphonic, arylsulphonic, dialkylphosphoric or diarylphosphoric acid R²⁹OH, e.g. an alkanesulphonic or arylsulphonic acid anhydride or a dialkylphosphoryl or diarylphosphoryl halide in the presence of a base. In Step A2, the resulting compound of formula (VIII) is then reacted without isolation with a mercaptan derivative of formula (Vb) in the presence of a base to give a compound of formula (VI). The desired compound of formula (I) may then be prepared, if necessary, by removal of the protecting group, R²⁸, from the carboxyl group in the compound of formula (VI).
In Step A1, examples of the reactive derivative of the reagent of formula R²⁹OH which may be employed include: alkanesulphonic acid anhydrides, such as methanesulphonic or ethanesulphonic acid anhydride; arylsulphonic acid anhydrides, such as benzenesulphonic or p-toluenesulphonic acid anhydride; dialkylphosphoryl halides, such as dimethylphosphoryl or diethylphosphoryl chloride; diarylphosphryl halides, such as diphenylphosphoryl chloride or diphenylphosphoryl bromide. Of these reagents, p-toluenesulphonic acid anhydride or diphenylphosphoryl chloride is preferred. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved. Examples of suitable solvents include: halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, 1,2-dichloroethane or chloroform; nitriles such as acetonitrile; amides such as N,N-dimethylformamide or N,N-dimethylacetamide There is likewise no particular limitation on the nature of the base to be employed, provided that it has no adverse effect upon other parts of the molecule, particularly the ^-lactam ring. Preferred bases which may be employed in this reaction include such organic bases as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a relatively low temperature in order to prevent side reactions, usually at a temperature from -20°C to 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 5 hours will usually suffice.
It is not necessary to isolate the resulting compound of formula (VIII) before the next step in the reaction scheme. Thus, in Step A2, the reaction mixture may be treated with a mercaptan derivative of formula (Vb) in the presence of a base. The nature of the base to be employed in the reaction is not critical but preferred bases include organic bases, such as triethylamine or diisopropylamine, and inorganic bases, such as potassium carbonate or sodium carbonate.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, however, we find it best to carry out the reaction at a relatively low temperature, e.g. at a temperature from -20°C to room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 5 days will usually suffice.
After completion of the reaction, the desired compound of formula (VI) may be recovered from the reaction mixture by conventional means, for example, one suitable recovery procedure comprises simply distilling off the solvent from the reaction mixture. The resulting compound may be further purified, if necessary, by conventional means, for example by recrystallization, reprecipitation or the various chromatography techniques, such as column chromatography or preparative thin layer chromatography.
If desired, before or after such further purification, the carboxy-protecting group may be removed. This is preferably effected without isolation of the compound of formula (VI).
The final reaction step of process A comprises the removal of the carboxy-protecting group R²⁸ from the compound of formula (VI), to give the corresponding carboxylic acid of formula (I), and, if required, conversion of the resulting free acid to another salt or ester. This step is optional, and it will be appreciated that the removal of the carboxy-protecting group may not always be necessary or desired, for example when the compound of formula (VI) is a pharmaceutically acceptable ester within the scope of the present invention. If it is desired to remove the carboxy-protecting group, this may be done by the use of conventional methods, the choice of which will depend upon the nature of the protecting group employed.
If the protecting group is removable by reduction, for example if it is a haloalkyl group, an aralkyl group or a benzhydryl group, it may be removed by contact with a reducing agent. In the case of haloalkyl groups, such as the 2,2-dibromoethyl or 2,2,2-trichloroethyl groups, the preferred reducing agent is a combination of zinc with acetic acid. If the protecting group is an aralkyl group (such as a benzyl or p-nitrobenzyl group) or a benzhydryl group, it is preferred to remove it either by catalytic reduction using hydrogen and a suitable catalyst, such as platinum or palladium on carbon; or by reduction with an alkali metal sulphide, such as sodium sulphide or potassium sulphide. Whatever the reduction technique, the reduction process is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include alcohols (such as methanol or ethanol), ethers (such as tetrahydrofuran or dioxane), aliphatic carboxylic acids (such as acetic acid), or a mixture of one or more of these organic solvents with water. The reaction temperature is not critical but will normally be in the range from 0°C to room temperature. The time required for the reaction will vary, depending upon the nature of the starting materials and reducing agents, as well as upon the reaction temperature, but a period of from 5 minutes to 12 hours will normally suffice.
After completion of the reaction, the desired compound, which will contain a free carboxy group, may be recovered by conventional means from the reaction mixture. For example, a suitable recovery technique comprises: separating off any insolubles; and then distilling off the solvent to give the desired product. This may, if necessary, be further purified by conventional means, for example recrystallization or the various chromatography techniques, such as preparative thin layer chromatography or column chromatography.
If desired, a carboxy group in the compound prepared as described above can be converted to an ester group hydrolysable under physiological conditions. This may be effected by conventional means. If R⁵ represents an ester which is hydrolysable under physiological conditions, e.g. a pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, methoxymethyl or 2-oxo-5-methyl-1,3-dioxolen-4-ylmethyl group, the compounds of formula (I) can be hydrolyzed in vivo under physiological conditions. Accordingly such a compound may be administered directly to a patient without deprotection.
This is as shown in the following Reaction Scheme B:
In the above formulae R¹, Ra, Rb, R²⁸, R³⁰ and ℓ are as defined above.
The compounds of formula (IX) used as starting materials in this reaction scheme can be prepared as described in Japanese Patent Application Kokai No. Sho 62-30781.
In Step B1, the compound of formula (VI) can be prepared by reacting a compound of formula (IX) with a mercaptan compound of formula (Vb) in the presence of a base and in an inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved. Examples of suitable solvents include: ethers, such as tetrahydrofuran; nitriles, such as acetonitrile; fatty acid amides, such as dimethylformamide; sulphoxides, such as dimethyl sulphoxide; water; or a mixture of any two or more thereof. The base used in the reaction is likewise not critical, provided that it does not affect other parts of the molecule, particularly the ^-lactam ring. Examples of suitable bases include: organic bases, such as diisopropylethylamine, triethylamine, N-methylpiperidine or 4-(N,N-dimethylamino)pyridine; and inorganic bases, particularly alkali metal carbonates, such as potassium carbonate or sodium bicarbonate. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention, although we prefer that the reaction is carried out at relatively low temperature in order to prevent side reactions. In general, we find it convenient to carry out the reaction at a temperature from -20°C to 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 5 days will usually suffice.
After completion of the reaction, the desired compound of formula (VI) can be recovered from the reaction mixture by conventional means. Also, the compounds of formula (I) can, if necessary, be prepared by deprotection of a compound of formula (VI) using the procedure described in Method A. Further separation and purification of the resulting compound may be effected as described in Method A.
Compounds of formula (Vb), which are also starting materials in the above reaction schemes may be obtained by conventional and well known means for preparing this type of compound . In the case of those compounds of formula (Vb), where these are not otherwise available, they may be prepared as follows:
First, a compound of formula (X):
L-Rc (X)
[in which L represents a leaving group, such as a hydroxy group, a halogen atom (such as a chlorine, bromine or iodine atom) or a sulphonyloxy group (e.g. a methanesulphonyloxy, propanesulphonyloxy, trifluoromethanesulphonyloxy or toluenesulphonyloxy group) and Rc represents a 2-oxopyrrolidinyl group, as defined in relation to the group of formula (III)]
is converted to the corresponding protected thio compound of formula (XI):
Rd-Rc (XI)
[in which Rd represents a thio-protecting group such as an alkanoyl group (e.g. an acetyl or propionyl group) or an aralkyl group (e.g. a 4-methoxybenzyl, 3,4-dimethoxybenzyl, benzhydryl, triphenylmethyl or di(4-methoxyphenyl)methyl group)].
When L represents a hydroxy group, this may be performed by means of the Mitsunobu reaction, which may be performed under conditions known per se, in the presence of diethyl azodicarboxylate, triphenyl phosphine and thioacetic acid.
When L represents a halogen atom or a sulphonyloxy group, the reaction may be performed by reacting the compound of formula (X) with a sodium or potassium salt of Rd-SH.
The second step is a conventional hydrolysis reaction and may be performed under conditions known per se. For example, when Rd is an alkanoyl group, it may be removed under alkaline or acidic conditions, for example, with sodium hydroxide in aqueous methanol. When Rd is an aralkyl group, it may be removed, e.g. with trifluoromethanesulphonic acid in the presence of trifluoroacetic acid and anisole.
The compounds of the present invention exhibit outstanding antibacterial activity with a wide spectrum of activity, and they are also resistant to β-lactamase. As assessed by the agar plate dilution method, they have been shown to be active against a wide range of pathogenic microorganisms, including both Gram-positive bacteria (such as Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (such as Escherichia coli, Shigella flexneri, Klebsiella pneumoniae, Proteus vulgaris, Serratia species e.g. Serratia marcescens, Enterobacter species e.g. Enterobacter cloacae, Salmonella enteritidis andPseudomonas aeruginosa) and are thus very useful for the treatment of diseases caused by such microorganisms in humans and non-human animals. Whereas thienamycin and its analogs are inactivated in vivo in mammals by dehydropeptidase I, the compounds of the invention are much more stable to this enzyme and exhibit good urinary recovery, and thus possess good biological activity. They also exhibit low toxicity when tested in laboratory animals.
Table 10 sets out the activities of a compound of the present invention against various bacteria, in terms of their minimal inhibitory concentrations (µg/ml).
Table 10
Table 10
| Cpd of Example | Microorganism | ||
| A | B | C | |
| 36 | 0.01* | 0.01* | 25 |
| 0.01*: no higher than 0.01 |
The results given above indicate that the compounds of the present invention may be used to treat or prevent diseases caused by a wide range of pathogenic bacteria.
The esters produced as described in Examples 39, 40 and 41 were incubated at 37°C for 1 hour with horse serum, after which the MIC values were determined. The values were all exactly the same as those of Example 36 and reported above. This means that the esters are easily cleaved by the esterase in the small intestines, after they have been orally administered, and that they are thus absorbed well through the digestive tracts, and exhibit in full the activity possessed by the free acid.
The compounds of the invention may be administered either orally or parenterally for the treatment of diseases in humans and other animals caused by pathogenic microorganisms. The compounds may be formulated into any conventional forms for administration. For example, for oral administration, suitable formulations include tablets, granules, capsules, powders and syrups, whilst formulations for parenteral administration include injectable solutions for intramuscular or, more preferably intravenous, injection.
The compounds of the invention are preferably administered parenterally, particularly in the form of an intravenous injection.
The dose of the compound of the invention will vary, depending upon the age, body weight and condition of the patient, as well as upon the form and times of administration. However, in general the adult daily dose is expected to be from 100 to 3000 mg of the compound, which may be administered in a single dose or in divided doses.
126 µℓ of diisopropylethylamine and 150 µℓ of diphenylphosphoryl chloride were added, whilst stirring and ice-cooling, to a solution of 250 mg of 4-nitrobenzyl (1R, 5R, 6S)-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 3 ml of dry acetonitrile, and then the mixture was stirred at 0 - 5°C for 1 hour. At the end of this time, 288 µℓ of diisopropylethylamine and a solution of 222 mg of a 1 : 1 by weight mixture of 3-mercapto-2-pyrrolidinone (prepared by a similar process to that described in Preparation 19) and trifluoromethanesulphonic acid in 2 ml of acetonitrile were added, with ice-cooling, to the previous reaction mixture. The whole mixture was then allowed to stand for 3 days in a refrigerator. At the end of this time, the mixture was diluted with ethyl acetate, washed, in turn, with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulphate. The solvent was then distilled off under reduced pressure to leave a crude product, which was dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of a 0.1M phosphate buffer solution (pH 7.1), and then hydrogenated at room temperature for 2 hours in the presence of 331 mg of 10% w/w palladium-on-charcoal. At the end of this period, insoluble matter was removed by filtration using a Celite filter aid and the filtrate was washed with diethyl ether. The aqueous phase was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through Diaion HP-20AG, eluted with water. The eluate was concentrated by evaporation under reduced pressure and then lyophilized to give a crude product. This was further purified by Lobar column chromatography (Merck, LiChroprep RP-8, size B), eluted with a 3% by volume aqueous methanol solution. The eluate was concentrated by evaporation under reduced pressure and lyophilized to give 35 mg of the title compound in the form of a colourless powder.
Ultraviolet Absorption Spectrum (H₂O) λmax nm: 302.
Nuclear Magnetic Resonance Spectrum (D₂O, 270 MHz) δppm:
1.00 (3H, doublet, J = 7.33 Hz);
1.11 (3H, doublet, J = 6.60Hz);
1.86 - 1.98 (1H, multiplet);
2.40 - 2.55 (1H, multiplet);
3.18 - 3.39 (4H, multiplet);
3.71 (1H, doublet of dooublets, J = 9.16 & 6.60 Hz);
4.02 - 4.12 (2H, multiplet).
126 µℓ of diisopropylethylamine and 150 µℓ of diphenylphosphoryl chloride were added, whilst stirring and ice-cooling, to a solution of 250 mg of 4-nitrobenzyl (1R, 5R, 6S)-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 5 ml of dry acetonitrile, and then the mixture was stirred at 0 - 5°C for 1 hour. At the end of this time, 144 µℓ of diisopropylethylamine and 97 mg of 4-mercapto-2-pyrrolidinone (prepared as described in Preparation 20) were added, with ice-cooling, to the previous reaction mixture. The whole mixture was then stirred at 0 - 5°C for 7 hours and then allowed to stand overnight in a refrigerator At the end of this time, the mixture was diluted with ethyl acetate, washed twice with an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulphate. The solvent was then distilled off under reduced pressure to leave a crude product, which was dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of a 0.1M phosphate buffer solution (pH 7.1), and then hydrogenated at room temperature for 2.5 hours in the presence of 331 mg of 10% w/w palladium-on-charcoal. At the end of this time, insoluble matter was removed by filtration using a Celite filter aid and the filtrate was washed with diethyl ether. The aqueous phase was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through Diaion HP-20AG, eluted with water. The eluate was concentrated by evaporation under reduced pressure and then lyophilized to give a crude product. This was further purified by Lobar column chromatography (Merck, LiChroprep RP-8, size B), eluted with a 3% by volume aqueous methanol solution. The eluate was concentrated by evaporation under reduced pressure and lyophilized to give 91 mg of the title compound in the form of a colourless powder. This is a mixture of the two isomers in respect of the carbon atom at the 4-position of the pyrrolidine ring, in proportions of about 1 : 1."
Ultraviolet Absorption Spectrum (H₂O) λmax nm: 300.
Nuclear Magnetic Resonance Spectrum (D₂O, 270 MHz) δppm:
1.02 & 1.03 (3H, doublet x 2, J = 7.33 & 6.96 Hz);
1.10 (3H, doublet, J = 6.60 Hz);
2.12 & 2.22 (1H, doublet of doublets x 2, J = 17.59 & 4.40 Hz and 17.59 & 4.03 Hz);
2.74 & 2.77 (1H, doublet of doublets x 2, J = 17.59 & 9.16 Hz and 17.59 & 9.16 Hz);
3.07 - 3.29 (3H, multiplet);
3.64 - 3.73 (1H, multiplet);
3.84 - 3.96 (1H, multiplet);
4.00 - 4.12 (2H, multiplet).
A solution of 66 mg of 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl iodide (prepared by heating 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl bromide and sodium iodide under reflux in acetone) in chloroform was added to a mixture of 47.6 mg of sodium (1R, 5S, 6S)-2-(2-oxo-3-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate and 0.4 ml of dry dimethylformamide. The mixture was stirred at room temperature for 80 minutes and then at 30 - 45°C for 4.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed four times with an aqueous solution of sodium chloride. The extract was dried and the solvent was distilled off under reduced pressure. The residue was purified by Lobar column chromatography (Merck, LiChroprep Si60, size A), eluted with a 10 : 1 by volume mixture of ethyl acetate and methanol, to give 27.4 mg of the title compound in the form of a colourless powder.
Ultraviolet Absorption Spectrum (CH₃OH) λmax nm:
322.
Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulphoxide, 270 MHz) δppm:
1.13 (3H, doublet, J = 7.32 Hz);
1.15 (3H, doublet, J = 6.35 Hz);
1.84 - 1.98 (1H, multiplet);
2.17 (3H, singlet);
2.50 - 2.65 (1H, multiplet);
3.12 - 3.45 (4H, multiplet);
3.77 - 4.06 (2H, multiplet);
4.14 (1H, doublet of doublets, J = 9.27 & 2.44 Hz);
5.08 (2H, singlet).
1.45 ml of diisopropylethylamine and 1.70 ml of diphenylphosphoryl chloride were added, whilst ice-cooling, to a solution of 2.93 g of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 50 ml of dry acetonitrile, and then the mixture was stirred at 0 - 5°C for 30 minutes. 1.45 ml of diisopropylethylamine and a solution of 1.35 g of 4-mercapto-2-pyrrolidinone (prepared as described in Preparation 20) in 5 ml of acetonitrile were added to the mixture, cooled at -20°C, and then the whole mixture was stirred at 0°C for 3 hours, after which it was allowed to stand at the same temperature overnight. The reaction mixture was then diluted with ethyl acetate, washed twice with an aqueous solution of sodium chloride and filtered. The organic phase was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure to give the 4-nitrobenzyl ester of the title compound as a foam. This was dissolved in 150 ml of tetrahydrofuran and the solution was filtered to remove insoluble matter. 150 ml of a 0.1M phosphate buffer solution (pH 7.1) were added to the filtrate and catalytic reduction was effected at room temperature for 2.5 hours in the presence of 1.5 g of 10% w/w palladium-on- charcoal. The reaction mixture was then worked up in a similar manner to that described in Example 34, to give 1.05 g of the title compound as a colourless powder. This is a mixture of the two isomers in respect of the carbon atom at the 4-position of the pyrrolidine ring, in proportions of about 9 : 1.
Ultraviolet Absorption Spectrum (H₂O) λmax nm: 299.
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1748, 1689, 1597, 1393, 1296.
Nuclear Magnetic Resonance Spectrum (D₂O, 270 MHz) δppm:
1.03 (3H, doublet, J = 7.3 Hz);
1.10 (3H, doublet, J = 6.2 Hz);
2.12 (0.9H, doublet of doublets, J = 17.9 & 4.4 Hz);
2.22 (0.1H, doublet of doublets, J = 17.9 & 4.4 Hz);
2.74, 2.77 (1H, 2 x doublet of doublets, J = 17.9 & 8.4 Hz);
3.08 - 3.24 (2H, multiplet);
3.26 (1H, doublet of doublets, J = 5.9 & 2.6 Hz);
3.69 (1H, doublet of doublets, J = 11.4 & 6.6 Hz);
3.84 - 3.93 (1H, multiplet);
4.02 - 4.11 (2H, multiplet).
A crude p-nitrobenzyl ester of the title compound was prepared, following substantially the same procedure as described in Example 36 above but using 330 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate. The ester was subjected to column chromatography through 50 g of silica gel, eluted with a 4 : 1 by volume mixture of ethyl acetate and methanol. The eluent was concentrated by evaporation under reduced pressure to give 260 mg of a colourless powder, which was mixed with 10 ml of ethyl acetate. This mixture was ice-cooled and filtered to remove insoluble matter. The filtrate was concentrated by evaporation under reduced pressure, and diisopropyl ether was added to the residue to give a precipitate. This was collected by filtration and dried to give 150 mg of the p-nitrobenzyl ester of the title compound as a powder which is either the R- or the S-isomer in respect of the carbon atom at the 4-position of the pyrrolidine ring.
Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulphoxide, 270 MHz) δppm:
1.16 (3H, doublet, J = 6.0 Hz);
1.18 (3H, doublet, J = 7.3 Hz);
2.02 (1H, doublet of doublets, J = 17.1 & 4.9 Hz);
2.72 (1H, doublet of doublets, J = 17.1 & 8.3 Hz);
3.12 - 3.48 (3H, multiplet);
3.74 (1H, doublet of doublets, J = 10.7 & 6.3 Hz);
3.94 - 4.05 (2H, multiplet);
4.24 (1H, doublet of doublets, J = 9.8 & 2.9 Hz);
5.06 (1H, doublet, J = 4.9 Hz);
5.30, 5.46 (2H, AB, J = 14.2 Hz);
7.71 (2H, doublet, J = 8.8 Hz);
8.23 (2H, doublet, J = 8.8 Hz).
100 mg of the p-nitrobenzyl ester obtained in the previous step were subjected to catalytic hydrogenation in a similar manner to that described in Example 34, to give 55 mg of the title compound having either the R- or the S-configuration, in respect of the carbon atom at the 4-position of the pyrrolidine ring, in a pure state as a powder.
Ultraviolet Absorption Spectrum λmax nm: 299 (H₂O).
Nuclear Magnetic Resonance Spectrum (D₂O, 270 MHz) δppm:
1.03 (3H, doublet, J = 7.3 Hz);
1.10 (3H, doublet, J = 6.2 Hz);
2.12 (1H, doublet of doublets, J = 17.9 & 4.4 Hz);
2.74 (1H, doublet of doublets, J = 17.9 & 8.4 Hz);
3.08 - 3.24 (2H, multiplet);
3.26 (1H, doublet of doublets, J = 5.9 & 2.6 Hz);
3.69 (1H, doublet of doublets, J = 11.4 & 6.6 Hz);
3.84 - 3.93 (1H, multiplet);
4.02 - 4.11 (2H, multiplet).
A crude p-nitrobenzyl ester of the title compound was prepared, following substantially the same procedure as that described in Example 34, but using 300 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate. The ester was subjected to column chromatography through 50 g of silica gel, eluted with a 4 : 1 by volume mixture of ethyl acetate and methanol. The eluent was concentrated by evaporation under reduced pressure to give 270 mg of a colourless powder. The product is about a 1 : 1 mixture of the two isomers in respect of the carbon atom at the 4-position of the pyrrolidine ring. 100 mg of this product were mixed with 10 ml of ethyl acetate. The mixture was filtered to collect the insoluble matter, which was recrystallized from a mixture of methanol and isopropanol to give 30 mg of the p-nitrobenzyl ester of the title compound as colourless needles. This is either the R- or the S-isomer in respect of the carbon atom at the 4-position of the pyrrolidine ring and is the other isomer having the opposite configuration of the compound obtained in the first step of Example 37.
Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulphoxide, 270 MHz) δppm:
1.16 (3H, doublet, J = 6.3 Hz);
1.17 (3H, doublet, J = 7.3 Hz);
2.13 (1H, doublet of doublets, J = 17.1 & 4.4 Hz);
2.79 (1H, doublet of doublets, J = 17.1 & 7.8 Hz);
3.10 (1H, doublet of doublets, J = 10.8, 3.4 Hz);
3.16 - 3.35 (1H, multiplet);
3.40 - 3.51 (1H, multiplet);
3.70 (1H, doublet of doublets, J = 10.7 & 7.3 Hz);
3.95 - 4.12 (2H, multiplet);
4.25 (1H, doublet of doublets, J = 9.3 & 2.5 Hz);
5.07 (1H, doublet, J = 5.4 Hz);
5.30, 5.46 (2H, AB, J = 14.2 Hz);
7.71 (2H, doublet, J = 8.8 Hz);
8.23 (2H, doublet, J = 8.8 Hz).
20 mg of the p-nitrobenzyl ester obtained in the previous step were subjected to catalytic hydrogenation in a similar manner to that described in Example 34, to give 11 mg of the title compound having either the R- or the S-configuration, in respect of the carbon atom at the 4-position of the pyrrolidine ring and having the opposite configuration to that obtained in Example 37, in a pure state as a powder.
Nuclear Magnetic Resonance Spectrum (D₂O, 270 MHz) δppm:
1.02 (3H, doublet, J = 7.3 Hz);
1.10 (3H, doublet, J = 6.6 Hz);
2.22 (1H, doublet of doublets, J = 17.6 & 4.4 Hz);
2.77 (1H, doublet of doublets, J = 17.6 & 8.4 Hz);
3.08 - 3.25 (2H, multiplet);
3.25 (1H, doublet of doublets, J = 5.9 & 2.6 Hz);
3.68 (1H, doublet of doublets, J = 11.4 & 6.4 Hz);
3.84 - 3.96 (1H, multiplet);
4.00 - 4.12 (2H, multiplet).
100 mg of sodium 2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate obtained by a similar procedure to that described in Example 36 were suspended in 3 ml of dry N,N-dimethylacetamide. 80 µℓ of pivaloyloxymethyl iodide were added, whilst ice-cooling, to the suspension, and then the mixture was stirred for 15 minutes, during which time the mixture became a solution. The reaction mixture was then diluted with 50 ml of ethyl acetate and washed twice with an aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by Lobar column chromatography (Merck, LiChroprep RP-8, size B), eluted with 60% by volume aqueous methanol. The eluent was evaporated under reduced pressure to remove the methanol, leaving the aqueous phase, which was mixed with sodium chloride and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure to give 110 mg of the title compound as a colourless powder.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323 (ε = 10760).
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1778, 1756, 1699.
Nuclear Magnetic Resonance spectrum (CDCℓ₃, 270 MHz) δppm:
1.23 (9H, singlet);
1.29 (3H, doublet, J = 7.3 Hz);
1.35 (3H, doublet, J = 6.2 Hz);
1.95 (1H, broad singlet);
2.33 (1H, doublet of doublets, J = 17.6 & 6.2 Hz);
2.79 (1H, doublet of doublets, J = 17.6 & 8.8 Hz);
3.22 - 3.34 (2H, multiplet);
3.38 (1H, doublet of doublets, J = 9.9 & 4.8 Hz);
3.80 (1H, doublet of doublets, J = 10.3 & 7.0 Hz);
3.95 - 4.05 (1H, multiplet);
4.20 - 4.27 (2H, multiplet);
5.79 (1H, broad singlet);
5.83, 5.97 (2H, AB, J = 5.5 Hz).
Following a similar procedure to that described in Example 39, but using (1-methylcyclohexan-1-yl)carbonyloxymethyl iodide in place of pivaloyloxymethyl iodide, the title compound was obtained.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323 (ε = 9655).
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1777, 1753, 1700.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
1.18 (3H, singlet);
1.29 (3H, doublet, J = 7.3 Hz);
1.35 (3H, doublet, J = 6.2 Hz);
1.25 - 1.75 (9H, multiplet);
2.00 - 2.08 (2H, multiplet);
2.33 (1H, doublet of doublets, J = 17.6 & 6.2 Hz);
2.79 (1H, doublet of doublets, J = 17.6 & 8.8 Hz);
3.21 - 3.33 (2H, multiplet);
3.38 (1H, doublet of doublets, J = 9.9 & 4.8 Hz);
3.79 (1H, doublet of doublets, J = 9.9& 7.0 Hz);
3.95 - 4.05 (1H, multiplet);
4.21 - 4.30 (2H, multiplet);
5.78 (1H, broad singlet);
5.87, 5.96 (2H, AB, J = 5.5 Hz).
Following a procedure similar to that described in Example 39, but using 54 mg of sodium 2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate obtained by a similar procedure to that described in Example 36 and 50 µℓ of 1-(cyclohexyloxycarbonyloxy)ethyl iodide, 62 mg of the title compound were obtained as a colourless powder.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323 (ε = 10766).
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1759, 1701.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
1.28 (3H, doublet, J = 7.0 Hz);
1.33, 1.36 (3H, two doublets, J = 6.2 Hz);
1.59, 1.61 (3H, two doublets, J = 5.5 Hz);
1.2 - 1.6 (6H, multiplet);
1.7 - 2.0 (5H, multiplet);
2.33 (1H, doublet of doublets, J = 17.6 & 6.2 Hz);
2.79 (1H, doublet of doublets, J = 17.6 & 8.8 Hz);
3.24 - 3.33 (2H, multiplet);
3.35 - 3.42 (1H, multiplet);
3.76 - 3.85 (1H, multiplet);
3.94 - 4.05 (1H, multiplet);
4.19 - 4.27 (2H, multiplet);
4.59 - 4.70 (1H, multiplet);
5.69 (1H, broad singlet);
6.88 (1H, quartet, J = 5.5 Hz).
Following a procedure similar to that described in Example 39, but using 1-(cyclopentyloxycarbonyloxy)ethyl iodide, the title compound was obtained.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 322 (ε = 10651).
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1760, 1701.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
1.28, 1.29 (3H, two doublets, J = 7.3 Hz);
1.33, 1.35 (3H, two doublets, J = 6.2 Hz);
1.58, 1.60 (3H, two doublets, J = 5.5 Hz);
1.65 - 1.95 (8H, multiplet);
2.33 (1H, doublet of doublets, J = 17.6 & 6.2 Hz);
2.79 (1H, doublet of doublets, J = 17.6 & 8.8 Hz);
3.23 - 3.32 (2H, multiplet);
3.38, 3.39 (1H, two doublet of doublets, J = 9.9 & 4.8 Hz);
3.68 - 3.87 (1H, multiplet);
3.96 - 4.07 (1H, multiplet);
4.19 - 4.27 (2H, multiplet);
5.08 - 5.16(1H, multiplet);
5.66 (1H, broad singlet);
6.87 (1H, quartet, J = 5.5 Hz).
Following a procedure similar to that described in Example 39, but using 1-(cyclohexylmethyloxycarbonyloxy)ethyl iodide, the title compound was obtained.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323 (ε = 10975).
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1766, 1700, 1269.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
0.95 - 1.26 (5H, multiplet);
1.28, 1.29 (3H, two doublets, J = 7.3 Hz);
1.33, 1.35 (3H, two doublets, J = 6.2 Hz);
1.59, 1.61 (3H, two doublets, J = 5.9 & 5.5 Hz);
1.64 - 1.76 (6H, multiplet);
1.87 (1H, broad singlet);
2.33 (1H, doublet of doublets, J = 17.6 & 6.2 Hz);
2.79 (1H doublet of doublets, J = 17.6 & 8.8 Hz);
3.24 - 3.35 (2H, multiplet);
3.37 - 3.42 (1H multiplet);
3.75 - 3.87 (1H, multiplet);
3.95 - 4.06 (3H, multiplet);
4.20 - 4.28 (2H, multiplet);
5.73 (1H, broad singlet);
6.86, 6.87 (1H, two quartets, J = 5.9 & 5.5 Hz).
Following a procedure similar to that described in Example 39, but using 1-(isopropoxycarbonyloxy)ethyl iodide, the title compound was obtained.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323 (ε = 10961).
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1762, 1701, 1272.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
1.26 - 1.36 (12H, multiplet);
1.59, 1.61 (3H, two doublets, J = 5.5 Hz);
1.80 (1H, broad triplet, J = 3.7 Hz);
2.33 (1H, doublet of doublets, J = 17.6 & 6.2 Hz);
2.79 (1H, doublet of doublets, J = 17.6 & 8.8 Hz);
3.24 - 3.34 (2H, multiplet);
3.35 - 3.42 (1H, multiplet);
3.76 - 3.87 (1H, multiplet);
3.95 - 4.07 (1H, multiplet);
4.19 - 4.28 (2H, multiplet);
4.82 - 4.99 (1H, multiplet);
5.63 (1H, broad singlet);
6.88 (1H, quartet, J = 5.5 Hz).
Following a procedure similar to that described in Example 39, but using (1R, 2S, 5R)-(ℓ)-menthyloxycarbonyloxymethyl iodide, the title compound was obtained.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 324 (ε = 10801).
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1763, 1695, 1266.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
0.78 (3H, doublet, J = 7.0 Hz);
0.89 (3H, doublet, J = 7.0 Hz);
0.92 (3H, doublet, J = 7.3 Hz);
1.29 (3H, doublet, J = 7.3 Hz);
1.35 (3H, doublet, J = 6.2 Hz);
0.95 - 1.55 (5H, multiplet);
1.63 - 1.73 (2H, multiplet);
1.88 - 2.03 (1H, multiplet);
2.08 - 2.17 (1H, multiplet);
2.34 (1H, doublet of doublets, J = 17.2 & 6.2 Hz);
2.79 (1H, doublet of doublets, J = 17.2 & 8.8 Hz);
3.22 - 3.34 (2H, multiplet);
3.39 (1H, doublet of doublets, J = 9.5 & 4.8 Hz);
3.74 - 3.86 (1H, multiplet);
3.96 - 4.06 (1H, multiplet);
4.18 - 4.28 (2H, multiplet);
4.56 (1H, doublet of triplets, J = 10.6 & 4.4 Hz);
5.70 (1H, broad singlet);
5.89, 5.91 (2H, AB, J = 5.9 Hz).
Following a procedure similar to that described in Example 39, but using 50 mg of sodium 2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate and 55 mg of 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl bromide, 50 mg of the title compound were obtained as a colourless powder.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 321.1 (ε = 8982).
Infrared Absorption Spectrum (CHCℓ₃) νmax cm⁻¹:
1820, 1772, 1701, 1627.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
1.30 (3H, doublet, J = 7.33 Hz);
1.36 (3H, doublet, J = 6.22 Hz);
1.80 (1H, broad singlet);
2.21 (3H, singlet);
2.35 (1H, doublet of doublets, J = 17.58 & 6.04 Hz);
2.81 (1H, doublet of doublets, J = 17.58 & 8.80 Hz);
3.25 - 3.43 (3H, multiplet);
3.73 - 4.05 (2H, multiplet);
4.17 - 4.32 (2H, multiplet),
4.96, 5.05 (2H, AB, J = 13.93 Hz);
5.59 (1H, broad singlet).
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 300.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
Ultraviolet Absorption Spectrum (CH₃CN) λmax nm: 323.
20 ml of trifluoroacetic acid and 0.41 ml of trifluoromethanesulphonic acid were added, whilst ice-cooling, to a solution of 949 mg of 3-(4-methoxybenzylthio)pyrrolidin-2-one in 4 ml of anisole, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced rpessure to leave a residue, which was purified by column chromatography through silica gel, eluted with a 10 : 1 by volume mixture of ethyl acetate and methanol, to give 728 mg of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (60 MHz, CDCℓ₃) δppm:
1.75 - 3.05 (3H, multiplet);
3.30 - 4.04 (3H, multiplet);
8.12 (1H, broad singlet);
9.32 (1H, broad singlet).
20-(1) 15.6 g of triphenylphosphine were added to a suspension of 3 g of 4-hydroxy-2-pyrrolidinone in 200 ml of tetrahydrofuran, and then the mixture was stirred at room temperature for 5 minutes, after which it was cooled to -20°C. A solution of 9.3 ml of diethyl azodicarboxylate in 9 ml of tetrahydrofuran was added dropwise, whilst cooling at -12°C to -20°C, to the previous solution. The mixture was then stirred at 0 - 5°C for 5 minutes, after which it was again cooled to -20°C. 4.2 ml of thioacetic acid were then added dropwise to the mixture, whilst cooling at -18°C to -20°C. The mixture was then warmed to 0 - 5°C and stirred at that temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was purified first by column chromatography through silica gel, eluted with a 10 : 1 by volume mixture of ethyl acetate and methanol, and then by column chromatography through silica gel, eluted with a 2 : 1 by volume mixture of acetonitrile and benzene, to give 2.45 g of 4-acetylthio-2-pyrrolidinone as colourless crystals.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 90 MHz) δppm:
2.00 - 4.44 (5H, multiplet);
2.31 (3H, singlet);
7.13 (1H, broad singlet).
20-(2) 1.82 of the product obtained in step (1) were dissolved in 30 ml of methanol. 2.3 ml of a 28% w/v methanolic solution of sodium methoxide were added dropwise, whilst ice-cooling, to the previous solution, and then the mixture was stirred for 30 minutes. 12 ml of 1N hydrochloric acid were then added, whilst ice-cooling, to the reaction mixture, which was then concentrated by evaporation under reduced pressure to leave a powdery residue. The residue was extracted with 50 ml of ethyl acetate and the extract was dried over anydrous sodium sulphate. The extract was concentrated by evaporation under reduced pressure to give 1.35 g of the title compound as colourless crystals.
Infrared Absorption Spectrum (KBr) νmax cm⁻¹:
1687, 1681, 1250.
Nuclear Magnetic Resonance Spectrum (CDCℓ₃, 270 MHz) δppm:
1.95 (1H, doublet, J = 7.0 Hz);
2.30 (1H, doublet of doublets, J = 17.2 & 6.6 Hz);
2.80 (1H, doublet of doublets, J = 17.2 & 7.1 Hz);
3.31 (1H, doublet of doublets of doublets, J = 9.9, 5.2 & 0.8 Hz);
3.59 - 3.73 (1H, multiplet);
3.80 (1H, doublet of doublets of doublets, J = 9.9, 7.3 & 0.7 Hz);
6.13 (1H, broad singlet).
Claims (20)
- A process for preparing a compound of formula (I): [in which: Ra represents a group of formula (III): and in which: one of the symbols R' represents a bond to the remainder of the compound of formula (I), and in said group of formula (III) the others of the symbols R' all represent hydrogen atoms; R¹ represents a methyl group; R2a represents a hydrogen atom, a C₁ - C₆ alkyl group or a C₁ - C₆ alkanoyl group; and -COOR⁵ represents a carboxy group, a group of formula -COO⁻, a group of formula -COOMx, where M is a cation and x is the reciprocal of the valence of the cation M, or a protected carboxy group and, where -COOR⁵ represents a carboxy group, a group of formula -COOMx or a protected carboxy group, the compound of formula (I) also contains an anion; ℓ, is zero, or an integer from 1 to 3; p is zero or the integer 1 or 2; or a pharmaceutically acceptable salt or ester thereof, which process comprises the steps:(a) reacting a compound of formula (IV): (in which R¹ is as defined above, R²⁷ represents a group of formula -OR²⁹ or -SO-R³⁰, in which: R²⁹ represents: an alkanesulphonyl group, represented by a methanesulphonyl, ethanesulphhonyl, propanesulphonyl, isopropanesulphonyl or butanesulphonyl group; an arylsulphonyl group, represented by a phenylsulphonyl, tolylsulphonyl, especially p-tolylsulphonyl, or naphthylsulphonyl group; a dialkylphosphoryl group, represented by a dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl or dipentylphosphoryl group; or a diarylphosphoryl group, represented by a diphenylphosphoryl or ditolylphosphoryl group; R³⁰ represents an alkyl group, represented by a methyl, ethyl, propyl or isopropyl group; a haloalkyl group, represented by a fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl, or trifluoroethyl group; a 2-acetyl- aminoethyl group; a 2-acetylaminovinyl group; an aryl group, represented by a phenyl or naphthyl group which may optionally be substituted with from 1 to 3 substituents, which may be the same or different and examples of the substituents include the fluorine, chlorine and bromine atoms, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, nitro, hydroxy and cyano groups; a heteroaryl group represented by a pyridyl or pyrimidinyl group which may optionally be substituted with from 1 to 3 substituents, which may be the same or different and examples of the substituent include the fluorine, chlorine and bromine atoms and the methyl, ethyl, propyl and isopropyl groups; and R²⁸ represents a protecting group for a carboxylic acid); with a compound of formula (Vb): HS-(CH₂)ℓ-RIII (Vb) [in which RIII represents said group of formula (III), in which, if required any active groups are protected, ℓ is as defined above, and X⁻ is a balancing anion], to give a compound of formula (VI): [in which R¹, R²⁸ and ℓ are as defined above, and Rb represents said group of formula (III), in which, if required any active groups are protected, and which, if necessary contains a balancing anion],(b) and then, if necessary, removing protecting groups and/or esterifying and/or salifying the resulting compound to give a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.
- A process according to Claim 1, wherein the reagents and reaction conditions are so chosen as to prepare a compound of formula (I), in which R⁵ represents: a C₁ - C₂₀ alkyl group; a C₃ - C₇ cycloalkyl group; an aralkyl group in which the alkyl part is C₁ - C₃ and the aromatic group is C₆ - C₁₄ and is unsubstituted or has at least one of substituents (c), defined below; a C₂ - C₆ alkenyl group which is unsubstituted or has at least one of substituents (a) defined below; a halogenated C₁ - C₆ alkyl group; a substituted silylalkyl group in which each alkyl part is C₁ - C₆ and the silyl group has up to 3 substituents selected from the group consisting of C₁ - C₆ alkyl groups and phenyl groups which are unsubstituted or have at least one of substituents (a) defined below; a phenyl group which is unsubstituted or has at least one C₁ - C₄ alkyl or acylamino substituent; a phenacyl group which is unsubstituted or has at least one of substituents (a) defined below; a cyclic or acyclic terpenyl group; an alkoxymethyl group, in which the alkoxy part is C₁ - C₆ which is unsubstituted or is itself substituted by a single unsubstituted alkoxy group; an aliphatic acyloxymethyl group, in which the acyl group is an alkanoyl group; a higher aliphatic acyloxyalkyl group in which the acyl group is an alkanoyl group, and the alkyl part is C₂ - C₆; a cycloalkyl-substituted aliphatic acyloxyalkyl group, in which the acyl group is an alkanoyl group, the cycloalkyl substituent is C₃ - C₇, and the alkyl part is a C₁ - C₆ alkyl group; an alkoxycarbonyloxyalkyl group, in which the alkoxy part is C₁ - C₁₀, and the alkyl part is C₁ - C₆; a cycloalkylcarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl group, in which the cycloalkyl group is C₃ - C₁₀, is mono- or poly-cyclic and is optionally substituted by at least one C₁ - C₄ alkyl group, and the alkyl group is a C₁ - C₆ alkyl group; a cycloalkylalkoxycarbonyloxyalkyl group in which the alkoxy group has a single cycloalkyl substituent, the cycloalkyl substituent being C₃ - C₁₀ and mono- or poly- cyclic; a terpenylcarbonyloxyalkyl or terpenyloxycarbonyloxyalkyl group; a 5-alkyl- or 5-phenyl- substituted (2-oxo-1,3-dioxolen-4-yl)alkyl group in which each alkyl group is C₁ - C₆ and in which the phenyl group is unsubstituted or has at least one of substituents (c); a phthalidyl group; an indanyl group; or a 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxolen-4-yl group; substituents (a): hydroxy groups, cyano groups, carbamoyloxy groups, azido groups, carboxy groups, nitro groups, oxo groups, halogen atoms, C₁ - C₆ alkoxy groups, C₁ - C₆ alkanoyl groups, C₁ - C₆ alkanoyloxy groups, C₁ - C₆ alkanoylamino groups, C₂ - C₇ alkoxycarbonyl groups, groups of formula -NR¹⁰R¹¹ and -CONR¹²R¹³ in which R¹⁰, R¹¹, R¹² and R¹³ are the same or different and each represents a hydrogen atom, a C₁ - C₆ alkyl group or a C₁ - C₆ alkanoyl group, groups of formula -SO₂NR¹⁴R¹⁵ and -S(O)kR¹⁶ wherein R¹⁴, R¹⁵ and R¹⁶ are the same or different and each represents a C₁ - C₆ alkyl group and k is zero or an integer 1 or 2, and groups of formula -NHSO₂R¹⁷, -N=CR¹⁸NR¹⁹R²⁰, -N=CR²¹CR²²=NR²³ and -C(=NH)NR²⁴R²⁵ wherein R¹⁷ to R²⁵ are the same or different and each represents a hydrogen atom or a C₁ - C₆ alkyl group; substituents (c): C₁ - C₄ alkyl groups, C₁ - C₄ alkoxy groups, C₁ - C₄ haloalkyl groups, C₁ -C₃ alkylenedioxy groups, halogen atoms, cyano groups and nitro groups.
- A process according to Claim 1, wherein the reagents and reaction conditions are so chosen as to prepare a compound of formula (I), in which R⁵ represents: a C₁ - C₆ alkyl group; a C₃ - C₇ cycloalkyl group; an aralkyl group in which the alkyl part is C₁ - C₃ and the aromatic group is C₆ - C₁₄ and is unsubstituted or has at least one of substituents (c), defined in Claim 2; a C₂ - C₆ alkenyl group which is unsubstituted or has at least one of substituents (a) defined in Claim 2; a halogenated C₁ - C₄ alkyl group; a substituted silylalkyl group in which each alkyl part is C₁ - C₆ and the silyl group has up to 3 substituents selected from the group consisting of C₁ - C₆ alkyl groups and phenyl groups which are unsubstituted or have at least one of substituents (a) defined in Claim 2; a phenyl group which is unsubstituted or has at least one C₁ - C₄ alkyl or acylamino substituent; a phenacyl group which is unsubstituted or has at least one of substituents (a) defined in Claim 2; a cyclic or acyclic terpenyl group; an alkoxymethyl group, in which the alkoxy part is C₁ - C₄, which is unsubstituted or is itself substituted by a single unsubstituted alkoxy group; an aliphatic acyloxymethyl group, in which the acyl group is a C₂ - C₆ alkanoyl group; a higher aliphatic acyloxyalkyl group in which the acyl group is a C₂ - C₆ alkanoyl group, and the alkyl part is C₂ - C₄; a cycloalkyl-substituted aliphatic acyloxyalkyl group, in which the acyl group is a C₂ - C₆ alkanoyl group, the cycloalkyl substituent is C₃ - C₇, and the alkyl part is a C₁ - C₄ alkyl group; a 1-(alkoxycarbonyloxy)ethyl group, in which the alkoxy part is C₁ - C₄, and the alkyl part is C₁ - C₄; a cycloalkylcarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl group, in which the cycloalkyl group is C₃ - C₇, is mono- or poly-cyclic and is optionally substituted by at least one C₁ - C₄ alkyl group, and the alkyl group is a C₁ - C₄ alkyl group; a cycloalkylalkoxycarbonyloxyalkyl group in which the alkoxy group has a single cycloalkyl substituent, the cycloalkyl substituent being C₃ - C₇ and mono- or poly- cyclic; a terpenylcarbonyloxyalkyl or terpenyloxycarbonyloxyalkyl group; a 5-alkyl- or 5-phenyl- substituted (2-oxo-1,3-dioxolen-4-yl)alkyl group in which each alkyl group is C₁ - C₄, and in which the phenyl group is unsubstituted or has at least one of substituents (c); a phthalidyl group; an indanyl group; or a 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxolen-4-yl group.
- A process according to Claim 2, in which the reagents and reaction conditions are so chosen as to prepare a compound of formula (I) or salt or ester thereof, in which R¹ represents a methyl group.
- A process according to Claim 1, where the reagents and reaction conditions are so chosen as to prepare a compound of formula (I) or salt or ester thereof, in which: p is 1; and R2a represents a hydrogen atom, a C₁ - C₄ alkyl group, or a C₁ - C₄ alkanoyl group.
- A process according to Claim 1, where the reagents and reaction conditions are so chosen as to prepare a compound of formula (I) or salt or ester thereof, in which: the group of formula (III) represents a pyrrolidin-2-one-4-yl group, which has the group R2a at its nitrogen atom; and R2a represents a hydrogen atom, a methyl, ethyl, propyl, butyl formyl, acetyl, propionyl or butyryl group.
- A process according to Claim 1, where the reagents and reaction conditions are so chosen as to prepare a compound of formula (I) or salt or ester thereof, in which: the group of formula (III) represents a pyrrolidin-2-one-4-yl group, which has the group R2a at its nitrogen atom; and R2a represents a hydrogen atom.
- A process according to any one of Claims 1 to 7, wherein the reagents and reaction conditions are so chosen as to prepare a compound of formula (I) or salt or ester thereof, in which the 1-hydroxyethyl group at the 6-penem position is in the 1(R)-hydroxyethyl configuration.
- A process according to any one of Claims 1 to 8, wherein the reagents and reaction conditions are so chosen as to prepare a compound of formula (I) or salt or ester thereof, in which R¹ represents a hydrogen atom, and the penem system has the (5R, 6S) configuration.
- A process according to any one of Claims 1 to 8, wherein the reagents and reaction conditions are so chosen as to prepare a compound of formula (I) or salt or ester thereof, in which R¹ represents a methyl group, and the penem system has the (1R, 5S, 6S) configuration.
- A process according to Claim 1, wherein the reagents and reaction conditions are so chosen as to prepare: Pivaloyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-Carboxylate; Pivaloyloxymethyl (1R, 5S, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate; (1-Methylcyclohexan-1-yl) carbonyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate; (1-Methylcyclohexan-1-yl)carbonyloxymethyl (1R, 5S, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate; 1-(Cyclopentyloxycarbonyloxy)ethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate; 1-(Cyclopentyloxycarbonyloxy)ethyl (1R, 5S, 6S)-2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate; or a pharmaceutically acceptable salt or ester thereof.
- A process for preparing a pharmaceutical composition comprising mixing an antibiotic with a pharmaceutically acceptable carrier or diluent, wherein the antibiotic is at least one compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, as defined in any one of Claims 1 to 11.
- A process according to Claim 12, in which the composition is formulated for oral administration.
- A process according to Claim 12, in which the composition is formulated for parenteral administration.
- The use for the manufacture of a medicament for the treatment or prevention of microbial infection of an antibiotic, wherein the antibiotic is at least one compound of formula (I) or a pharmaceutically acceptable salt or ester thereof as defined in any one of Claims 1 to 11.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8097488 | 1988-04-01 | ||
| JP63080974 | 1988-04-01 | ||
| JP11164088 | 1988-05-10 | ||
| JP63111640 | 1988-05-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1005733B true HK1005733B (en) | 1999-01-22 |
| HK1005733A1 HK1005733A1 (en) | 1999-01-22 |
Family
ID=26421941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK98104834A HK1005733A1 (en) | 1988-04-01 | 1998-06-03 | 2-(heterocyclylthio)carbapenem derivatives their preparation and their use as antibiotics |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5104867A (en) |
| EP (2) | EP0337637B1 (en) |
| KR (2) | KR0133071B1 (en) |
| AT (1) | ATE114654T1 (en) |
| AU (1) | AU615729B2 (en) |
| CA (1) | CA1336092C (en) |
| DE (1) | DE68919508T2 (en) |
| DK (2) | DK175029B1 (en) |
| ES (1) | ES2067534T3 (en) |
| FI (1) | FI91258C (en) |
| GR (1) | GR3015128T3 (en) |
| HK (1) | HK1005733A1 (en) |
| HU (2) | HU204275B (en) |
| IE (2) | IE66711B1 (en) |
| NO (1) | NO168304C (en) |
| NZ (1) | NZ228589A (en) |
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|---|---|---|---|---|
| JPS6425779A (en) * | 1987-04-11 | 1989-01-27 | Lederle Japan Ltd | (1r,5s,6s)-2-substituted-thio-6-((r)-1-hydroxyethyl)-1-methyl -carbapenem-3-carboxylic acid derivative |
| US5227376A (en) * | 1990-02-14 | 1993-07-13 | Sumitomo Pharmaceuticals Co., Ltd. | β-lactam compounds and their production |
| CA2050255C (en) * | 1990-09-07 | 1997-02-04 | Tameo Iwasaki | 1-methylcarbapenem derivatives and process for preparation thereof |
| US5208348A (en) * | 1990-09-07 | 1993-05-04 | Tanabe Seiyaku Co., Ltd. | Mercaptan compound |
| GB9122988D0 (en) * | 1991-10-30 | 1991-12-18 | Ici Plc | Heterocyclic compounds |
| GB9127279D0 (en) * | 1991-12-23 | 1992-02-19 | Ici Plc | Heterocyclic derivatives |
| US5612352A (en) * | 1992-04-10 | 1997-03-18 | Zeneca Limited | Heterocyclic compounds |
| GB9211796D0 (en) * | 1992-06-04 | 1992-07-15 | Ici Plc | Heterocyclic derivatives |
| GB9216721D0 (en) * | 1992-08-06 | 1992-09-23 | Ici Plc | Therapeutic heterocyclic derivatives |
| JP2696807B2 (en) * | 1992-08-06 | 1998-01-14 | 田辺製薬株式会社 | Preparation of carbapenem derivatives |
| GB9218334D0 (en) * | 1992-08-28 | 1992-10-14 | Ici Plc | Heterocyclic compounds |
| US6011150A (en) * | 1992-11-13 | 2000-01-04 | Tanabe Seiyaku Co., Ltd. | Azetidinone compound and process for preparation thereof |
| US5631363A (en) * | 1992-11-13 | 1997-05-20 | Tanabe Seiyaku Co., Ltd. | Azetidinone compound and process for preparation thereof |
| US5442055A (en) * | 1992-11-13 | 1995-08-15 | Tanabe Seiyaku Co., Ltd. | Azetidinone compound and process for preparation thereof |
| DE69324106T2 (en) * | 1992-11-17 | 1999-12-09 | Sankyo Co., Ltd. | Crystalline carbapenem derivative |
| GB9226573D0 (en) * | 1992-12-21 | 1993-02-17 | Ici Plc | Heterocyclic compounds |
| US5495012A (en) * | 1992-12-28 | 1996-02-27 | Tanabe Seiyaku Co., Ltd. | Process for preparing optically active 4-mercapto-2-pyrrolidone derivative and intermediate therefor |
| JP2701685B2 (en) * | 1992-12-28 | 1998-01-21 | 田辺製薬株式会社 | Method for producing optically active 4-mercapto-2-pyrrolidone derivative and its synthetic intermediate |
| IL109451A0 (en) * | 1993-04-29 | 1994-07-31 | Zeneca Ltd | Heterocyclic derivatives |
| AU4912393A (en) * | 1993-06-15 | 1994-12-22 | Dong Kook Pharmaceutical Co., Ltd. | 1-beta-methyl-2-thiolic carbapenem derivatives |
| US5550229A (en) * | 1993-06-23 | 1996-08-27 | Tanabe Seiyaku Co., Ltd. | Alkylation process for preparing azetidinone compound and starting compound therefor |
| JP2969616B2 (en) * | 1994-11-24 | 1999-11-02 | 田辺製薬株式会社 | Method for producing 4-mercaptopyrrolidine compound |
| JPH09143156A (en) | 1995-11-17 | 1997-06-03 | Tanabe Seiyaku Co Ltd | Production of acetoxyazetidinone derivative and its synthetic intermediate |
| TW420681B (en) * | 1995-12-08 | 2001-02-01 | Lederle Japan Ltd | Carbapenem-3-carboxylic acid ester derivatives |
| KR20000064997A (en) * | 1996-04-26 | 2000-11-06 | 가와무라 요시부미 | 1-methylcarbapenem derivative |
| JPH1077285A (en) | 1996-09-04 | 1998-03-24 | Sumitomo Pharmaceut Co Ltd | Novel β-lactam compound and method for producing the same |
| EP1078927B1 (en) | 1998-05-01 | 2006-08-23 | Kyoto Pharmaceutical Industries, Ltd. | Carbapenem derivatives, utilization thereof and intermediate compounds of the same |
| CA2331586A1 (en) | 1998-05-08 | 1999-11-18 | Sumitomo Pharmaceuticals Company, Limited | Novel .beta.-lactam compounds and process for producing the same |
| WO2000042041A1 (en) * | 1999-01-13 | 2000-07-20 | Sankyo Company, Limited | Carbapenem ester compounds |
| JP2003507376A (en) * | 1999-08-18 | 2003-02-25 | シエーリング アクチエンゲゼルシャフト | Piperidine and pyrrolidine derivatives showing neuronal activity |
| SK15822003A3 (en) * | 2001-05-21 | 2004-06-08 | Kyoto Pharmaceutical Industries, Ltd. | Carbapenem compound |
| US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| US7186855B2 (en) | 2001-06-11 | 2007-03-06 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| CA2519794A1 (en) * | 2003-04-08 | 2004-10-21 | Sumitomo Pharmaceuticals Co., Ltd. | Novel carbapenem compounds |
| US20070265242A1 (en) * | 2004-09-03 | 2007-11-15 | Makoto Sunagawa | Novel Carbapenem Compound |
| US7932381B2 (en) * | 2005-02-15 | 2011-04-26 | Shionogi & Co., Ltd. | Process for producing carbapenem derivative and intermediate crystal therefor |
| JPWO2006103999A1 (en) * | 2005-03-25 | 2008-09-04 | 大日本住友製薬株式会社 | New carbapenem compounds |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0017992A1 (en) * | 1979-04-19 | 1980-10-29 | Merck & Co. Inc. | 2-Substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, processes for preparing them, antibiotic pharmaceutical compositions containing same and process for preparing intermediates |
| FR2508440B1 (en) * | 1981-06-25 | 1985-11-08 | Saint Gobain Isover | PROCESS FOR THE PREPARATION OF ORTHOHYDROXYBENZYL ALCOHOLS |
| US4552873A (en) * | 1981-08-19 | 1985-11-12 | Sankyo Company Limited | Carbapenem compounds, and compositions containing them |
| JPS58198486A (en) * | 1982-05-14 | 1983-11-18 | Sankyo Co Ltd | Penem- or carbapenem-3-carboxylic acid derivative and its preparation |
| US4640799A (en) * | 1982-06-18 | 1987-02-03 | Bristol-Myers Company | Carbapenem antibiotics |
| US4665170A (en) * | 1982-06-18 | 1987-05-12 | Bristol-Myers Company | Carbapenem antibiotics |
| CA1283906C (en) * | 1983-05-09 | 1991-05-07 | Makoto Sunagawa | .beta.-LACTAM COMPOUNDS AND PRODUCTION THEREOF |
| JPS60202886A (en) * | 1984-03-27 | 1985-10-14 | Sankyo Co Ltd | 1-substituted carbapenem-3-carboxylic acid derivative and its preparation |
| CA1273011A (en) * | 1984-07-02 | 1990-08-21 | Susan M. Schmitt | Carbapenems having an externally alkylated mono- or bicyclic 2-quaternary heteroarylalkylthio substituent |
| CA1272719A (en) * | 1986-03-06 | 1990-08-14 | Pierre Dextraze | Carbapenem antibiotics |
-
1989
- 1989-03-31 DK DK198901580A patent/DK175029B1/en not_active IP Right Cessation
- 1989-03-31 IE IE103589A patent/IE66711B1/en not_active IP Right Cessation
- 1989-03-31 DE DE68919508T patent/DE68919508T2/en not_active Expired - Fee Related
- 1989-03-31 ES ES89303216T patent/ES2067534T3/en not_active Expired - Lifetime
- 1989-03-31 EP EP89303216A patent/EP0337637B1/en not_active Expired - Lifetime
- 1989-03-31 AT AT89303216T patent/ATE114654T1/en not_active IP Right Cessation
- 1989-03-31 FI FI891572A patent/FI91258C/en not_active IP Right Cessation
- 1989-03-31 NO NO891364A patent/NO168304C/en not_active IP Right Cessation
- 1989-03-31 IE IE950607A patent/IE950607L/en not_active IP Right Cessation
- 1989-03-31 EP EP94100573A patent/EP0597821A1/en not_active Ceased
- 1989-04-01 KR KR1019890004321A patent/KR0133071B1/en not_active Expired - Fee Related
- 1989-04-01 HU HU891629A patent/HU204275B/en not_active IP Right Cessation
- 1989-04-03 AU AU32386/89A patent/AU615729B2/en not_active Ceased
- 1989-04-03 CA CA000595556A patent/CA1336092C/en not_active Expired - Fee Related
- 1989-04-03 NZ NZ228589A patent/NZ228589A/en unknown
-
1990
- 1990-06-20 US US07/540,878 patent/US5104867A/en not_active Expired - Lifetime
-
1995
- 1995-02-22 GR GR950400348T patent/GR3015128T3/en unknown
- 1995-06-29 HU HU95P/P00545P patent/HU211836A9/en unknown
-
1997
- 1997-08-16 KR KR1019970039082A patent/KR0132907B1/en not_active Expired - Fee Related
-
1998
- 1998-06-03 HK HK98104834A patent/HK1005733A1/en not_active IP Right Cessation
- 1998-11-30 DK DK199801576A patent/DK199801576A/en not_active Application Discontinuation
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