This invention relates to heterocyclic derivatives having antibacterial activity , to processes for their preparation to compositions containing them and to their use in medicine .

Thus the present invention provides compounds of the general formula (I )

in which R^ represents the group CHθαθ)pR ₅

R ₄ O

wherein R^ represents a hydrogen atom or a C _j ^^alkyl group; p is zero or one, and R ₅ represents a group selected from C ₁ _ ₆ alkyl, C ₅ _gcycloalkyl optionally substituted by a C ₁ _ ₃ alkyl group, phenyl, or C^^alkyl substituted by a C^^alkoxy group.

R ₂ represents a C _1-3 alkyl, hydroxy, or hydroxymethyl group or ₂ represents the group XR3 wherein X is oxygen and R3 represents a ^c 3_7 cycloalkyl or phenyl group or X is the group S(0)n wherein n is zero or the integer 1 or 2 and R3 is C ₁ _ςalkyl, C ₃ _ ₇ cycloalkyl or phenyl.

In addition to the fixed stereochemical arrangement as defined in formula (I) the molecule contains a further asymmetric carbon atoms at the 8 and another at the 4 position. Also the group ^ contains at least one asymmetric carbon atom when R4 is other than hydrogen. It will be appreciated that all stereoisomers including mixtures thereof arising from these additional asymmetric centres, are within the scope of the compounds of formula (I).

The general formula (I) as drawn includes at least 4 stereoisomers and mixtures thereof and these may be represented by the formulae (la, lb, lc and Id).

The wedge shaped bond ^ indicates that the bond is above th plane of the paper. The broken bond . m indicates that the bond i below the plane of the paper.

The configuration shown for the carbon atom at the 8-positio in formulae la and lb is hereinafter referred to as the β configuration and in formulae lc and Id as the a- configuration.

The configuration shown for the carbon at the 4-position in f ormu lae lb and I d is hereina f ter ref erred to a s the a- configuration and in formulae la and lc as the R configuration .

In general , in the specific compounds named below, the j3- configuration at the 8-position corresponds to the S isomer and the β-conf iguration at the 4-position to the R isomer . The a- configuration at the 8-position corresponds to the R isomer and the a- configuration at the 4-position corresponds to the S isomer . The assignment of the R or S configuration at the 4- and 8-positions has been made according to the rules of Cahn . Ingold and Prelog , Experientia 1956, ____, 81.

The term alkyl as usual herein refers to a straight or branched chain alkyl group. When R ₄ represents a C^_ ₄ alkyl group this may be for example methyl, ethyl, propyl, isopropyl or butyl.

When Rt _j represents an alkyl group this may conveniently be a C ₁ _ ₄ alkyl group such as methyl, ethyl, isopropyl or t-butyl .

When Rς represents a C^_ ₄ alkyl group substitued by Cη _j alko y, this may be for example a methyl, ethyl, propyl or isopropyl group substituted by methoxy.

When R ₅ represents C _j ^gcycloalkyl optionally substituted by C _3alkyl this may be for example a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group optionally substitued by a methyl or ethyl group .

When R ₂ represents the group S(θ)nR ₃ , n is preferably zero or one and within this group R ₃ is preferably C ₁ _ ₅ alkyl e.g. methyl or phenyl .

A preferred class of compounds of formula (1) are those having the β-conf iguration at the 8-position. Within this class those having the α-conf iguration at the 4-position are particularly preferred .

A further preferred class of compounds of formula (I) are those wherein R represents, hydrogen, methyl, propyl isopropyl, more particularly hydrogen or methyl.

Yet a further preferred class of compounds of formula (I) are those wherein R ₅ represents a C ₁ _ ₄ alkyl group such as methyl, ethyl, isopropyl or t-butyl, or a C ₁ _ ₄ alkyl group substituted by methoxy such as 1-methoxy-l-methylethyl, or phenyl or a C ₅ _ ₆ cycloalkyl group such as cyclopentyl or cyclohexyl optionally substituted by a methyl or ethyl group e.g. ethylcyclohexyl.

Compounds of formula (I) wherein R ₂ is a hydroxy, hydroxymethyl, phenythio, alkylthio group such as methylthio or methylsulphinyl, represent a further preferred class of compound according to the invention.

A particularly preferred group of esters according to the invention are those wherein R ₄ represents a hydrogen atom or a methyl group, p is zero or 1 and R ₅ represents a methyl, ethyl, isopropyl, t-butyl, 1-methoxy-l-methylethyl, phenyl, cyclohexyl, or 4-ethylcyclohexyl group.

A specific preferred class of compounds according to the invention are those of formula (la) wherein R ₂ is a hydroxy hydroxymethyl, phenylthio, methylthio or methylsulphinyl, and R- _j _ is pivaloyloxymethyl , 1 -pivaloyl xyethyl , acetoxymethyl , 1- acetoxyethyl, 1-methoxy-l-methylethylcarbonyloxymethyl , 1-(1- methoxy-1-methylethylcarbonyloxyethyl ) , 1-benzoyloxyethyl , 1- isopropoxycarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, l-( 4- ethylcyclohexyloxycarbonyloxyethyl or more particularly 1-

cyclohexyloxycarbonyloxyethyl group . Particularly pref erre compounds from within this class are those wherein R ₂ represent methylthio or methylsulphinyl .

Specific preferred compounds according to the invention includ esters of ( 4S , 8S, 9R, 10S, 12R) -4-methylthio-10-( 1-hydroxyethyl ) ll-oxo-l-azatricyclo[ 7.2 -.0.0 . . . ] undec-2-ene-2 carboxylic aci such as the pivaloyloxy ethyl, 1-pivaloyloxyethyl, acetoxymethyl , 1 acetoxyethyl , 1-methoxy-l-methylethylcarbonyloxymethyl , 1- ( 1 methoxy-1-methylethylcarbonyloxyethyl ) , 1-benzoyloxyethyl , 1 isopropoxycarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl , l-( 4 ethylcyclohexyloxycarbonyloxyethyl or more particularly 1 cyclohexyloxycarbonylσxyethyl ester .

Compounds according to the invention when administered orally exhibit a broad spectrum of antibacterial activity against a wid range of pathogenic microorganisms . Also they have a very hig resistance to all β-lactamases . Compounds of the invention are als relatively stable to renal dehydropeptidase .

Compounds of the invention have been found to exhibit usefu levels of activity against strains of staphylococcus aureus ,

Streptococcus f aecalis, Escherichia coli, Pseudomonas aeruginosa,

Clostridium perfrinqens and Bacteriodes fragilis.

The compounds of the invention may therefore be used fo treating a variety of diseases caused by pathogenic bacteria in human beings and animals .

Thus, according to another aspect of the present invention, we provide a compound of formula ( I ) for use in the therapy or prophylaxis of systemic bacterial infections in a human or animal subject .

According to a further aspect of the invention we provide the use of a compound of formula ( I ) f or the manuf acture of a therapeutic agent f or the treatment o f systemic bacterial infections in human beings and animals .

According to a yet further aspect of the invention we provide a method of treatment of the human or non-human animal body to combat bacterial infections which method comprises administering to the body an effective amount of a compound of formula ( I ) .

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms .

It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however doses employed for adult human treatment will typically be in the range of 200-2000mg per day e.g. lOOOmg per day.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for exmaple as two, three, four or more sub-doses per day.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulation for oral administration comprising a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions according to the invention may take the form of, for example tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelantinised maize starch, polyvinyl- pyrrolidone or hydroxypropylmethylcellulose) , fillers (e.g. starch, lactose, micro-crystalline cellulose or calcium phosphates), lubricants (e.g. magnesium stearate, hydrogenated vegatable oils, talc, silica, polyethyleneglycols ) , disintegrants (e.g. potato starch or sodium starch glycloate), or wetting agents (e.g. sodium lauryl sulphate). Flow aids e.g. silicon dioxide may also be used if desired. The tablets may be coated by methods well know in the art.

Liquid preparations for oral administration may take the for of, for example, solutions, syrups or suspensions, or they may b presented as a dry product either for consitution with water o other suitable vehicle before use for administration as a liquid o for direct administration and then washed down with water or other suitable liquid. Such liquid preprations may be prepared by conventional means with pharmaceutically accepable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats and oils such as hydrogenated castor oil), emulsifyng or thickening agents (e.g. lecithin, aluminium stearates or acacia), non-aqueous vehicles (e.g. almond oil, fractionated coconut oil, oily esters or ethyl alcohol), preservatives (e.g. methyl or butyl p-hydroxybenzoates or sorbic acid) and suitable flavouring and sweetening agents.

Compounds of formula (I) may be prepared by esterification of the carboxylic acid (II)

in which R _a is hydrogen or a hydroxy1 protecting group and _2a has the meanings defined for R ₂ in formula (I) or is a protected derivative thereof; or a reactive derivative thereof and if required or desired subjecting the resulting compound prior to or subsequent to any separation into its sterochemical isomers, to removal of one or more protecting groups. When R _a represents an hydroxyl protecting groups this may be for example a hydrocarbyl silyl group such as trialkylsilyl e.g. trimethylsilyl or t-butyldimethysilyl.

The esterification of a compound of formula (II) may be carried out by reaction with a compound R^X in which R^ has the meanings defined above in formula (I) and X is a leaving group such a halogen e.g. chlorine, bromine or iodine, or an alkyl or aryl sulphonate such as mesylate or tosylate, in the presence of a base. The reaction 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 dimethylformamide, dimethylacetamide, or dimethylsulphoxide.

In one embodiment of this process the reaction is conveniently carried out using a salt such as an alkali metal salt e.g. potassium or sodium salt of the carboxylic acid (II) in a polar solvent such as dimethylformamide and optionally in the presence of tetrabutylammonium bromide.

The esterification reaction may be conveniently carried out using a compound of formula (II) in which R _a represents a hydrogen atom. If the esterfication reaction is carried out on a compound of formula (II) in which R _a represents a hydroxyl protecting group and or R _2a is a protected hydroxyl or protected hydroxymethyl group then the hydroxy protecting group may be removed by conventional procedures. For example when R _a and the hydroxy protecting group in R _2a is a tert butyldimethylsilyl group this may be removed by treatment with tetrabutylammonium fluoride and acetic acid.

The compounds of formula (II) may be prepared by known methods e.g. as described in EP-A-0416963.

In the formulae (I) and (II) shown above when there is an asymmetric carbon atom and no specific configuration is shown then the formulae include all possible configurations.

Specific stereoisomers of the compounds of formula (I) and as defined in formulae la, lb, lc and Id, essentially free of the other stereoisomers may be prepared by using the general processes described above starting with the appropriate stereoisomer of formula (II) .

In order that the invention may be more fully understood the following examples are given by way of illustration only.

In the Examples, unless otherwise stated:

Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus and are uncorrected. All temperatures refer to C.

Infrared spectra were measured in chloroform-dl solutions on a FT-IR instrument. Proton Magnetic Resonance (1H-NMR) spectra were recorded at 300 MHz as solutions in chloroform-d _j . Chemical shifts are reported in ppm downfield (δ) from Me ₄ Si, used as an internal standard.

Example 1 l-(Cyclohexyloxycarbonyloxy)-ethyl(4S,8S,9R,10s,12R)-4-methy lthi 10-(l-hydroxyethyl)-ll-oxo-l-azatricyclo r7.2.0.0 ³ ' ⁸ 1undec-2-ene- carboxylate

A solution of potassium (4S,8S,9R,10S, 12R) -4-methylthio-10-( hydroxyethyl)-ll-oxo-l-azatricyclo [7.2.0.03,8]undec-2-ene- carboxylate (0.270g) in dry N,N-dimethylformamide (20ml) was add dropwise under nitrogen at -10 , to a stirred solution of cyclohex 1-bromoethylcarbonate (0.319g in N,N-dimethylformamide (10ml) a potassium carbonate (0.189g). The resulting mixture was stirred -10 for three hours and then concentrated in vacuum. Ethyl aceta (50ml) was added to the solution, which was then washed with wat (30ml) and dried over sodium sulfate. The solvent was removed unde vacuum and the residue (520mg) was purified by column chromatograp on silica gel, using cyclohexane/ ethylacetate 7/3, to obtain afte evaporation of the solvent the title compound as a white solid 0.22g;m.p 45-65°; t.l.c. cyclohexane/ethylacetate 1/1 R _f = 0.64; I (CDCl ₃ ), V _maχ (Cm ^-1 ): 1776(c=0), 1765 (c=o) , 1626(c=σ), 1620(c=c); ^-NM ^OO MHz, CDCl ₃ ) : 6.887(q), 4.72(bs), 4.64(m), 4.3-4.18(m) 3.481(ιn} , 3.242(d.d), 2.013(s), 2.005(s), 2.06-1.98( ) , 1.98 1.85(m), l./85-1.7(m), 1.702(d), 1.604(d), 1.586(d), 1.6-1.3(m) 1.314(d), 1.299(d). ppm. Pharmacy Examples Tablets g/tab

Compound of Example 1 320

Lactose 150

Ethyl cellulose 20 Sodium Lauryl sulphate 7

Magnesium stearate 3

Tablet core 500mg

The active ingredient and the lactose are blended together an then granulated using water as the granulation fluid. The drie granules are blended with ethyl cellulose, sodium lauryl sulphat and magnesium stearate and the tablet core formed using a appropriate punch. The tablet may then be coated using conventiona techniques and coatings.

Granules

mg/unit dose

Compound of Example 1 320

Starch 100

Cellulose 40

Polymethacrylate 30

Sodium lauryl sulphate 7

Magnesium stearate 3

Flavouring agent qs

A solution of the active ingredient in ethanol is sprayed into a suitable fluid bed granulator charged with the major excipients. The granules so formed are dried and screened. If desired the granules may then be coated with a suitable enteric coating and dried. The dried granules are then blended with the remaining excipients including any flavouring agent and coated, for example with an enteric coating. The granules thus obtained may be filled into capsules or the like for a single dose presentation or filled into bottles for subsequent preparation of a multi dose oral liquid presentation.

The antibacterial activity of the compounds of the invention may be determined by oral administration to mice in a conventional protection test.

The compounds of the invention are essentially non-toxic at therapeutically useful dose levels.