AP238A

AP238A - Heterocyclic compounds.

Info

Publication number: AP238A
Application number: APAP/P/1991/000320A
Authority: AP
Inventors: Alcide Perboni; Tino Rossi; Giovannie Gaviraghi; Giorgio Tarzia; Antonella Ursini
Original assignee: Glaxo Spa
Priority date: 1990-08-21
Filing date: 1991-08-20
Publication date: 1993-02-04
Also published as: PT98729B; MX9100743A; CZ121392A3; WO1992003437A1; PL169425B1; HRP940556B1; NO300176B1; NZ239474A; SK121392A3; IE66122B1; YU142791A; YU48079B; US5587374A; JP2000351730A; HU9201303D0; FI97136C; AU647178B2; CA2067741C; FI921717A; NO921521D0

Abstract

Compounds of general formula (1)

Description

HETEROCYCLIC COMPOUNDS

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

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

CHin which R^ represents the group

CHOC(O)pR_s <=»« O wherein R^ represents a hydrogen atom or a C^.^alkyl group; p 13 zero or one; R5 represents a group selected from Ci__₆aikyl, Cc,_gcycLoalkyl optionally substituted by a Cj_jalkyl group, phenyl, or C₁_₄alkyl substituted by a C^_jalkoxy group; and represents the group OR3 in which R-j represents a C^.^alkyl group.

In addition to the fixed stereochemical arrangement as defined in formula (I) the molecule contains two further asymmetric carbon atoms at the 4 and 8 positions. Also the group R^ contains at least one asymmetric carbon atom when R^ 13 other than hydrogen. It will be appreciated that all stereoisomers including mixtures thereof arising from these additional asymmetric centres are within the scope of formula (I) .

The general formula (I) as dcawn includes at least 4 stereoisomers and mixtures thereof and these may be represented by the formulae (la, lb, 1c and Id).

BAD ORIGINAL

Id

The wedge shaped bond indicates that the bend is above the plane of the paper. The broken bond .·ι indicates that the bond is below the plane of the paper.

The configuration shown for the carbon atom at the 8-position. in formulae la and lb is hereinafter referred to as the £configuration and in formulae Ic and Id a3 the a- configuration.

The configuration shown for the carbon at the 4-position in formulae lb and Id is hereinafter referred to a3 the «configuration and in formulae la and 1c as the a-configuration.

Γη general, in the specific compounds named below, the jJconfiguration at the 8-position corresponds to the S isomer and the 3-configuration at the 4-position to the R isomer. The aconfiguration at the 8-position corresponds to the R isomer and the a- configuration at the 4-position corresponds to the 5 isomer. The assignment of the R or S configuration at the 4- and 3-positions has been made according to the rules of Cahn. Ingold and ?reiog, Szcerientia 1956, 12, 31.

The term alkyl as used herein refers to a straight or branched chain alkyl group. When R^ represents a C^_₄ alkyl group this may be for example methyl, ethyl, propyl, isopropyl or butyl.

When Rc, represents an alkyl group this may conveniently be a C^.^alkyl group such as methyl, ethyl, isopropyl or t-butyl.

When R5 represents a Cj^alkyl group sub3titued by C^.^alkoxy, this may be for example a methyl, ethyl, propyl or isopropyl group substituted by methoxy.

BAD ORIGINAL fi

IT* U U Μ 2 θ when R^ represents C^_^cycloalkyl optionally substituted by Cj^-jalkyl this may be for example a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group optionally substitued by a methyl or ethyl group.

A preferred, class of compounds of formula (1) are those hawing the ^-configuration at the 3-po3ition. Within this class those hawing the «-configuration at the 4-position are particularly preferred.

A further preferred class of compounds of formula (I, are those wherein R₄ represents hydrogen, methyl, propyl or isopropyl, more particularly hydrogen or methyl.

Yet a further preferred class of compounds of formula (I) are those wherein Rg represents a Cj__₄aikyl group such as methyl, ethyl, isopropyl or t-butyl; a C₁_₄alkyl group substituted by methoxy such as 1-methoxy-l-methylethyl; phenyl; or a C^_g cycloalkyl group 3uch as cyclopentyl or cyclohexyl optionally substituted by a methyl or ethyl group e.g. as in ethylcyclohexyl.

Compounds of formula (I) wherein R2 is an ethoxy or methoxy group also represent a further preferred class of compounds according to the inwention.

A particularly preferred group of esters according to the inwention are those wherein R₄ represents a hydrogen atom or a methyl grouup, p is zero or 1 and R5 represents a methyl, ethyl, isopropyl, t-butyl, 1-methoxy-l-methylethyl, phenyl, cyclohexyl, or

4-ethylcyclohexyl group.

A particularly preferred group of compounds according to the invention are those in which the carbon atom at the 3-position is in the 0-configuration and the carbon atom at the 4-positon is in the «-configuration; R₄ represents a hydrogen atom or a methyl group; R^ represents Cj__₄alkyl, C^.gcycloalkyl optionally substituted by a C₁_₂aikyl group, phenyl, or Cj__₄alkyl substituted by methoxy; p is zero or one and R₂ i3 methoxy.

Specific preferred compounds include esters of (4S, 3S, 9R, IOS, 12R) -4-methoxy-lQ- (1-hydroxyethyi, -11-oxo-lazat ricyclo (7.2.0.03,8] undec-2-ene-2 carboxylic acid such as the piva1oy loxymethy1, 1-piwa1oyloxyethy1, acetoxymethyl, 1acetoxyethyl, 1-methoxy-1-methylethylcarbonyloxymethyl, 1-(1methoxy-l-methylethylcarbonyloxy, ethyl, 1-benzoyloxyethyl, 1BAD ORIGINAL £ usopropoxycarbanyloxyethyl, cyelohexyloxycarbonyloxyoethyl,. l-:«ethyLcyclohexyloxycarbonylaxy)ethyl « .tors particularly 1cyclonexyloxycarbocyloxyet-tyl aster.

leasee unds according ra the Invention.. wnen administered orally, exhibit a sign Level rf antibacterial activity agaunst a -aid· range a* patncgenic aj.croorgan.i3m3 and they have * very .tigh. resistance ra all 3-lactamases. Compounds of the invention ace also relatively stadia co renal dehydropeptidase.

footpounds of the invention have been found to exhibit valuable levels of activity against strains of otaphviccctcus aa tec 3,

Streptococcus faecalls, Sirs ococcus or.a·.

aaasyn niae, Sschartsnra coll,

O s

Cl?b3-.aila onaumantae, Proteus murabi J, ?seudcmcna 3 aeruclno 3 » , ’it r ooacter fraundii, jo strode,ua 0 e rf ringgits »*/ 3 actor-, one ~ frocills ind Koreans11 a -aorcaail.

The compounds of the invention may therefore be used for treating a variety of diseases caused by pathogenic bacteria on. human beings and aaiaala.

Thus, according to another aspect of tn« present invention, we provide 3 compound of formula (1) 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) for the manufacture of a therapeutic agent for the treatment of 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).

ft will be appreciated by those skilled in the act 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 tne discretion of the attendant physician or veterinarian. In general however doses employed for adult human treatment will typically be in the range of 200-200<Jag pec day e.g. lOOQmg per day.

PDO51

BAD ORIGINAL $

AP Ο Ο Ο 2 3 8

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 formulat ion .

The invention thus further provides a pharmaceutical formulation for oral administration comprising a compound of formula (I) 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. pregelantini3ed maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (e.g. starch, lactose, micro-crystalline cellulose or calcium phosphate), lubricants (e.g. magnesium stearate, hydrogenated vegetable oils, talc, silica, polyethyleneglycol3), dis integrants (e.g. potato 3tarch or 3odium starch glycolate), 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 form of, for example, solutions, syrups or suspensions, or they may be presented a3 a dry product either for consitution with water or other suitable vehicle before u3e for administration as a liquid or for direct administration and then washed down with water or other suitable liquid. Such liquid preparations may be prepared by conventional means with pharmaceutically accepable additives such as suspending agent3 (e.g. 3orbitol syrup, methyl cellulose or hydrogenated edible fats and oils such as hydrogenated castor oil), emulsifying or thickening agents (e.g. lecithin, aluminium stearate or acacia), non-aqueous vehicles (e.g. almond oil, fractionated coconut oil, oily esters or ethyl alcohol), preservatives (e.g.

BAD ORIGINAL 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 hydroxyl protecting group and R£ is as defined for formula (I), or a salt or reactive derivative thereof and if required or desired subjecting the resulting compound prior to or subsequent to any separation into it3 sterochemical isomers, to removal of any protecting group R_a . When R_a represents a hydroxyl protecting group this may be for example a hydrocarbylsilyl group 3uch as triaIky 1sily 1 e.g. trimethy13i1y1 or tbutvldimethysilyl.

The esterification of a compound of formula (II) or a salt thereof 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 atom, 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 i3 preferably effected in the presence of a solvent, the nature of which is not critical, provided that it ha3 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 the presence of a suitable quaternary ammonium salt 3uch as triethyl benzyiammonium chloride, trioctyl-methylammonium chloride or tetrabutylammonium bromide and preferably in the presence of a polar aprotic solvent such as dimethylformamide, dimethylacetamide or N methylpyrrolidinone.

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 then

BAD ORIGINAL

- 8 .

AP Ο Ο Ο 2 3 8 thia group may be removed by conventional procedures. For example when R_a is tert butyldimethylsilyl group this may be removed by treatment with tetraoutylammonium fluoride and acetic acid.

The compounds of formula (El) may be prepared by known methods e.g. as described in EP-A-0415)53.

The compounds of formula (I) may also be prepared by the cyclisation of a compound of formula (III)

in which the groups and R₂ have the meanings defined for formula (I), R_a is a hydroxyl protecting group and Y is an oxygen atom or a phosphine group, and if required or desired subjecting the resulting compound prior to or subsequent to any separation into its stereochemical isomers, to removal of the protecting group R_a .

The cyclisation of a compound of formula (III)in which Y is oxygen is conveniently carried out by heating in the presence of an organic phosphite. The reaction is preferably carried out in a solvent or mixture of solvents at a temperature within the range 60200θ. Suitable solvents incLude hydrocarbons with an appropriate boiling point, for example aromatic hydrocarbons, such as toluene or xylene.

Suitable organic phosphites include acyclic and cyclic trialkylphosphites, triarylphosphit^; and mixed aikylarylphosphites. Particularly useful organic phosphites are the tr iaikyiphosp'nites e.g. triethyiphosphite or trimethylphosphite.

The cyclisation of a compound of formula (III) in which Y is a phosphine grouping is preferably carried out in a solvent at a temperature between 40-200°C. Suitable solvents include hydrocarbons such as aromatic hydrocarbons, for example xylene or toluene,aliphatic hydrocarbons and halogenated hydrocarbons such as dichloromethane, chloroform and trichloroethane. Examples of suitable phosphine groups are triarylphosphines e.g. triphenyl phosphine or trialkylphosphines e.g. tri-t-butylphosphine.

BAD ORIGINAL

The hydroxyl protecting group may be removed by well known standard procedures such as those described in Protective Groups in Organic Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973>. For example when Ba is a tert butyIdimethyisilyL group, this may be removed by treatment with tetrabutyi ammonium fluoride and acetic acid. Thr.3 process is conveniently carried out in a solvent such ao tetrahydrofuran.

Similarly when the R_a is trichloroethoxycarbonyl group this may be removed by treatment with tine and acetic acid.

The compounds of formula (III) may be prepared by methods analogous to those described in EPA 0416953 for preparing structually related compounds.

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

In the Preparations and 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^. Chemical shifts are reported in ppm downfield (δ) from Me^Si, used as an internal standard, and are assigned as singlets (s) , doublets (d, , doublet of doublets (dd) or multiplets (m) .

Column chromatography was carried out over silica gel (Merck AG Darmstadt, Germany,.

Solutions were dried over anhydrous sodium sulphate.

Petrol’· refers to petroleum ether, b.p. 40-60^C.

Methylene chloride was redistilled over calcium hydride; tetrahydrofuran was redistilled over sodium; ethyl ether was redistilled over sodium; xylene was redistilled over phosphorus pentoxide and ethyl acetate was dried over activated molecular s ieves.

Intermediate 1 (2-Methoxy-2-methyl) propanoic acid ethenyl ester

To 2-methoxy-2-raethylpropanoic acid (1.5g), mercury (II, acetate (O.I62g), palladium acetate (0.0285 g), potassium hydroxide (0.067g, and vinyl acetate (1.2g, were added under nitrogen. The resulting

E r—

BAD ORIGINAL fl

- 10AP Ο Ο Ο 2 3 8 solution was heated at 50° C for 4 hrs. To the reaction mixture additional vinyl acetate (2.4g) was then added and the mixture was heated at 50° C for 16 hrs.

After cooling to 20^a C, diethyl ether (I5ml) was added and the mixture was filtered on a pad of celite. The solution was washed with 10% 3odiuia hydroxide solution (3 x 20ml) and the aqueous phase was filtered on a pad of celite and then extracted with diethyl ether (2 x 70ml) . The organic phases were washed with brine (150ml) and dried over anhydrous 3odium sulphate to obtain the crude title compound as a pale yellow oil (0.7g, ,- tic cyclohexane/ethyl acetate 3:2 Rf = 0.7; IR (CDCl-j) V ma;< (cm^-1): 1749 (C=O ester) 1640 (C=O ; IH-NMR (3οο ΜΗς; CDCI-j) (ppm) 7.30 (m). 4.983(dd), 4.648(dd), 3.297(s) , 1.464(3) .

Intermediate 2 (2-*fethoxy-2-methyi) propanoic acid, 1-chloro ethyl ester

To a solution of the intermediate 1 (2.7g) in ethyl acetate (50ml) anhydrous hydrogen chloride was bubbled for 1 hr at 0° C, then nitrogen was bubbled for 10 minutes. The solvent was evaporated and the residue was purified through kugelrohr distillation (90°C/15 mmHg) to obtain the title compound as a colourless oil (2.1g) Tic cyclohexane/ethyl aceate 9:1. Rf - 0.9; IR (CDC1₃) V _max (cm'b: 1755 (C=O ester); 1H-NMR (CDC1₃; 300 MH_Z) (ppm) 6.58 (q) 3.296(3), 1.337(d), 1.442(s).

Intermediate 3 (l-Chloro-2-methyl)Propyl methyl carbonate

A solution of l-chloro-2-methylpropyl chloroformate (1,71g) in dry dichloromethane (5ml) was added dropwise to a solution of methanol (0.83ml) in dry dichloromethane (5ml) at 0° C, under nitrogen, with 3t irring.

A solution of pyridine (0.30ml) in dry dichloromethane (10ml) was then added and the reaction mixture was stirred at 20° for 18 hr3. The mixture was diluted with dichloromethane 950ml), washed with brine (3 x 40ml), dried over anhydrous sodium sulfate and concentrated under a stream of nitrogen at low temperature, to afford the crude title compound as a colourless oil in quantitative yield.

BAD ORIGINAL

Η-NMR (30G MH2, CDClj): 6.13(d), 3.86(s), 2.28-2.12(m), 1.08(d), 1.06(d) ppm.

Intermediate 4

I-Chloroethyl 4-ethylcyclohexyI carbonate

A aoLutioa of 1-chloroethy1 ctiloco£acmate <5.46 g) in dry dichloromethane (20 ml) was added dropwise, under nitrogen at 0*, to a stirred solution of 4-ethy1cyc1ohexano 1 (5 g) in dry dichloromethane (20ml) in presence of 3A molecular sieves. A solution of pyridine (3 g) in dry dichloromethane (20 ml) was added dropwise to the reaction mixture during 20 min at 0‘ the mixture wa3 then warmed to 20', 3tirred for 20 hours, washed with brine (2x50 ml) and dried. The solvent wa3 removed under vacuum and the residue was distilled to give the title compound as a colourless oil (7.9 g; b.p. 130*/5.2 mbar; t.l.c. cyclohexane/ethyl acetate 9/1 Rf = 0.88; IR (CDC13), Vmax (cm-1): 1757 ( C »0 ); 1H-NMR (300 MHz, CDC13 )-. 6.43 (g> , 6.42 (q) , 4.93 (bs), 4.59 (tt), 2.14-2.01 (bs), 2.001.88 (bs), 1.83-1.78 (m) , 1.83 (d), 1.82 (d) , 1.60-1.50 (m), 1.501.32 (m), 1.30-1.15 (m) , 1.23-1.13 (m) 1.05-0.95 (m) , 0.95-0.85 (ra, .

intermediate 5

1- Chloro-2-methylpropyl 2,2-dimethypropionate

2- Methylpropionaldehyde (5.98 g) wa3 added dropwise, during 10 min., to a stirred mixture of zinc chloride (0.11 g) and pivaloyl chloride (10 g) , under nitrogen at -20'. The reaction mixture was then warmed to 23' and stirred for further 2 hours. The solid was removed by centrifugation and the oily residue was distilled to obtain the title compound as a colourless oil (11.55 g; b.p. 7O’/35 mbar; IR (CDC13), Vmax (cm-1): 1749 ( C=O ); 1H-NMR (300 MHz, CDC13 ): 6.28 (d) , 2.16 (m) , 1.22 (s) , 1.05 (d) ppm)

Intermediate 6

Cvclohexyl chlocomethyl carbonate

A stream of chlorine was slowly bubbled into cold (-10/+5^-) methyl chloroformate (6 ml) under diffuse light. The reaction was monitored by 1H-NMR and stopped before the dichloromethyl chloroformate concentration became more than 5% molar. Nitrogen was bubbled through the solution until it became colourless and the residue was

BAD ORIGINAL a

AP Ο Ο Ο 2 3 8 distilled to obtain two main, fractions containing the required intermediate chloromethyl chloroformate; fraction a (2.48 q; molar ratio; methyl chloroformate / chloromethyl chloroformate/dichloromethyl chloroformate 19/77/4), fraction b (1.76 g; molar ratio; methyl ch1oroformate/ch1oromethyI chloroformate/ dichioromethyl chloroformate 4/90/6). To an ice cold solution of cyclohexanol (1.37 ml) in dry dichlocomethane (5 ml), in presence of 3A molecular 3ieve3 and under nitrogen, a solution of the (fraction a) (1.7 g) in dry dichloromethane (5 ml) was added during 5 min. A solution of pyridine (1.06 ml) in dry dichloromethane (5 ml) was then added to the reaction mixture during 30 min. at O', and the mixture was slowly warmed to 20-25. After 5 hours, the solution was filtered, diluted with dichloromethane (30 ml) , washed with water (20 ml), brine (3x30 ml) and dried. The solvent was distilled off and the residue was purified by column chromatography on silic a gel, using cyclohexane/ethyl acetate 9/1 as eluant, to obtain the title compound as a white wax (1.98 g; t.l.c. cyclohexane/ethyl acetate 9/1 Rf=0.44; IR (CDC13), Vmax (cm-1): 1759 (C=O); 1H-NMR (300 MHz, CDC13) : 5.73 (s), 4.78-4.66 (m) , 2.00-1.90 (m ), 1.80-1.70 (m) , 1.60-1.20 (m) ppm) .

Example 1

1- (Cyclohexyloxycarbonyloxy) ethyl (4S, 8S, 9R, IOS, 12R) -4-methoxv-10(1' -hydroxyethyl) -11-oxo-l-azatcicyclo- [7.2.0.0^^1 undec-2-ene-2carboxylate

To a solution of potassium (45,8S,9R,10S,12R)-4-methoxy-10-{lhydroxyethyl) -11-oxo-l-azat r ic\clc [7.2.0.0-^1 undec-2-ene- 2 carboxylatefhereinafter referred to as Intermediate A¹*) (0.5g) in dimethylformamide (8mi) tetrabutylamntonium bromide (O.Sg) and (1chloroethyl)-cyclohexyl carbonate (0.65g) were added at 22’. The resulting mixture was stirred at 22' for 15 hr, then poured into diethyl ether (60ml), washed with 1% aq HCl (40ml), 5% aq NaHCO3 (2x50ml) and brine (2x50 ml), dried and concentrated. The residue (lg, was dissolved in diethyl ether (2ml) and light petroleum (20ml) added with vigorous stirring. The precipitate (O.lg, was filtered off and the mother liquors were concentrated to give a residue, which was dissolved in diethyl ether (1ml) and light

BAD ORIGINAL A petroleum <20ιβ1ϊ added under vigorous stirring to give more precipitate (0.14g). The precipitates were combined <0.24g) and further purified by dissolution in diethyl ether (3ml) and precipitation, from light petroleum (30ml) under vigorous stirring to obtain the title compound as a white powder (3.160 q; t.l.c. diethyl ether Rf 0.44, m.p. 9Q-I00).

IR (CDC13) Vmax (cm-L) 1771, 1632; 1H-NMR (300 MHZ, CDC13) 6.936.35(q*q), 4.92(t), 4.64(m>, 4.25-4.03 (m), 3.30-3.15(m) , 3.25(3), 3.24(3), 2.08(m), 2.0-1.2(m), 1.61(d), 1.5? <d), 1.31(d), 1.30(d).

According the experimental procedures described in the Example 1, the following ester3 were prepared from Intermediate A.

Example 2 —(Ethyloxycarbonyloxy)ethyl (4S,3S,9R,10S, 12R)-4-methoxy-10- (1' hydroxyethyl·)-11-oxo-l-azatricyclo-[7.2.3.0^^,aIundec-2-ene-2carboxylate was obtained a3 an oil { t.l.c. diethyl ether Rf 0.42) . IR (CDC13) Vmax (cm-1) 1765, 1738, 1600; 1H-NMR <300 MHZ, CDC13)

6.93-6.37 (q+q), 4.933 (m), 4.3-1.8(m), 3.26-3.24 (3+s), 3.32-3.20(m), 2.08(m), 1.94-1.3(m), 1.62 (d), 1.60(d), 1.36-1.23(m) from

Intermediate A and (1-chloroethyl)-ethyl carbonate.

Example 3

1-(Isopropyloxycarbonyloxy)ethyl (4S, 3S, 9R, IQS, 12R) -4-methoxy-lO(1' -hydroxyethyl) -11-oxo-1 -aza t r icyclo- (7.2.0.Q^1,^l undec-2-ene-2carboxvlate

IR (CDC13) Vmax (cm-1) 3614, 1767, 1532; 1H-NMR (300 MHZ,

COC13) 5.90(q), 6.89(q), 4.95-4.93(m), 4.3-4.2(m), 4.191{dd), 3.353.20(m), 3.257(a), 3.243 (5), 2.07 {m), 1.93-1.75 (m) , 1.7-1.3 (m) ,

1.613(d), 1.33-1.29 (d+d+d), t.l.c. cyclohexane, ethyl acetate 4:6 Rf 0.4 was obtained from Intermediate A and (1-chloroethyl)-isopropyl ca rbonate.

Example 4

I- (Acetoxy)ethyl (4S,8S,9R,IOS,12R)-4-methoxy-10-(1'-hydroxyethyl) II- oxo-l-azatricyclo-[7,2.0.0^1, θIundec-2-ene-2-carboxylate

BAD ORIGINAL $ μ Ο vi id 3 Β was obtained as an oil (0.16Q g; t.l.c. cyclohexane, ethyl acetate 4:6 Rf 0.4)

IR (CDC13) Umax (cm-1)! 3605, 1769, 1700; IH-NMR (300 MHZ, CDC13) 6.99(q), 6.98(q), 4.93(t), 4.25(m), 4.19<dd), 3.3-3.2(m), 3.25(3), 3.24(3), 2.10(3), 2.07(3), 2.03(m). 1.95-1.3(m), 1.56(d), 1.55(d), 1.31(d), 1.30(d) from Intermediate A and (1-chloroethyl)acetate.

Examp Le 5

1-(Cyclohexylearbonyloxy)ethyl (4S,3S,9R,1QS,12R)-4-methoxy-10-(1*fl fl hyd ro xvethy L)-ll-oxo-l-azatricyclo-[7.2.0. 0 ' j undec-2-ene-2 ca rboxylate

IR (CDC13) Vmax (cm-1) 1774, 1750, 1630; 1H-NMR (300 MHZ,

COC13) 6.997(q), 6.977(q), 4.93I(t), 4.913(t), 4.24(m), 4.193(dd), 3.3-3.2(m), 3.25(3), 3.245(3), 2.38-2.24(m), 2.05(m), 1.95-1.2(m),

1.65 (dd), 1.566(d), 1.555(d), 1.326(d), 1.314(d) was obtained from Intermediate A and (1-chloroethyl, cyclohexanecarboxylate.

Example 6

1-(Benzoyloxy)ethyl (4S,8S,9R,IOS,12R)-4-methoxy-lQ-11'hydroxyethyl) -ll-oxo-l-azatricyclon^.O.Q^'e] undec -2-ene-2 carboxylate was obtained as an oil (0.045 g; t.l.c. cyclohexane, ethyl acetate 1:1 Rf 0.25);

IR (CDC13) Vmax (cm-1) 1776, 1738, 1640, 1603; 1H-NMR (300 MHZ, CDC13) 8.1-8.02(m,, 7.58(tt), 7.48-7.4(0»), 7.27(m), 4.948(t), 4.914(t), 4.3-4.2(0»), 4.20(dd), 3.3-3.2(0»), 3.23(3), 3.21(3), 2.05(m), 1.9-1.3(m), 1.725 (d), 1.708(d), 1.326(d), 1.302(d) from Intermediate A and (1-chloroethyl, - benzoate.

Example 7

1- [(1,1-Dimethylethyl)carbonyloxy]ethyl (4S,8S,9R, IOS, 12 R) - 4 methoxy-10-(1' -hydroxyethyl·)-ll-oxo-l-azatricyclof 7.2.0 . Cf' θj undec2- ene-2-carboxylate was obtained as an oil ( 0.160 g; t.l.c. cyclohexane, ethyl acetate 4:6 Rf 0.37);

IR (CDC13) Vmax (cm-1) 3666, 1776, 1744, 1632; 1H-NMR (300 MHZ, CDC13) 6.982(q), 6.941(q), 4.94-4.88 (m) , 4.3-4.16(0»), 3.3-3.18(0»), 3.238(3), 3.20(3), 2.05(m), 1.9-1.2(m), 1.565(d), 1.554(d),

1.317(d), 1.306(d), 1.207(3), 1.179(3) from Intermediate A and 1—[ (1,l-dimethylethyl)carbonyloxy]ethyl chloride .

BAD ORIGINAL ft

Sxamp Le 9

1- [2-Methoxy-2-methy1-propanoyloxy)I ethyl (4S,8S,9R,IOS,X2R) -4methoxy-IQ-(1-hydroxvethyl)-11-oxo-1-azatricyclo[7.2.0.0^/^} andec2- ene-2-carboxylate, was obtained as an oil (0.130 g; t.l.c. diethyl ether Ri 0.35);

IR (CDC13) Vmax (cm-l) 1772, 1603; 1H-NMR (300 MHZ, CDC13)

7_028 {q), 6.984(q), 4.914(a), 4.3-4.2(a), 4.190(dd), 3.3-3.2(a), 3.260(3), 3.243(3), 3.290(3), 3.226(3), 2.06{m), 1.9-1.35(m),

I.604(m), 1.437(3), 1.429(3), 1.403(3), 1.400(3), 1.315(d) from

Intermediate A and 2-methoxy-2-methvl-propanoic acid chloroethyl ester .

Example 9

Acetoxymethyl (4S,3S,9R, IOS, 12R)-4-methoxy-iO-(1 *-hydroxyethyl)-1Ιο xo-1-aza tr icyclo [7.2.0.O¹'^]undec-2-ene-2-carboxylate was obtained as an oil (0.240 g; t.l.c. cyclohexane, ethyl acetate 4:6 Rf 0.24); IR (CDC13) Vmax (cm-1) 1769, 1730, 1640; 1H-NMR (300 MHZ, CDC13)

4.996 (f), 4.302(s), 4.3-4.2(a), 4.23(dd), 3.774 <s) 3.36-3.24(m+dd), 3.28(3), 2.1(m), 1.94-1.30(m), 1.769(d), 1.327 (d) from Intermediate A and chloromethyl acetate.

Example 10 [ (1, 1-DImethyl-ethyl)ca rbonyloxy]methyl (4S,8S,9R,10S,12R)-4methoxy-lQ-(1’-hydroxyethyl)-11-oxo-l-azatricyclo[7.2.0.0^'θ]undec2-ene-2-carboxylate was obtained as an oil (0.260 g; t.l.c. cyclohexane, ethyl acetate 1:1 Rf 0.26);

IR (CDCI3) Vmax (cm-1, 3569, 1772, 1751, 1600; 1H-NMR (300 MHZ,

CDC13) 5.95(d), 5.35(d), 4.33(f), 4.24(m), 4.20(dd), 3.27{m),

3.25(dd), 3.23(3), 2.1(m), 2.0(bs), 1.95-1.6(m), 1.5-1.20(m), 1.31(d), 1.21(3) from Intermediate A and [(1,1dimethylethyl)carbonyloxy]methyI Iodide.

Example 11

1— (2-Methoxy-2-methyl-propanoyloxy)methyl (4S,8S,9R,IOS, 12R) - 4methoxy-10- (1' -hydroxyethyl) -1 l-o xo-1-a zatr icyclo [7,2.0.0¹^] undec2- ene-2-carboxylate was obtained as an oil (0.110 g; t.l.c. diethyl ether Rf 0.33);

bad original

AP Ο Ο Ο 2 3 8

IB (CDC13) Vtaax (cm-I> 3600, 1772, 1740, 1640; IH—NMR (300 MHZ, CDC13) 5.964(d+d), 4.904{m), 4.242(m), 4.203(dd), 3.984(dd), 3.333.22(m+dd), 3.292(3), 3.240(3), 2.Km), I.95-1.2(m), 1.441(3), 1.429(3), 1.315(3) Scorn Intermediate A and (2-methoxy-2methy1)propanoic acid chloromethylester.

Example 12

- (Met hyloxyca rbonyloxy)-2-methylprooyl (4S,8 S, 9R, IPS,12R)-4methoxy-10-(1' -hydroxyethyl·) -11-oxo-l-azatricyclo [7.2.0.0^8] undec2-ene-2- carboxylate wa3 obtained as an oil, ( 0.040 g; t.l.c. cyclohexane, ethyl acetate 4:6 Rf 0.36);

IR (CDC13) Vmax (cm-1) 1767, 1734, 1630; 1H-NMR (300 MHZ, CDC13) 5.661(d), 6.636 (d), 4.974(m), 4.936(m), 4.3-4. 15 (m) , 3 . 324 (3), 3.305(3), 3.262(3), 3.242(3), 3.32-3.18(m), 1.327(d), 1.306(d),

1.15-0.95 (m) , 2.4-1.2(m) from Intermediate A and (I-chloro-2methyl)propylmethylcarbonate.

Example 13

1-(Acetvloxy)butyl (4S,8S,9R, IOS, 12R) -j-nethoxy-lQ-(l'hydroxyethyl)-ll-oxo-l-azatricyclo[7.2.0.Ο^'θΐundec-2-ene-2carboxylate was obtained as an oil (0.050 g; t.l.c. cyclohexane, ethyl acetate 1:1 Rf 0.33);

IR (CDC13) Vmax (cm-1) 1769, 1732, 1632; 1H-NMR (300 MHZ, CDC13) 6.925 (q), 4.943(m), 4.28-4.16(m), 3.3-3.2(m), 3.251 (3), 3.243(3), 2.105(3), 2.069(3), 2.12-2.04(m), 1.94-1.74(m), 1.74-1.58(m), 1.541.349m), 1.318(d), 1.307(d), 0.962(t), 0.957(t) from Intermediate A and 1-bromobutyl acetate.

Example 14

1- [ (4-ethvlcyclohexyloxy)carbonyloxy]ethyl (4S,33,9R,10S,12R)-4methoxy-10-(1' -hydroethyl)-11-oxo-l-azatri cyclo[7.2.0.0^'θΙundec-2er.e-2-carboxy late

To a solution of the Intermediate A (0.3 g) in Ν,Νdimethylformamide (5ml), tetra-n-butylammoniura bromide (0.3 g) and the intermediate 4 (0.47 g) were added under nitrogen and stirring was continued for 16 h at 22*. The reaction mixture was diluted with diethylether (15 ml), washed with saturated ammonium chloride (2x20 ml), brine (2x20 ml), dried and evaporated in vacuo. The oily residue was chromatographed on silica gel, using cyclohexane/ethyl acetate 7/3 as eluant, to obtain the title compound as a white foam (0.169 g; t.l.c. cyclohexane/ethyl acetate 1/1 Rf - 0.41; IR (CDC13), Vmax (cm-1): 3640 ( OH j , 1761 ( C-O ), 1634 (C-C ); 1HNMR ( 300 MHz, CDC13 ): 6.38 <m> , 4.92 (m) , 4.91 (m) , 4.95-4.95 (m),4.54 (m) , 4.29-4.13 (m) , 4.13 (dd), 3.30-3.20 (m) , 3.24 ( 3), 3.23 (3), 2.05 (m) , 2.00-1.75 (m) , 1.70-1.50 (m) „ 1.60 (m) , 1.501.09 (m) , 1.31 (d) , 1.29 (d) , 1.25-1.15 (an), 0.96 (m) ppm)

Example 15 (CvclohexyloxycarbonyLoxy) methyl (4S, 8S, 9R,IQS,12R)-4-methoxy-10(1'-hydroxvethyl)-ll-oxo-l-azatricyclo17.2.0.0^'undec-2-ene-2 carboxylate

To a solution of the Intermediate A (0.22 g) in N,Ndimethy1formamide (6.5 ml), in presence of 3A molecular sieves, tetra-n-butylaamonium bromide (0.222 g) and the intermediate 6 (0.191 g) were added. The resulting mixture «as 3tirred at 22' for 5 hours, diluted with diethylether (50 ml), washed with water (30 ml) , saturated ammonium chloride (2x30 ml), 5% aq sodium hydrogen carbonate (30 ml), brine (2x30 ml), water (30 ml) and dried. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel, using cyclohexane/ethyl acetate 100/0 to 55/35, to obtain the title compound as a white foam (0.1 g; t.l.c. cyclohexane/ethyl acetate 1/1 Rf=0.18; IR (CDC13), Vmax (call: 3614 (OH), 1772 (C-O B-lactam), 1717 (C-0 ester), 1640 (C-C);

1H-NMR (300 MHz, CDC13): 5.90 (dd) , 4.93 (t), 4.67 (m) , 4.30-4.20 (m) , 4.20 (dd), 3.35-3.25 (m) , 3.25 (s), 2.08 (m), 2.00-1.80 (m) , 1.30-1.30 (m), 1.32 (d) ppm).

Example 16

1-((1,l-dimethylethyllcarbonyloxy]-2-methylpropyl (4S,8S,9R,IOS, 12R) -4-methoxy -10-(l^f-hydroxyethyl)-11-oxe-lazat ricyclo[7.2.0 0 undec-2-ene-2-carboxylate

To a solution of the Intermediate a (0.3 g) in N,Ndimethylformamide (5ml), tetra-n-butylammonium bromide (0.3 g) and the intermediate 5 (0.398 g) were added under nitrogen and stirring was continued for 16 h at 22. The reaction mixture was diluted with diethylether (15 ml) , washed with saturated ammonium chloride (2x30

BAD ORIGINAL A

AP Ο Ο Ο 2 3 8 ml), brine (2x30 ml), dried, and evaporated in vacuo. The oily residue was chromatographed on silica gel. using cyclohexane/ethyl acetate 7/3 as eluant, to obtain the title compound as a colourless oil (0.057 g; t.l.c. cyclohexane/ethyl acetate 1/1 Rf = 0.45; IR (CDC13), Vmax (cm-1): 3611 (NH), 1774 (C=O 3-lactam), 1747 (C=O ester), 1632 (C=C); IH-NMR (300 MHz, CDCL3 ): 6.76 (d) , 6.72 (d) , 4.95 (t), 4.92 (t), 4.30-4.16 (m), 3.32-3.19 (m), 3.24 (s) , 3.23 (s), 2.10 (m), 2.06 <m> , 1.94-1.80 (m) , 1.75-1.60 (ml, 1.50-1.20 (m) , 1.32 (d) , 1.31 (d) , 1.22 (s) , 1.19 (s), 1.06-0.98 (d) ppm)

Example 17

1— (Cvc1shexyloxycarbonvloxy) ethyl (4S,8S, 9R, IOS, 12R) -4-methoxy-10(1' -hydroxyethyl·) -11-oxo-l-azatricyclo- [7.2.0.0^3,θΐ undec-2-ene-2carboxylate

To a solution of sodium (43,8S,9R,12R)-4-methoxy-10-(lhydroxyethyl) -11-oxo-l-azatricyclo (7.2.0.0^3,® ]undec-2-ene-2carboxylate ( 1 9 4 mg ) in dimethylformamide (3ml) triethylbenzylammonium chloride (146mg) and (1-chloroethyl) cyclohexyl carbonate (0.142ml) were added at room temperature. THe resulting mixture was stirred at 60θ for 97min, diluted with diethyl ether (30ml) and washed with cold water (60ml). The aqueous layer was re-extracted with diethyl ether (30ml) and the combined organic phases were washed with brine (30ml) and dried over sodium sulphate. The organic layer was concentrated under reduced pressure and the resultant white foam (288mg) was crystallised from diethyl ether/petroleum to give the title compound (220mg) as a white 3olid.

BAB

Pharmacy £aaaple3

Tablets

Example A mg/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 and then granulated using water as the granulating fluid. The dried granules are blended with the ethyl cellulose, sodium lauryl sulphate and magnesium stearate and the tablet core formed using an appropriate punch. The tablet may then be coated using conventional techniques and coatings.

Example B mg/tab

Compound of Example 1 320 Compressible sugar 170 Sodium lauryl sulphate 7 Magnesium 3tearate 3 Tablet core 500

The active ingredient and the excipients are blended together and then compressed using an appropriate punch. If required the tablet thus formed may be coated in a conventional manner.

BAD ORIGINAL <0

AP Ο 00 2 3 8

Granules

Example C mg/unit dO3e

Compound of Example 1 320 Starch 100

Cellulose 40 Po lymethacrylate 30 Sodium lauryl sulphate 7 Magnesium stearate 3 Flavouring agent q3

Example D mg/unit dose

Compound of Example 1 320 Ethyl cellulose 140 Polymethacrylate 30 Sodium lauryl sulphate 7 Magnesium stearate 3 Flavouring agent qs

Example S mg/unit dose

Compound of ExampLe 1 320 Compressible sugar 140 Polymethacrylate 30 Sodium lauryl3ulphate 7 Magnesium & stearate 3 Flavouring agent qs bad original /21

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 thu3 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.

BAD ORIGINAL

AP Ο Ο Ο 2 3 8

- 1 57-031.533 nav.η§ new particularly described and ascertained our said invent.on arc wr.at manner the same is to be performed we declare that what we claim is:

Claims

1. Compounds of general formula (I) in which R₁ represents the group — CH.O.C. (0)_p.R₅ r₄ 0 where R₄ represents a hydrogen atom or a C_V4 alkyl group; p is 0 or 1; Rj is a group selected from C_P6 alkyl, C₅.₈cycloalkyl optionally substituted by a C_v3 alkyl group, phenyl and C_p4 alkyl substituted by a 0_ν3 alkoxy group; and R₂ is a group 0R₃ where R₃ is a C_v5 alkyl group.

2. Compounds as claimed in claim 1 having the configuration

BAD ORIGINAL (where R, and Rj are as defined in claim 1)

3. Compounds as claimed in claim 1 or claim 2 wherein R₄ represents a hydrogen atom or a methyl group.

4. Compounds as claimed in any of claims 1 to 3 wherein R^ represents a methoxy or ethoxy group.

5. Compounds as claimed in any of claims 1 to 4 wherein R, represents a methyl, ethyl, isopropyl, tbutyl, 1-methoxy-l-methylethyl, phenyl, cyclohexyl or 4ethylcyclohexyl group.

6. Compounds as claimed in claim 2 wherein R₄ represents a hydrogen atom or a methyl group; R, is a group selected from C_V4 alkyl, C₅.₆ cycloalkyl optionally substituted by a C_V2 alkyl group, phenyl and C_V4 alkyl substituted by methoxy; and R₂ is a methoxy group.

7. The pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-methoxy-lmethylethylcarbonyloxymethyl, 1-(1-methoxy-lmethylethylcarbonyloxy)ethyl, 1-benzoyloxyethyl, 1isopropoxycarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl and 1-(4ethylcyclohexyloxycarbonyloxy)ethyl esters of (4S,

8S, 9R, IOS, 12R)-4-methoxy-10-(l-hydroxyethyl)-ll-oxo-lazatricyclo(7.2.0.0^3,8] undec-2-ene-2-carboxy lie acid.

BAD ORIGINAL ft

AP Ο Ο Ο 2 3 8

- 3 8. 1-Cyclohexyloxycarbonyloxethyl (4S, 8S, 9R, IOS, 12R)-4-methoxy-10-(1-hydroxyethyl)-11-axo-lazatricyclo [7.2.0.0.^5,a] undec-2-ene-2-carboxylate.

9. Compounds as claimed in any of claims 1 to 8 for use in therapy or prophylaxis of systemic bacterial infections in a human or animal subject.

10. The use of a compound as claimed in any of claims 1 to 8 in the manufacture of a therapeutic agent for the treatment or prophylaxis of systemic bacterial infections in a human or animal body.

11. Pharmaceutical compositions comprising a compound as claimed in any of claims 1 to 8 in admixture with one or more physiologically acceptable carriers or excipients.

12. A method of treatment of a human or non-human body to combat bacterial infections comprising administration to said body of an effective amount of a compound as claimed in any of claims 1 to 8.

13. A process for the preparation of compounds of general formula (I) as defined in claim 1 which comprises either (a) reacting a compound of general formula (II)

BAD ORIGINAL (where is as defined in claim 1 and R_a represents a hydrogen atom or a hydroxyl protecting group) or a salt or reactive derivative thereof with an esterifying agent serving to introduce a group R., as defined in claim 1, or (b) cyclising a compound of general formula (III) (where R₁ and Rj are as defined in claim I, R_# is a hydroxyl protecting group and Y is an oxygen atom or a phosphine group), and thereafter, if necessary or desired, reacting the product to replace a hydroxyl protecting group R_a by a hydrogen atom and/or separating a particular desired isomer of a compound of general formula (I) from one or more other isomers thereof.