WO1984001776A1

WO1984001776A1 - Beta-lactam compounds, preparation and use

Info

Publication number: WO1984001776A1
Application number: PCT/GB1983/000258
Authority: WO
Inventors: Pamela Ann Hunter; John Sidney Davies
Original assignee: Beecham Group Plc
Priority date: 1982-10-26
Filing date: 1983-10-13
Publication date: 1984-05-10
Also published as: JPS59502063A; EP0126090A1

Abstract

A compound of formula (I): R1 is C1-6 alkyl, C3-6 cycloalkyl, C5-8 cyclo-alkenyl or an aromatic group; R2 is primary amino or an acid addition salt thereof, or a carboxy group or an ester thereof; R3 is hydrogen or a hydrocarbon moeity; any of the above groups R1, R2 and R3 being optionally substituted; and R4 is a group of formula (II), wherein R is an inert organic group of up to 18 carbon atoms. Processes for the preparation of these compounds and pharmaceutical compositions containing them are also described and claimed.

Description

Beta-Lactam compounds, preparation and use.

This invention relates to novel β-lactam antibacterial agents, their preparation and their use, and in particular to penicillins which are active against β-lactamase-producing bacteria.

UK Patent No 2,044,255 (corresponding to US Patent No 4,342,772) discloses compounds of formula A

wherein R_a is phenyl, 4-hydroxyphenyl, 1,4-cyclohexadienyl or a 3-thienyl group, R_b is a primary amino or a carboxy group; R_c is a hydrogen atom, or a lower alkyl, aryl or aralkyl radical, and R_d is a radical of a β-lactamase inhibitor.

The present invention provides a compound of formula ( I) :

or an acid addition salt thereof,

R¹ is C_1-6 alkyl, C_3-6 cycloalkyl, C_5-8 cycloalkenyl or an aromatic group;

R² is primary amino, or a carboxy group or an ester thereof;

R³ is hydrogen or a hydrocarbon moeity; any of the above groups R¹, R² and R³ being optionally substituted; and

R⁴ is a group of formula (II):

wherein R is an inert organic group of up to 18 carbon atoms.

Suitable inert organic groups R for inclusion in the residues of the formula (II) include hydrocarbon groups and hydrocarbon groups inertly substituted by halo, an ether group, acyloxy, acyl, ester, carboxy or salted carboxy, hydroxy, nitro, cyano, amino and substituted amino and the like so that suitable groups R include hydrocarbon and hydrocarbon substituted by halogen and/or groups of the sub-formulae OR⁵, OH, OCOR⁵, CO.R⁵, CO₂R⁵. NR⁶.CO.R⁵, NR⁶CO₂R⁵, SOR⁵, SO₂R⁵, NH2_, NR⁵R⁶, NO₂, CN or CO.NR⁵R⁶ wherein R⁵ is a hydrocarbon group of up to 8 carbon atoms and R⁶ is a hydrocarbon group of up to 4 carbon atoms.

As used herein the term 'inert organic group' means that the organic group is one which does not render the compound inherently unstable or unsuitable for use as a medicinal agent.

Similarly the term 'inertly substituted' means that inclusion of the substituent does not produce an inherently unstable compound which cannot be used as a medicinal agent.

When used herein the term 'hydrocarbon' includes alkyl, alkenyl and alkynyl groups and such groups substituted by phenyl or hydrocarbon substituted phenyl groups and the like.

Suitable inert organic groups R for inclusion in the residues of the formula (II) include hydrocarbon groups and hydrocarbon groups inertly substituted by halo and/or groups of the sub-formulae OR⁵, O.COR⁵, CO.R⁵, CO₂R⁵ wherein R⁵ is a hydrocarbon group of up to 8 carbon atoms.

Most suitably R⁵ is an alkyl group of 1 - 4 carbon atoms or a phenyl or benzyl group. A preferred group R⁵ is the methyl group. A preferred group R⁶ is the methyl group.

A further suitable sub-group of residues of the formula (II) are those wherein R is a group CR⁸R⁹R¹⁰ wherein R⁸ and R⁹ are independently alkyl groups of up to 3 carbon atoms or a phenyl group optionally substituted by halo or a group of the formula R¹¹ or OR¹¹ where R¹¹ is an alkyl group of up to 3 carbon atoms; and R¹⁰ is a hydrogen atom or an alkyl group of up to 3 carbon atoms or a phenyl group optionally substituted by halo or a group of the formula R¹² or OR¹² where R¹² is an alkyl group of up to 3 carbon atoms.

More suitably, R is a group CH₂R¹³ wherein R¹³ is a naphthyl, phenyl or phenyl group substituted by halo or a group R¹⁴ or OR¹⁴ where R¹⁴ is an alkyl group of up to 3 carbon atoms.

A further particularly suitable value for R is R¹⁵-COOH wherein R¹⁵ is a hydrocarbon group of 1 - 8 carbon atoms optionally inertly substituted by halo and/or OR¹⁶, OCOR¹⁶, CO.R¹⁶ or OH group where R¹⁶ is an alkyl group of 1 - 4 carbon atoms.

Most suitably R¹⁵ is an alkylene group of 1 - 4 carbon atoms, a phenylene group or an alkylene group of 1 - 4 carbon atoms substituted by a phenyl or phenylene group.

Preferably R¹⁵ is an alkylene group of 1 - 4 carbon atoms such as the -CH₂- or -CH₂.CH₂- groups.

A particularly suitable group of residues of the formula (II) are those of the formula (III):

wherein R¹⁶ is an alkylene group of 1 - 4 carbon atoms and R¹⁷ is a hydrogen atom or an alkyl group of 1 - 4 carbon atoms or an alkyl group of 1 - 4 carbon atoms substituted by a phenyl group.

Preferably R¹⁶ is a -CH₂- or -CH₂.CH₂- group.

A further particularly suitable group of residues is that of the formula (IV):

wherein R¹⁸ is a divalent hydrocarbon group of 2 - 8 carbon atoms; R¹⁹ is a hydrogen atom or an alkyl group of 1 - 4 carbon atoms and R²⁰ is a hydrogen atom or a R²¹, CO.R²¹ or CO₂R²¹ group where R²¹ is an alkyl group of 1 - 4 carbon atoms optionally substituted by a phenyl group.

Most suitably R²¹ is an alkylene group of 2 - 4 carbon atoms, a phenylene group or an alkylene group of 2 - 4 carbon atoms substituted by a phenyl or phenylene group.

Certain favoured residues of the formula (II) include those of the formula (V):

wherein R²² is hydrogen, an alkyl group of 1 - 4 carbon atoms or a phenyl group or one of the aforenamed groups substituted by a carboxylic acid group or a salt or C_1-4 alkyl ester or R²² is a carboxylic acid group or a salt of C_1-4 alkyl ester thereof. Especially favoured are those where R²² is hydrogen or unsubstituted alkyl, preferably hydrogen.

In formula (I) R¹ is suitably C_1-6 alkyl such as methyl or ethyl; C_3-8 cycloalkyl such as cyclohexyl; or ^C5-8 cycloalkenyl, such as cyclohexenyl or cyclohexadienyl such as 1,4-cyclohexadienyl.

Suitably also R¹ is an aromatic group such as optionally-substituted phenyl or naphthyl, or heteroaryl wherein the heteroaryl ring comprises 5 to 7 atoms, preferably 5 to 6, up to 4 of which may be heteroatoms selected from oxygen, sulphur and nitrogen.

More suitably, when R¹ is an aromatic group R¹ is an optionally substituted 5-membered heterocyclic ring comprising one or two heteroatoms selected from oxygen, sulphur and nitrogen, such heterocyclic rings include furyl, thienyl, such as thien-3-yl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl and imidazolyl, any of which ring systems may be optionally substituted for example by halo, hydroxy, amino, C_1-6 alkyl or C_1-6 alkoxy.

Aptly, when R¹ is an aromatic group, R¹ is phenyl; mono-substituted phenyl wherein the substituent is halo, hydroxy, C_1-6 alkoxy, nitro, amino, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkanoyloxy or C_1-6 alkylsulphonylamino; or di-substituted phenyl wherein the substituents are selected from hydroxy, halo, methoxy, acetoxy and amino. More aptly, when R¹ is an aromatic group, R¹ is phenyl; phenyl mono-substituted by fluoro, chloro, hydroxy, methoxy, nitro, amino, acetoxy or trifluoromethyl; or di-substituted by substituents selected from acetoxy, hydroxy and methoxy.

Preferably, R¹ is 1,4-cyclohexadienyl, phenyl, p-hydroxyphenyl, p-aminophenyl, p-acetoxyphenyl, thien-2-yl, thien-3-yl or 2-aminothiazol-4-yl.

More preferably, R¹ is phenyl, p-hydroxyphenyl, 1,4-cyclohexadienyl or 3-thienyl.

Preferably, when R² is amino, R¹ is phenyl or substituted phenyl such as p-hydroxyphenyl; and when R² is a carboxy group or an ester thereof such as the optionally substituted phenyl ester, or benzyl or indanyl ester, R¹ is phenyl or thienyl such as 3-thienyl.

When R² is amino, it may be in the form of an acid addition salt thereof, such as the hydrochloride salt.

Suitably, in the compounds of formula (I), R³ is a hydrogen atom, or a C_1-6 alkyl, aryl or aryl C_1-6 alkyl group. In the definition of R³, the C_1-6 alkyl moiety may be straight or branched chained; and the aryl moiety is a monocyclic or bicyσlic carbocyclic radical.

More suitably R³ is hydrogen, methyl, ethyl, phenyl or benzyl. Preferably R³ is a hydrogen atom, or a methyl, phenyl or benzyl group.

Especially preferred compounds of formula ( I ) are those wherein:

R¹ is phenyl, p-hydroxy-phenyl, 1,4-cyclohexadienyl or 3-thienyl; R² is amino, carboxy, phenoxycarbonyl or benzyloxycarbonyl;

R³ is a hydrogen atom, or methyl, phenyl or benzyl; and

R⁴ is a residue of a clavulanate of formula (II) as defined above wherein R is alkyl such as methyl.

If a carboxy group is present as a substituent in any of the compounds of this invention, then it may be presented as the free acid or in salified or esterified or zwitterionic form.

Its salts would suitably be in pharmaceutically acceptable form and include metal salts, for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with C_1-6 alkylamines such as triethylamine, hydroxy-C_1-6 alkylamines such as 2-hydroxethylamine, bis(2-hydroxyethyl)amine or tri(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine. Preferably, any such salts are sodium or potassium.

Alternatively, any carboxy present in the compounds of this invention may be esterified with a pharmaceutically acceptable esterifying radical such as an alkyl, aryl or aralkyl group. Preferred esterifying radicals would include C_1-6 alkyl such as methyl and ethyl, phenyl, benzyl and substituted benzyl such as nitrobenzyl, bromobenzyl, C_1-6 alkoxycarbonylbenzyl, C_1-6 alkoxybenzyl and C_1-6 alkylbenzyl, and in vivo hydrolysable esters such as phthalidyl.

The compounds of this invention, if desired, may be presented in the form of their acid addition salts if a basic group (e.g. -NH₂) is present as a substituent. The acid used to form the salt will most suitably be pharmaceutically acceptable, but non-pharmaceutically acceptable acid addition salts are also envisaged, for example as intermediates in the preparation of the pharmaceutically acceptable salts by ion-exchange. Suitable pharmaceutically acceptable acid addition salts include those of inorganic and organic acids such as hydrochloric, phosphoric, sulphuric, methanesulphonic, toluenesulphonic, citric, maleic, acetic, lactic, tartaric, propionic and succinic acid.

It is possible for certain compounds of this invention to exist in diastereoisomeric forms, and this invention covers all such diastereoisomers either separated or mixed.

In another aspect the present invention provides a pharmaceutical composition which comprises a compound of formula (I) together with a pharmaceutically acceptable carrier therefor.

The compositions of this invention may be prepared by conventional methods for preparing antibiotic compositions and in conventional manner may be adapted for oral, topical or parenteral administration.

Unit dose forms according to this invention normally contain from 50 to 1000 mg of a compound of this invention, for example about 62.5, 100, 150, 200, 250, 500 or 750 mg. Such compositions may be administered from 1 to 6 times a day or more conveniently 2, 3 or 4 times a day so that the total daily dose for a 70 kg adult is about 200 to 2000 mg, for example about 400, 600, 750, 1000 or 1500 mg. Suitable pharmaceutically acceptable carriers used in the compositions of this invention include diluents, binders, disintegrants, lubricants, colours, flavouring agents or preservatives in conventional manner. Thus suitable agents include lactose, starch, sucrose, calcium phosphate, sorbitol, polyvinylpyrrolidone, acacia, gelatin, tragacanth, potato starch or polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.

Orally-administrable forms of the compositions of this invention are most suitably in the form of unit-dose units such as tablets or capsules.

Certain of the compounds of this invention tend to be sparingly soluble, so if it is preferred that their solubility be increased for use in pharmaceutical compositions, in one embodiment, if appropriate and an amino or carboxylic acid group is present, it is preferred to use an acid addition salt or carboxylic acid salt.

One feature of the compounds of the present invention is that they are believed to break down in-vivo to liberate the moieties of the antibacterial penicillin and the β-lactamase inhibitor. This is believed to occur more readily via the oral route. Thus the compounds of the formula (I) may be regarded as pro-drugs of the penicillin and as pro-drugs of the β-lactamase inhibitor.

The present invention further provides a synergistic pharmaceutical composition which comprises a pharmaceutical composition as hereinbefore described together with a penicillin or cephalosporin.

Suitable penicillins for inclusion in the synergistic compositions of this invention include benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxycillin, ticarcillin, suncillin, sulbenicillin, azlocillin or mezlocillin; in particular, amoxycillin as its sodium salt or trihydrate is preferred.

Suitable cephalosporins for inclusion in the synergistic compositions of this invention include cephaloridine, cefazolin and cephradine.

The penicillin or cephalosporin is generally included in its conventionallly-administered amount.

The weight ratio between the compound of this invention and penicillin or cephalosporin is generally in the range of from 20:1 to 1:5, more usually 10:1 to 1:2 and normally 5:1 to 1:1.

The compounds and compositions of this invention are suitable for use as agents to treat a bacterial infection in animals such as mammals including humans, for example infections of the repiratory tract, urinary tract or soft tissues, or mastitis in cattle.

Therefore, in a further aspect, the present invention provides a method of treatment of bacterial infections (such as those described above) to an animal in need thereof, which method comprises the administration to said animal of a non-toxic, effective antibacterial amount of a compound of formula (I) or a pharmaceutical formulation thereof.

In a still further aspect, the present invention provides a process for the preparation of a compound of the formula (I), which process comprises reacting together a source of the side-chain R¹-CHR²-CO-, a source of the 6-amino penicillanic acid moiety and a source of the esterifying group -CHR³-O-CO-R⁴, wherein R⁰, R³ and R⁴ are as hereinbefore defined. In one embodiment of the process of the present invention there is provided a process for the preparation of a compound of formula (I) which process comprises the reaction of a compound of formula (VI):

or a salt or other reactive derivative thereof, wherein R¹, R² and R³ are as hereinbefore defined; and Y is a leaving group;

with a compound of formula (VII) or a salt thereof:

R⁴-CO-OH (VII)

wherein R⁴ is as hereinbefore defined;

provided that any functional group in R¹-CHR²- and amino group in R⁴ is suitably protected;

and thereafter if necessary:

(i) removing any protecting group

(ii) converting the product into a pharmaceutically acceptable salt.

Suitably, Y is a good leaving group such as a halo atom for example chloro, bromo or iodo. The reaction is suitably performed in a substantially inert organic solvent known to be convenient for esterification reactions, such as dimethylformamide, acetone, ethyl acetate or a halogenated hydrocarbon. Preferably, such a reaction is performed at a depressed, ambient or elevated temperature such as between 0°C and 50°C, preferably at ambient temperature.

Suitably, the compound of formula (VII) is reacted in the form of its salt, which need not be pharmaceutically acceptable. Suitable salts include inorganic salts for example metal salts, alkali metal salts such as lithium, potassium or sodium salts; or tertiary amine salts.

The compounds of formula (VI) may be prepared by the reaction of a penicillin or salt or other reactive derivative thereof, with a compound of formula (VIII):

Y-CHR³-Z (VIII)

wherein Y and R³ are as hereinbefore defined and Z is a better leaving group than Y. Such a reaction may be conveniently performed under conditions analogous to those described for the reaction of the compounds of formulae (VI) and (VII).

The compounds of formula (VII) may be prepared by a method described in, for example, British patent specification No. 1,565,209.

In a further embodiment of the process of the present invention there is provided a process for the preparation of a compound of formula (I) which process comprises the reaction of a compound of formula (IX) or a derivative thereof which permits N-acylation to occur:

wherein R³ and R⁴ are as hereinbefore defined, with an N-acylating derivative of a carboxylic acid of the formula (X):

R¹-CHR²-CO₂H (X)

wherein R¹ and R² are as hereinbefore defined, and any reactive group is optionally protected; and thereafter if necessary:

(i) removing any protecting group,

(ii) converting the product into a pharmaceutically acceptable salt.

Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (IX) include N-silyl, N-stannyl and N-phosphorus groups, for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, groups of formula -P.R^aR^b wherein R^a is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkloxy or dialkylamino group, R^b is the same as R^a or is halogen or R^a and R^b together form a ring; suitable such phosphorus groups being -P(OC₂H₅)₂, -P(C₂H₅)₂,

and

A reactive N-acylating derivative of the acid (X) is employed in the above process. Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide. Acylation with an acid halide may be effected in the presence of an acid binding agent for example tertiary amine (such as triethylamine or dimethylaniline), an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction. The oxirane is preferably a (C_1-6)-1,2- alkylene oxide - such as ethylene oxide or propylene oxide. The acylation reaction using an acid halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°C, in aqueous or non-aqueous media such as aqueous acetone, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof.

Alternatively, the reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate.

The acid halide may be prepared by reacting the acid (X) or a salt thereof with a halogenating (eg chlorinating or brominating) agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Alternatively, the N-acylating derivative of the acid (X) may be a symmetrical or mixed anhydride. Suitable mixed anhydrides are alkoxyformic anhydrides, or anhydrides with, for example carbonic acid mono-esters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, phosphorus acids (such as phosphoric or phosphorous acids, sulphuric acid or aliphatic or aromatic sulphonic acids such as p-toluenesulphonic acid). The mixed or symmetrical anhydrides may be generated using N-ethoxycarbonyl-2-ethoxyl-2-ethoxy-1,2-dihydroquinoline. When a symmetrical anhydride is employed, the reaction may be carried out in the presence of 2,4-lutidine as catalyst.

Alternative N-acylating derivatives of acid (X) are the acid azide, or activated esters such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, thioalcohols such as thiophenol, methanethiol, ethanethiol and propanethiol, halo-phenols, including pentachlorophenol, monomethoxyphenol or 8-hydroxyquinoline, N-hydroxysuccinimide or 1-hydroxybenztriazole; or amides such as N-acylsaccharins or N-acylphthalimides; or an alkylidine iminoester prepared by reaction of the acid with an oxime.

Other reactive N-acylating derivatives of acid (X) include the reactive intermediate formed by reaction in situ with a condensing agent such as a carbodiimide, for example N,N-diethyl-, dipropyl- or diisopropylcarbodiimide, N,N'-di-cyclohexylcarbodiimide, or N-ethyl-N'- -dimethylaminopropylcarbodiimide; a suitable carbonyl compound, for example N,N'-carbonyldiimidazole or N,N'-carbonylditriazole; an isoxazolinium salt, for example N-ethyl-5-phenylisoaxazolinium-3-sulphonate or N-t-butyl-5-methylisoxazolinium perchlorate; or an N-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline, such as N-ethoxycarbonyl2-ethoxy-1,2-dihydroquinoline. Other condensing agents include Lewis acids (for example BBr₃ - C₆H₆); or a phosporic acid condensing agent such as diethylphosphorylcyanide. The condensation reaction is preferably carried out in an organic reaction medium, for example methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran. In a further embodiment of the process of thepresent invention there is provided a process for the preparation of a compound of formula (I) which process comprises :

(a) treating a compound of the formula (XI) :

wherein R³ and R⁴ are as hereinbefore defined, and R²³ is an acyl group with an agent forming an imino halide;

(b) treating the imino halide with a compound to introduce a group QR_f on the imino carbon atom, wherein Q is oxygen, sulphur or nitrogen and R_f is an alkyl group of from 5 to 14 carbon atoms, to form an iminoester, iminothioether, or amidine (when Q is O, S, or N respectively);

(c) reacting with an N-acylating derivative of an acid of formula (XI) above;

(d) treating with water;

and thereafter if necessary;

(i) removing any protecting group,

(ii) converting the product into a pharmaceutically acceptable salt. A suitable agent for preparing an imino halide is an acid halide in the presence of an acid binding agent such as a tertiary amine, e.g. pyridine, triethylamine, or N,N-dimethylaniline. Examples of suitable acid halides are phosphorus pentachloride, phosgene, phosphorous pentabromide, phosphorus oxychloride, oxalyl chloride and p-toluene sulphonic acid chloride. Phosphorus pentachloride and phosphorus oxychloride are preferred. The reaction may be conducted under cooling, preferably at temperatures from 0°C to -30°C when phosphorus pentachloride is employed. The amount of the tertiary amine is preferably 3 - 5 mols per mol of phosphorus pentachloride. It is also preferable to use the phosphorus halide in an amount slightly in excess of that of the starting material.

The resulting imino compounds are then treated to introduce a -QR_f group onto the imino carbon atom. This is preferably effected by reacting the imino halide with a corresponding alchohol. Examples of suitable alcohols for reaction with the imino halide are aliphatic alcohols containing from 1 to 12 carbon atoms, preferably 1 to 5 carbon atoms, such as methanol, ethanol, propanol, isopropyl alcohol, amyl alcohol and butyl alcohol, and aralkyl alcohols such as benzyl alcohol and 2-phenylethanol.

The reaction of the alcohol with the imino halide is preferably effected in the presence of an acid binding agent, such as a tertiary amine, preferably pyridine, and the reaction is usually carried out without isolating the imino halide from the reaction mixture.

Thereafter, the imino compound is caused to react with an N-acylating derivative of an acid of formula (X). The comments made above concerning such N-acylating derivatives, and the conditions for carrying out acylations also apply in this case. In particular, the presence of a tertiary amine such as pyridine of N,N-dimethylaniline in the reaction system is preferred.

Finally, the product is treated with water. The water treatment may be conducted together with the isolation of the desired material. That is the reaction mixture may be added to water or a saturated aqueous solution of sodium chloride and then the aqueous layer formed is separated from the organic solvent layer.

In any of the above reactions where a functional or reactive group is protected, such protecting groups include benzyl or substituted benzyl esters for carboxylic groups, and N-benzyloxycarbonyl or substituted benzyloxycarbonyl groups for amino groups. Deprotection may take place by a standard method such as catalytic hydrogenolysis.

The following Examples illustrate the invention.

Example 1:

Preparation of Methylclavulanyloxymethyl - 6- (D-α-azido-α-phenylacetamido) penicillanate.

A solution of iodomethyl 6-(D-α-azido-α-phenylacetamido) penicillanate (1.2g;2.3m mole) in hexamethyl phosphoric acid triamide (12 ml) was treated with calcium 9-0-methylclavulanate (0.38g;1.5m mole) and the mixture stored at room temperature for 1 hr.

Ethylacetate was added and the organic layer washed thoroughly with water and dried over anhydrous magnesium sulphate. Evaporation gave a brown oil. Chromatography on silica-gel using ethyl acetate-petrol (bp.60-80º) (1:1) gave the title compound (0.36 g; 46%) as a colourless oil. v_max(CHCL₃) 2100, 1800, 1700 and 1500 cm^-1. P.m.r. δ (CDCL₃) 1.51 (3H,s,2-CH₃), 1.61 (3H,s,2-CH₃) , 3.05 (IH,dJ17H_z, 6¹ β-CH) , 3.29 (3H,s,9-OCH₃), 3.49 (IH,dd J17H_z and J2.5H_z ,6¹ α-CH) , 3.98 (2H, d, 9¹-CH₂) , 4.46 (IH,s,3-CH), 4.81 (IH,t, 8¹-CH) , 5.1 (2H,s,3¹-CH and 5-CH) , 5.5 - 5.75 (3H,m,5¹-CH. 6-CH and -CH N₃) , 5.85 (2H,s,-O-CH₂-O),7.25 (IH,NH) , 7.39 (5H, Ar-H) .

Preparation of Methylclavulanyloxymethyl - 6 -(D-α-amino- α-phenylacetamido) penicillanate.

A solution of methylclavulanyloxymethyl-6-(D-α-azido- α-phenylacetamido) penicillanate (0.362 g; 0.6m mole) in ethyl acetate (30 ml) was treated with water (40 ml) and 10% palladium. on carbon catalyst (0.362 g) . The system was flushed with nitrogen, and hydrogen was passed through the solution whilst the pH-value was maintained at 2.5 by the simultaneous addition of 0.1M aqueous hydrochloric acid. When the take up of acid had ceased, the flask was flushed with nitrogen and the catalyst filtered off. The aqueous layer was separated, filtered and freeze-dried to give the title compound as its hydrochloride salt. Yield: 0.264 g) . P.m.r.δ(CD₃)₂ SO 1.3 (3H,s,2-CH₃) , 1.45 (3H,s, 2-CH₃), 3.05-3.65 (2H,m,6α and 6β -H) , 3.15 (3H,s,9 - OCH₃), 3.9 (2H,d,9 -CH₂) , 4.4 (1H,s,5-CH) , 4.71 (IH,t,8-CH) 5.12 (2H,s,3 -CH and 5-CH) , 5.3 - 5.75 (3H,m,5 -CH, 6-CH, and CH-Ph) , 5.84 (2H,s,-O-CH₂-O) , 7.4 (5H,br.s,Ar-H).

Claims

CLAIMS :

A compound of formula ( I ) :

or an acid addition salt thereof,

R¹ is C_1-6 alkyl, C_3-6 cycloalkyl, C_5-8 cyclo-alkenyl or an aromatic group;

R² is primary amino, or a carboxy group or an ester thereof;

R⁴ is a group of formula (II):

where in R is an inert organic group of up to 18 carbon atoms .

2 A compound according to claim 1 wherein R⁴ is a group of formula ( III ) :

3 A compound according to claim 1 wherein R⁴ is a group of formula (IV):

4 A compound according to claim 1 wherein R⁴ is a group of formula (V):

wherein R²² is hydrogen, an alkyl group of 1 - 4 carbon atoms or a phenyl group or one of the aforenamed groups substituted by a carboxylic acid group or a salt or C_1-4 alkyl ester or R²² is a carboxylic acid group or a salt of C_1-4 alkyl ester thereof.

5 A compound according to claim 4 wherein R²² is hydrogen.

6 A compound according to any one of claims 1 to 5 wherein R¹ is phenyl or substituted phenyl and R² is amino or an acid salt thereof.

7 Methylclavulanyloxymethyl-6-(D-α-amino-α-phenyl-acetamido)penicillanate. 8 A process for the preparation of a compound of formula (I) which process comprises either:

(A) reacting a compound of formula VI

or a salt or other reactive derivative thereof, wherein R¹, R² and R³ are as defined in claim 1; and Y is a leaving group;

with a compound of formula (VII) or a salt thereof :

R⁴-CO-OH (VII)

wherein R⁴ is as defined in claim 1;

or

(B) reacting a compound of formula (IX) or a derivative thereof which permits N-acylation to occur;

wherein R³ and R⁴ are as defined in claim 1, with an N-acylating derivative of a carboxylic acid of the formula (X):

R¹-CHR²-CO₂H (X)

wherein R¹ and R² are as defined in claim 1, and any reactive group is optionally protected;

or

(C)

(a) treating a compound of the formula (XI):

wherein R³ and R⁴ are as defined in claim 1 and R²³ is an acyl group with an agent forming an imino halide;

(b) treating the imino halide with a compound to introduce a group QR_f on the imino carbon atom, wherein Q is oxygen, sulphur or nitrogen and R_f is an alkyl group of from 5 to 14 carbon atoms, to form an iminoester, iminothioether, or amidine (when Q is 0, S, or N respectively);

(c) reacting with an N-acylating derivative of an acid of formula (XI) above;

(d) treating with water;

and thereafter if necessary:

(i) removing any protecting group,

(ii) converting the product into a pharmaceutically acceptable salt.

9 A pharmaceutical compositon comprising a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier.

10 A compound of formula (I) as defined in claim 1 for use in the treatment of bacterial infection.