GB2266715A

GB2266715A - Penicillins

Info

Publication number: GB2266715A
Application number: GB9209832A
Authority: GB
Inventors: Gisela Quittschorr; Herbert Teubner; Sabine Gunter; Ragna Oehlmann; Leonid Kononov; Edmund Lukewitsch
Original assignee: Arzneimittelwerk Dresden GmbH
Current assignee: Teva GmbH
Priority date: 1992-05-07
Filing date: 1992-05-07
Publication date: 1993-11-10
Also published as: GB9209832D0

Abstract

Compounds of the formula I:- <IMAGE> wherein R<2> is hydrogen or an alkoxycarbonyl group; R<3> is hydrogen, alkyl, alkoxy or halogen; R<4> is hydrogen, alkyl, alkoxy, halogen, alkoxymethylene, phenoxymethylene, substituted phenoxymethylene, substituted phenylmercaptomethylene or dialkylamino-methylene group, in which the alkyl groups may be ring closed to form a piperidinomethylene, a morpholinomethylene, a pyrrolidinomethylene or an N-alkylpiperazinomethylene group; R<5> is hydrogen, alkyl, alkoxy group or halogen; R<6> is hydrogen, alkyl or alkylcarbonyl; or R<3> and R<4> can be (CH)n as a fused ring system wherein n is preferably 3 or 4; and pharmaceutically acceptable derivative thereof have antibacterial activity. Novel intermediates have the formula: <IMAGE> wherein R<7> is hydrogen or a reactive cation or group.n

Description

NEW a-AMINOQUINOLINOYL-(3)-PENICILLINS AND PROCESSES AND INTERMEDIATES USEFUL IN THEIR PRODUCTION DESCRIPTION This invention relates to new a-aminoquinolinoyl (3)-penicillins which have a good activity spectra against gram-positive and, in particular, against gram-negative bacteria and to pharmaceutical compositions thereof, for treating bacterial infections in both human and animal patients. The invention also relates to methods for preparing these new a-amino quinolinoyl-(3)-penicillins and to novel substituted quinoline-3-carboxylic intermediates, useful in said methods.

Many useful antibiotic compounds have been derived from 6-aminopenicitlanic acid, the parent substance of the semi-synthetic penicillins. The main differences between these compounds lie in the'identities of the substituents, carried by the amino group in the 6-position of each compound. These substituents not only determine the physicial and chemical properties of these penicillins, but they also affect their activity profiles and their stability against inactivating enzymes.The most important of these compounds include ampicillin, in which the acyl residue (bound to the 6-amino group) is derived from D-(-)-a-aminophenylacetic acid, amoxicillin, in which the acyl residue is derived from D-(-)-a-amino-4hydroxyphenylacetic acid, carbenicillin, in which the acyl residue is derived from a-carboxyphenylacetic acid, and which is particularly effective against Pseudomonadae, and the ss-lactamase-stable penicillins of the oxacillin type, which can be produced by acylation of 6-penicillanic acid with an activated form of substituted isoxazolecarboxylic acid.

These penicillins are especially effective against gram-negative organisms and also, in some cases, exhibit a degree of ss-lactamase stability.

The characteristics of some of these known penicillins can be improved by introducing substituents into their functional groups, especially the a-amino group of ampicillin or amoxcillin. However, there are still substantial gaps in the efficacy spectra of the known penicillins and, therefore, a need to develop new and more effective a-aminoacyl penicillins.

There have been a number of attempts at improving the properties of a-aminoacyl penicillins, especially by acylation of the a-amino group to, thereby, introduce a carbonyl group carrying a heterocyclic ring system in a side chain. See, for example, German Patent No. 2152967; 2152968; 2226822; 2258973; 2104579 and 2104580; Belgian Patent No. 767648; East German Patent No. 117882; US Patent No. 4112090 and Japanese Patent Nos. 8218686 and 8218687 in which some of these methods and the resulting substituted penicillins are described.

The substituted guinoline-3-carboxylic acid esters, known as quinolones, have become known and accepted for their good antibacterial characteristics over recent years. Examples of these compounds are described in German Patent No. 3142854 and Belgian Patent No.

870576. In these compounds, because the quinolinoyl nitrogen atom is substituted, the quinolinoyl heterocyclic system is not entirely aromatic and, in particular, the ring which includes the substituted nitrogen atom is mainly aliphatic.

It is an object of the present invention to provide new oc-aminoacyl penicillins which, preferably, are effective against gram-negative organisms and, at the same time, exhibit a high degree of efficacy against ss-lactamase-forming species. Another object of the invention is to provide new penicillins which are less likely to induce resistance after long term exposure.

According to a first aspect of the present invention there is provided a new a-aminoquinolinoyl-(3)-penicillin of the general formula (I):

wherein: R2 is hydrogen, or an alkoxycarbonyl, preferably an ethoxycarbonyl or isobutoxycarbonyl, group; R3 is hydrogen, a straight chain or branched alkyl group having 1-6 carbon atoms, preferably an ethyl or an isopropyl group, an alkoxy group having 1-5 carbon atoms, preferably a methoxy group, or a halogen, preferably bromine;; R4 is hydrogen, a straight chain or branched alkyl group, preferably having 1-4 carbon atoms, an alkoxy group, preferably a methoxy group, a halogen, preferably chlorine or bromine, a straight chain or branched alkoxymethylene group, having 1-6 carbon atoms in the alkoxy residue, a phenoxymethylene group, a substituted phenoxymethylene group, preferably substituted in the 3- or 4- position or in both the 3- and 4- positions with an alkyl, alkoxy, phenoxy, or acetyl group or a halogen, preferably chlorine or bromine, a substituted phenylmercaptomethylene group, preferably substituted in the 4- position with an alkyl residue, or a dialkylaminomethylene group, preferably having 1-4 carbon atoms in at least one of the alkyl residues, which residues are in a straight chain, branched or ring-closed to form a piperidinomethylene, morpholinomethylene, pyrrolidinomethylene or an N-alkylpiperazinomethylene group; R5 is hydrogen, a straight chain or branched alkyl group, an alkoxy, preferably a methoxy, group, or a halogen, preferably chlorine; R6 is hydrogen, a straight chain or branched alkyl group having 1-4 carbon atoms, or an alkoxycarbonyl, preferably an acetyl or propionyl, group; and R3 and R4 can be the same or different, or R3 and R4 can be (CH)n as a fused ring system where n is preferably 3 or 4; or a pharmaceutically acceptable salt thereof, preferably an alkali metal salt, such as a sodium, potassium, or calcium salt, or a dialkylammonium or trialkylammonium salt, in which the alkyl residues are straight chain or branched and include 1-6 carbon atoms, preferably 1-4 carbon atoms, or an ester.

In embodiments, the a-aminoquinolinoyl-(3)penicillins of the present invention can exist, as either the R- or S- isomer, with respect to the chiral centre indicated (C in formula I), or as a racemate comprising a mixture of said diastereoisomers.

Preferably, the a-aminoquinolinoyl-(3)-penicillin is as defined in any one of claims 2-10, hereinafter set out.

An advantage of the new a-aminoquinolinoyl-(3)penicillins of the present invention, is that they are particularly effective against bacteria of the species Pseudomonas aeruginosa, Klebsiella pneumoniae, Serratia marcescens, Staphylococcus aureus and Staphylococcus epidermidis as well as Enterococci, Escherichia coli, Enterobacter cloacae and Citrobacter freudii. Additionally, certain of the a-aminoquinolinoyl (3)-penicillins of the present invention have proven to be highly effective against lactamase-forming species, particularly the ss-lactamase forming species of Acetobacter chroococcum, Enterobacter cloacae and Staphylococcus aureus. Hence, the a-aminoquinolinoyl (3)-penicillins according to the present invention offer the prospect of enhanced clinical efficacy against certain strains of ss-lactamase producing pathogenic organisms.

Moreover, a-aminoquinolinoyl- (3 ) -penicillins in accordance with the present invention exhibit aspectrum of anti-bacterial activity which combines that of the known substituted quinoline-3-carboxylic acids, or quinolones, with that of the penicillins, such as ampicillin. Therefore, the inventive compounds have a greatly expanded spectrum of powerful antibacterial activity, when compared to the aforementioned separate precursors.

As suggested above, the quinolones all include substituent groups on their heterocyclic nitrogen atoms. It, therefore, was most surprising to note that the a-aminoguinolinoyl-(3)-penicillins according to the present invention only exhibit their excellent antibacterial properties when their quinolinoyl groups are aromatic, that is, when the ring nitrogen atoms therein are unsubstituted. Thus, a simple combination of an antibacterially effective aminobenzylpenicillin and a similarly useful quinolone does not result in a compound which exhibits good antibacterial action. Such efficacy was only achieved, in accordance with the present invention, once the critical nature of the substituents on the quinoline ring system was realised and their identities were determined.

The antibacterial effect of compounds in accordance with the first aspect of the present invention was determined and compared, in vitro, to the effect of ampicillin, used as a control, upon the following species of bacteria: I = Bacillus subtilis SG 119 II = Staphylococcus aureus SG 511 m = Proteus vulgaris OX 19 IV = Pseudomonas aeruginosa NCTC 10701 V = Pseudomonas aeruginosa SG 137 VI = Salmonella gallinarium ATCC 9184 VII = Klebsiella pneumoniae SG 117 VIII = Serratia marcescens SG 621 IX = Staphylococcus aureus X = Staphylococcus epidermidis ) XI = Enterococci ) XII = Escherichia coli ) laboratory cultures XIII = Enterobacter cloacae ) XIV = Citrobacter freud ii ) The compounds, in accordance with the present invention, employed in the tests were selected from those compounds identified in the examples set out hereinafter. The test results were as follows: I II III IV V VI VII VIII IX X XI XII XIII XIV Example 2 7 8 9 6 5 8 9 8 4 5 5 8 6 6 Example 3 8 9 10 7 5 7 9 9 3 5 4 8 6 6 Example 4 10 9 9 8 7 8 8 8 5 7 6 8 7 6 Example 5 9 8 9 9 7 7 7 8 6 7 6 8 6 6 Example 6 8 8 10 9 6 8 9 8 5 6 5 8 7 7 Example 9 8 8 10 10 4 8 8 8 5 6 4 7 4 4 Example 11 7 7 9 8 5 7 7 7 4 5 5 7 5 5 Example 12 7 9 10 7 5 7 9 7 6 7 5 7 6 6 Example 14 6 9 11 9 6 8 9 9 7 7 6 9 7 7 Example 15 7 9 10 7 7 8 9 9 6 7 6 8 7 7 Example 17 8 8 9 6 6 7 10 8 4 6 4 8 6 6 Example 18 8 8 10 9 6 7 9 7 10 6 4 8 6 6 Example 20 8 8 10 10 5 7 8 6 4 6 5 7 5 5 Example 21 8 8 10 9 6 7 9 8 5 6 5 8 6 6 Example 22 8 8 10 9 5 8 9 8 4 5 5 8 6 7 Comparative standard ampicillin 11 9 5 1 -1 9 5 3 5 6 6 5 -1 -1 In the foregoing table, numbers larger than 1 indicate an antibacterial effect and represent the minimum concentration of the active compound, at which its effect on the growth of the specified organism could no longer be observed.A higher number is indicative of a stronger antibacterial effect and the concentrations of active compound, represented by numbers -1 to 14, are as follows: -1 = growth with 0.2 mM not impeded 1 = with 0.2 mM ) 2 = with 0.1 mM 3 = with 0.05 mM 4 = with 0.025 mM ) 5 = with 0.0125 mM ) 6 = with 0.00625 mM ) no visible growth occurs 7 = with 0.00312 mM ) 8 = with 0.00156 mM 9 = with 0.00078 mM 10 = with 0.00039 mM ) 11 = with 0.0002 mM ) 12 = with 0.0001 mM ) 13 = with 0.00005 mM ) 14 =with0.000025 mM ) Form the foregoing, it can be seen that not only do the a-aminoguinolinoyl-(3)-penicillins of the present invention provide an enhanced antibacterial effect, when compared to that of ampicillin, but also that those compounds in which R4 comprises a ring-closed morpholinomethylene residue, an acetylphenoxymethylene residue, or an alkoxymethylene residue, in which the alkyl group is straight chained or branched and includes 1-4 carbon atoms, or in which R3 and R4 comprise a fused ring system exhibit the best antibacterial activity.

These latter compounds, therefore, are the preferred compounds in accordance with the first aspect of the present invention.

Compounds in accordance with the first aspect of the present invention can be prepared via a reactive form of a novel and correspondingly substituted, acylated heterocyclic quinoline-3-carboxylic acid or derivative, in accordance with a second aspect of the present invention, as an intermediate. According to the second aspect of the present invention, there is provided a quinoline-3-carboxylic acid, or a derivative thereof, having the formula II:

wherein R7 is hydrogen, a reactive cation or, another reactive gorup, and R-R6 have the same meanings as given above with regard to compounds of formula I.

Preferably, R2 and R6 are not simultaneously hydrogen.

In accordance with a third aspect of the present invention, there is provided a method of preparing an a-aminoquinolinoyl- (3)-penicillin, in accordance with the first aspect of the invention, wherein a reactive form of the heterocyclic quinoline-3-carboxylic acid, or derivative, of formula II and in accordance with the second aspect of the invention, is used as an acylating agent in a reaction with an a-aminobenzylpenicillin, such as ampicillin, of the general formula III::

or with a derivative thereof, preferably an alkali metal salt, such as a sodium, potassium or calcium salt, a dialkylammonium or trialkylammonium salt, in which the alkyl residues are straight chain or branched and include 1-6 carbon atoms, preferably 1-4 carbon atoms, or an ester, to provide an a-aminoguinolinoyl- (3)-penicillin, in accordance with the first aspect of the invention. The reactive form of the intermediate of formula II, preferably, is an acid halogenide, for example a chloride, an acid azide, an acid anhydride, a mixed anhydride or, a reactive ester. Preferably, the compound of formula II is in the form of a mixed anhydride or a reactive ester; most preferably the compound is a mixed anhydride.

The mixed anhydrides can be prepared, in accordance with a further aspect of the invention, by reacting a guinoline-3-carboxylic acid, of formula II, in which R7 is hydrogen, with a halogenated, for example chlorinated, carbonic ester, such as chlorocarbonic ethyl or chlorocarbonic isobutyl ester. The reactive esters can be prepared by reacting a substituted guinoline-3-carboxylic acid, of formula II, with a halo (preferably chloro) carbonyl-5-norbornene-2,3 e dicarboximit ester, or with N,N' -bis-(5-norbornene- 2,3-dicarboximidoyl)-carbonate.

In a preferred embodiment of the method in accordance with the present invention the mixed anhydride is prepared from a substituted guinoline-3-carboxylic acid, of formula II, in which R2 and R7 are hydrogen, by reacting the latter with a halocarbonic alkyl ester, to provide substituted quinoline-3-carboxylic acid derivatives, in which R2 and R7 are alkoxycarbonyl groups, derived from the halocarbonic alkyl ester.

Preferably, the halocarbonic alkyl ester is chlorocarbonic ethyl ester or chlorocarbonic isobutyl ester and R2 and R7 are ethoxycarbonyl or isobutoxycarbonyl groups. The reaction at the 4 position in the quinoline ring, which provides the preferred alkoxycarbonyl R2, is not reversed during the remainder of the preparative steps required to provide the target a-aminoquinolinoyl-(3)-penicillin, of formula I. NMR spectroscopy has demonstrated that this group remains intact in the final product. This preferred embodiment of the inventive method provides an unexpected and efficient route towards compounds in accordance with the first aspect of the invention.

Preferably, the reaction of the substituted guinoline-3-carboxylic acid of formula II, with the chlorocarbonic alkyl ester (to provide a reactive mixed anhydride) is carried out in a water-free organic solvent, such as a chlorinated hydrocarbon, preferably dichloromethane, a cyclic ether, preferably tetrahydrofuran or dioxane, or in dimethylformamide.

The reaction, preferably, is carried out at a temperature of between 0oC and -400 and, more preferably, between -100C and -200C and in the presence of a tertiary amine, for example triethylamine.

The a-aminobenzylpenicillin parent substance, of general formula III, may be used in the form of an anhydrous salt, such as a sodium or trialkylammonium salt in which the alkyl residues, preferably, have 2-4 carbon atoms, or as an ester, preferably as a trialkylsilyl ester, in which the alkyl groups comprise 1-4 carbon atoms.

The acylation reaction in accordance with the second aspect of the invention, is preferably carried out in a water-free organic solvent, such as a chlorinated hydrocarbon, preferably dichloromethane, a cyclic ether, preferably dioxane or tetrahydrofuran, or in dimethylformamide. The acylation reaction is preferably carried out at a temperature of between -400C and +400C, more preferably at a temperature of between -200 and +100C. The new semi-synthetic a-aminoquinolinoyl-(3)-penicillins of the general formula I thus obtained, may be isolated as carboxylic acids or as salts.The salts, preferably, should be pharmaceutically acceptable and, where a compound of formula I is recovered as a carboxylic acid, it, preferably, should be converted into the stable and pharmaceutically acceptable sodium salt, by reaction with sodium 2-ethylhexanoate.

In yet a further aspect, the present invention provides a pharmaceutical composition, for antibacterial use, comprising a compound in accordance with the first aspect of the invention, in admixture with a pharmaceutical carrier or carriers. Said composition can comprise two or more such compounds and preferably the composition comprises from 0.0002 - 0.025 millimols of the or each such compound.

The following examples are provided, in order to further describe and illustrate the invention.

Example 1 Sodium 6-P-(-)-a-([4 'ethoxycarbonyloxy-6'ethyl-7'-(4" chloro) -phenoxy- methylene-quinolinoyl-3 'J-carboxamido)-a-phenylacetamido] penicillanate.

2.55 g (0.0067 mol) sodium salt of 4-hydroxy-7-(4'chloro-phenoxymethylene) 6-ethyl-quinoline-3-carboxylic acid is suspended in 50 ml waterfree tetra-hydrofuran, the solution being cooled to -200C. 1.2 ml (0.014 mol) chlorocarbonic ethyl ester is added drop by drop and stirred for 30 minutes over ice. Then a solution of 2.5 g (0.0067 mol) sodium ampicillin is cooled in a mixture of 15 ml water and 50 ml tetrahydrofuran and added to the reaction mass while it is being cooled. The ice bath is removed and the mixture is stirred again for 30 minutes. It is then evaporated under vacuum, the residue being dissolved in water. After adding acetic acid ethyl ester, the solution is acidified with dilute hydrochloric acid and the phases are separated.

Following extraction with acetic acid ethyl ester, the organic phases are washed, dried and again evaporated under vacuum. The residue is dissolved in a small quantity of dried methylene chloride and added, drop by drop, to a solution of 0.0067 mol sodium ethylhexanoate-(2) in dried methylene chloride while cooling. The sodium salt of the above-mentioned penicillanic acid is precipitated, by the addition of dried ether or petroleum ether. This is followed by separation by suction and washing with petroleum ether.

2.5 g A 51.8 % of the theoretical yield of the above end product is obtained. It shows the B-lactam band in the IR spectrum at 1780 cm?1.

Example 2 Sodium 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7' -(4" -bromo)-phenoxy methylend-quinolinoyl-3'-]doxamido)-a-phenylacetamido] penicillanate, 2.1 g (0.005 mol) sodium salt of 4-hydroxy-7-(4'-bromo-phenoxymethylene)-6- ethyl-quinoline-3-carboxylic acid is reacted in the same way as in example 1.

2.5 g e 65.2 % of the theoretical yield of the above-mentioned sodium salt is obtained, showing a B-lactam band in the IR spectrum at 1775 cm.'.

Example 3 Sodium 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7'-(4"-methyl)- phenoxymethylene-quinolinoyl-3']-carboxamido)-α-phenylacetamido] penicillanate.

1.8 g (0.005 mol) sodium salt of 4-hydroxy-7-(4'-methylphenoxymethylene)-6- ethylquinoline-3carboxyiic acid is reacted in the same way as in example 1.

2.1 g A 61.1 % of the theoretical yield of the above-mentioned sodium salt is obtained. It shows the characteristic B-lactam band in the IR- spectrum at 1780 cm-l.

Example 4 Sodium 6-[D-(-)-a-([4'-ethoxycarbonyloxy-6' ethyl-7'-n-butoxymethylene- quinolinoyl3 ']-carboxamido)-ar-phenylacetamido] penicillanate 1.04 g (0.003 mol) 4-hydroxy-7n-butoxymethylene-6 ethyl-quinoline-3- carboxylic acid is dissolved with 1.26 ml (0.009 mol) triethylamine in 50 ml dried methylene chloride while cooling the solution to -200C. After adding 0.54 ml (0.006 mol) chlorocarbonic ethyl ester it is stirred for 30 minutes over ice.Then a solution of 1.26 g (0.0036 mol) of waterfree ampicillin in 20 ml dned methylene chloride and 1.26 ml (0.009 mol) triethylamine is added drop by drop, ensuring that the temperature does not rise above -10 C. The reaction mixture is stirred further for 30 minutes over ice and then for 30 minutes at room temperature. It is then evaporated under vacuum and the residue is dissolved in water. After adding acetic acid ethyl ester, the solution is acidified with dilute hydrochloric acid. The phases are separated. After extraction the organic extracts are washed, dried and again evaporated under vacuum. The residue is dissolved in a small quantity of dried methylene chloride and the sodium salt is formed with 0.003 mol sodium ethyl hexanoate while cooling with ice water.If required, the salt is precipitated with dried ether or petroleum ether, separated by suction and washed with petroleum ether.

1.97 g a 89.95 % of the theoretical yield of the above sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1785 cunt1.

Example 5 Sodium 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7'-n-propoxy-methylene- quinolinoyl-3']-carboxamido)-α-phenylacetamido] penicillanate.

0.87 g (0.003 mol) 4-hydroxy-7n-propoxymethylene-6-ethyl-quinoline-3- carboxylic acid is reacted in the same way as example 4. 1.85 g A 86.45 % of the theoretical yield of the above-mentioned sodium salt is obtained.

It shows the characteristic B-lactam band in the IR spectrum at 1780 cm-1.

Example 6 Sodium 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7'-ethoxymethylene- quinolinoyl-3'-]-carboxamido)-α-phenylacetamido] penicillanate.

0.83 g (0.003 mol) 4-hydroxy-6ethyl-7-ethoxy-methylene-quinoline-3carboxylic acid is reacted in 50 ml distilled dimethyl formamide in the same way as in example 4.

1.35 g A 64.3 % of the theoretical yield of the above-mentioned sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1780 cint1.

Example 7 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-8'-ethyl-quinolinoyl-3']-carboxamido)-α- phenylacetamido]-penicillanic acid.

0.65 g (0.003 mol) 4-hydroxy-8-ethyl-quinoline-3-carboxylic acid is dissolved in 50 ml distilled dimethyl formamide, mixed with 1.25 ml (0.009 mol) triethylamine and cooled to -20 C. After addition of 0.78 ml (0.006 mol) chlorocarbonic isobutyl ester, the mass is stirred for 15 minutes at -20 C whereupon a solution of 1.26 g (0.0036 mol) waterfree ampicillin in 25 ml dried methylene chloride and 1.26 ml (0.009 mol) triethyl amine is added drop by drop. The mixture is stirred for 30 minutes over ice and for 60 minutes at room temperature. Then the residue is largely evaporated under vacuum and taken up in a large amount of water. Insolubles are separated by suction acidified with dilute hydrochloric acid and thoroughly stirred and cooled over ice, to precipitate the penicillanic acid.It is separated by suction, washed with water and dried.

1.4 g 4 73.4 g of the above-mentioned penicillanic acid is obtained. It shows the X -lactam band in the IR spectrum at 1785 cm 1 Example 8 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-7',8'-dimethyl-quinolinoyl-3']-carboxamido)- a-phenylacetamido]-penicillanic acid.

0.65 g (0.003 mol) 4-hydroxy-7,8-dimethyl-quinoline-3-carboxylic acid is reacted in the same way as in example 7. 1.3 g A 70.1 % of the theoretical yield of the above-mentioned penicillanic acid is obtained. It shows the characteristic B-lactam band in the IR spectrum at 1785 cm-1.

Example 9 Sodium 6-1D-(-)-a-(t4'-hydroxy-6'-methoxy-quinolinoyl-3'] carboxamidol-a- phenylacetamido]-penicillanate 0.88 g (0.004 mol) 4-hydroxy-6-methoxy-quinoline-3carboxyli acid is suspended in 40 ml dried tetrahydrofuran and mixed with 0.54 ml (0.004 mol) triethyl amine.

During - formation of the salt the reaction mixture is cooled with ice water. Then a solution of 0.97 g (0.004 mol) chloro-carbonyl-5-norbornene-2,3-dioximidester is added in 10 ml dried methylene chloride, as is a pinch of dimethylaminopyridine on the tip of a spatula, whereupon the mixture is left to react for 11A hours at room temperature. A solution of 1.68 g (0.0048 mol) waterfree ampicillin is prepared in 20 ml dried methylene chloride with 1.89 ml (0.0133 mol) triethyl amine, said solution being cooled to -170C and mixed with 0.55 ml (0.0048 mol) tri-methylchlorosilane.

The latter mixture is stirred for 30 minutes over ice, whereupon the first reaction mixture is added thereto. After a further reaction time of 30 minutes over ice and 30 minutes at room temperature, 5 ml water is added and the mixture is stirred for another 10 minutes. The organic solvents are largely removed and the residue is mixed with water. Acetic acid ethyl ester is added and acidification is effected with dilute hydrochloric acid. The phases are separated and the aqueous phase is twice again extracted with acetic acid ethyl ester.

The combined organic phases are carefully washed with saturated sodium chloride solution, dried over sodium sulphate and again evaporated under vacuum. The resulting penicillanic acid is dissolved in a small quantity of dried methylene chloride and the sodium salt is formed with an equivalent amount of sodium-2-ethylhexanoate while cooling with ice water. If required, the mass is precipitated with dried ether or petroleum ether, separated by suction and dried.

1.99 g A 74.2 % of the theoretical yield of the above-mentioned sodium salt is obtained, showing the characteristic B-lactam band in the IR spectrum at 1780 emA.

Example 10 Sodium 6-[D-(-)-α-([4'-hydroxy-6'-bromo-quinolinoyl-3']-carboxyamido)-α- phenylacetamido]-penicillanate.

1.07 g (0.004 mol) 4-hydroxy-6-bromo-quinoline-3carboxylic acid is reacted in the same way as in example 9. 2.0 g e 69.4 % of the theoretical yield of the abovementioned sodium salt is obtained, showing a B-lactam band in the IR spectrum at 1775 cm''.

Example 11 Sodium 6-[1)-(-)-a-([4'isobutoxycarbonyloxy-6'-isopropylsuinolinoyl-3']- carboxamido)-a-phenylacetamidol-penicillanate.

0.69 g (0.003 mol) 4-hydroxy-6-isopropyl-quinoline-3-carboxylic acid is mixed with 0.84 ml (0.006 mol) triethylamine in 50 ml absolute tetrahydrofuran and cooled to -20"C. Following the addition of 0.78 ml (0.006 mol) chlorocarbonic isobutyl ester, the mixture is allowed to react for 30 minutes at -200C. Then a solution of 1.26 g (0.0036 mol) waterfree ampicillin in 25 ml dried methylene chloride and 1.26 ml (0.009 mol) triethylamine is added drop by drop at a temperature of not less than -10 C. The reaction mixture is maintained for 30 minutes over ice and for 30 minutes at room temperature. Then the reaction mixture is evaporated under vacuum, the residue is taken up in water and, after filtering off the insolubles, mixed with acetic acid ethyl ester and acidified with dilute hydrochloric acid.The phases are separated, the aqueous phase being subjected to two extractions with acetic acid ethyl ester.

The combined organic phases are washed, dried and again concentrated under vacuum. The residue is dissolved in a small amount of dried methylene chloride and the sodium salt is formed with 0.0003 mol sodium-2-ethyl-hexanoate.

1.63 g A 79.59G of the theoretical yield of the above-mentioned sodium salt is obtained, showing the characteristic fi-lactam band in the IR spectrum at 1780 cm-1.

Example 12 Sodium 6-[D-(-)-α-([4'isobutoxycarbonyloxy-benzo[1,2n]quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanate.

0.72 g (0.003 mol) 4-hydroxy-3-carboxylic acid-benzo[l,2n)-quinoline is reacted in the same way as in example 11, 70 ml distilled dimethyl formamide being used in order to dissolve the quinoline carboxylic acid.

1.06 g ^ 51.0% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the ss-lactam band in the IR spectrum at 1780 cint1.

Example 13 Sodium 6-[D-(-)-α-([4'isobutoxycarbonyloxy-5'-propionyl-quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanate.

0.69 g (0.003 mol) 4-hydroxy-5-propionyl-quinoline-3-carboxylic acid is reacted in the same way as in example 11, 50 ml dried methylene chloride being used in order to dissolve the quinoline carboxylic acid. 1.2 g A 57.4% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1780 cm~l.

Example 14 Sodium 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6'-ethyl-7'morpholinomethylene- quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanate 0.95 g (0.003 mol) 4-hydroxy-Gethyl-7-morpholinomethylenesuinoline-3- carboxylic acid is reacted in the same way as in example 11, 50 ml dried methylene chloride being used in order to dissolve the substituted quinoline-3-carboxylic acid.

1.2 g A 52.6% of the theoretical yield of the above-mentioned sodium salt is obtained.

It shows the characteristic B-lactam band in the IR spectrum at 1770 cm?1.

Example 15 Sodium 6-lD-(-)-a-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-(4"-acetyl)- phenoxymethylene-quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanate.

1.1 g (0.003 mol) 4-hydroxy-6-ethyl-7-(4'acetyl)-phenoxymethylenequinoline-3-carboxylic acid is reacted in the same way as in example 11, 50 ml distilled dimethylformamide being used in order to dissolve the quinoline carboxylic acid. 1.7 g A 69.9% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1780 cm-1.

Example 16 Sodium 6-[D-(-)-a-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-(4"-methyl) phenylmercaptomethylene-quinolinoyl-3']-carboxamido)-α-phenylacetamido]- penicillanate.

1.06 g (0.003 mol) 4-hydroxy-6-ethyl-7-(4'-methyl)-phenylmercaptomethylene- quinoline-3-carboxylic acid was reacted in the same way as in example 11, 70 ml distilled dimethyl formamide being used in order to dissolve the substituted quinoline3-carboxylic acid. 1.28 g A 54.4% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1780 cm-1.

Example 17 Sodium 6-[1)-(-)-a-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-(3"-methyl4"- chloro)-phenoxymethylene-quinolinoyl-3 "I-carboxamido)-a-phenylacetamido]- penicillanate.

1.2 g (0.003 mol) 4-hydroxy-6-ethyl-7-(3 '-methyl-4' -chloro)-phenoxymethylene- quinoline-3-carboxylic acid is reacted in the same way as in example 11, as a result of which 1.6 g A 66.6% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1785 cm-1.

Example 18 Sodium 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-methoxymethylene- quinolinoyl-3 'J -carboxamido)-a-phenylacetamido] -penicillanate.

0.78 g (0.003 mol) 4-hydroxy-6ethy1-7-methoxymethylene-quinoline-3carboxylic acid is reacted in the same way as in example 11, 70 ml distilled dimethyl formamide being used in order to dissolve the quinoline carboxylic acid. 1.43 g A 66.8% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the characteristic B-lactam band in the IR spectrum at 1780 cm-1.

Example 19 Sodium 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-8'-methoxy-quinolinoyl-3']- carboxamido) -a-phenylacetamido]-penicillanate.

0.66 g (0.003 mol) 4-hydroxy-8-methoxy-quinoline-3-arboxylic acid is reacted in the same way as in example 11. 2.48 g A 73.8% of the theoretical yield of the abovementioned sodium salt is obtained, showing a B-lactam band in the IR spectrum at 1770 cm-1.

Example 20 Sodium S[D-(-)-a-([4'-isobutoxycarbonyloxy-6',7'-dimethoxy-quinolinoyl- 3']-carboxamido)-α-phenylacetamido]-penicillanate.

0.75 g (0.003 mol) 4-hydroxy-6,7-dimethoxy-quinoline-3-carboxylic acid is reacted in the same way as in example 11, 50 ml distilled dimethyl formamide being used in order to dissolve the quinoline carboxylic acid. 1.26 g A 59.7% of the theoretical yield of the above-mentioned sodium salt is obtained. It shows the characteristic band for B-lactam antibiotics in the IR spectrum at 1780 cint'.

Example 21 Sodium 6-s-(-)-a-([4'-isobutoxycarbonyloxy-6'ethyl-7'-isopropoxy- methylene-quinolinoyl-3'-]-carboxamido)-α-phenylacetamido]-penicillanate.

0.87 g (0.003 mol) 4-hydroxy-6-ethyl-7-isopropoxymethylene-quinoline-3-carboxylic acid is reacted in the same way as in example 11, a mixture of in each case 20 ml absolute tetrahydrofuran, dried methylene chloride and distilled dimethylformamide being used in order to dissolve the substituted quinoline-3-carboxylic acid.

1.42 g e 63.9% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1785 cm-1.

Example 22 Sodium 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-sec.butoxy- methylene-quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanante.

0.91 g (0.003 mol) 4-hydroxy-6ethyl-7-sec. butoxymethylenequinoline-3arboxylic acid is reacted in the same way as in example 11, using the solvent mixture stated in example 21. 1.49 g A 65.6% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the B-lactam band in the IR spectrum at 1780 cm-1.

Example 23 Sodium 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-isobutoxymethylene- quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanate.

0.91 g (0.003 mol) 4-hydroxy-6-ethyl-7-isobutoxymethylene-quinoline-3-carboxylic acid is reacted in the same way as in example 11, the solvent being a mixture consisting of equal parts of dried tetrahydrofuran, dried methylene chloride and distilled dimethyl formamide. 1.75 g # 79.9% of the theoretical yield of the sodium salt is obtained, showing the -lactam band in the IR spectrum at 1785 cam 1 Example 24 Sodium 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-8'-methoxy-quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanate.

0.72 g (0.003 mol) 4-hydroxy-8-methoxy-quinoline-3-carboxylic acid is reacted in the same way as in example 11 in 50 ml absolute tetrahydrofuran. 1.49 g A 73.8% of the theoretical yield of the above-mentioned sodium salt is obtained, showing the ss-lactam band in the IR spectrum at 1785 cm1.

Example 25 Sodium 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-7',8'-dichloro-quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanate.

0.78 g (0.003 mol) 4-hydroxy-7,8-dichloro-quinoline-3-carboxylic acid is reacted in the same way as in example 11, 50 ml distilled dimethyl formamide being used by way of solvent.

1.07 g A 50.0% of the theoretical yield of the above-mentioned sodium salt is obtained. It shows the characteristic B-lactam band in the IR spectrum at 1775 cm-l.

Claims

1. An a-aminoguinolinoyl-(3)-penicillin of the formula I:

wherein; R2 is hydrogen or an alkoxycarbonyl group; R3 is hydrogen, a straight chain or branched alkyl group having 1-6 carbon atoms, an alkoxy group having 1-5 carbon atoms or, a halogen; R4 is hydrogen, a straight chain or branched alkyl group, an alkoxy group, a halogen, a straight chain or branched alkoxymethylene group, having 1-6 carbon atoms in the alkoxy residue, a phenoxymethylene group, a substituted phenoxymethylene group, a substituted phenylmercaptomethylene group, or a dialkylaminomethylene group, in which the alkyl groups are straight chain, branched or ring closed to form a piperidinomethylene, a morpholinomethylene, a pyrrolidinomethylene or an N-alkylpiperazinomethylene group; R5 is hydrogen, a straight chain or branched alkyl group, an alkoxy group or, a halogen;; R6 is hydrogen, a straight chain or branched alkyl group having 1-4 carbon atoms, or an alkylcarbonyl group, and; R3 and R4 can be the same or different, or R3 and R4 can be (CH)n as a fused ring system wherein n is preferably 3 or 4; or a pharmaceutically acceptable derivative thereof.

2. A compound as claimed in claim 1, wherein said pharmaceutically acceptable derivative is a sodium, potassium, calcium, dialkylammonium or trialkylammonium salt, in which the alkyl residues are straight chain or branched and have 1-6 carbon atoms, or an ester.

3. A compound as claimed in claim 1 or claim 2, wherein R2 is an ethoxycarbonyl or an isobutoxycarbonyl group.

4. A compound as claimed in any of the preceding claims, wherein R3 is an ethyl, an isopropyl or, a methoxy group, or bromine.

5. A compound as claimed in any of the preceding claims, wherein R4 is an alkyl group having 1-4 carbon atoms, a methoxy group, chlorine, bromine, a phenoxymethylene group, a phenoxymethylene group substituted in the 3- or 4- position or in both the 3and 4- positions with an alkyl, alkoxy, phenoxy, or an acetyl group or a halogen, preferably chlorine or bromine, a phenylmercaptomethylene group substituted in the 4- position with an alkyl group, or a dialkylaminomethylene group having 1-4 carbon atoms in at least one of the alkyl residues.

6. A compound as claimed in any of claims 1-5, wherein R4 is a ring-closed morpholinomethylene, an acetylphenoxymethylene or, an alkoxymethylene group, in which the alkyl residue is straight chain or branched and includes 1-4 carbon atoms.

7. A compound as claimed in any of the preceding claims, wherein R3 and R4 are (CH)n as a fused ring ring system where n is 3 or 4.

8. A compound as claimed in any of the preceding claims, wherein R5 is a methoxy group, or chlorine.

9. A compound as claimed in any of the preceding claims, wherein R6 is an acetyl or propionyl group.

10. A compound as claimed in any of the preceding claims, comprising: 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7'-(4"-chloro)phenoxymethylene-quinolinoyl-3']-carboxamido)-α-phenylacetamido]- penicillanic acid, 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7'-(4"-bromo)phenoxymethylene-quinolinoyl-3']-carboxamido)-α-phenylacetamido]- penicillanic acid, 6-[D-(-)-a-([4' -ethoxycarbonyloxy-6' -ethyl-7' -(4" -methyl) phenoxymethylene-quinolinoyl-3']-carboxyamido)-α-phenylacetamido]- penicillanic acid, 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7'-n-butoxy-methylene- quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α;-([4'-ethoxycarbonyloxy-6'-ethyl-7'-n-propoxy-methylene- quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α-([4'-ethoxycarbonyloxy-6'-ethyl-7'-ethoxy-methylene- quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-8'-ethyl-quinolinoyl-3']-carboxamido)- a-phenylacetamido]-penicillanic acid 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-7',8'-dimethyl-quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanic acid 6-[D-(-)-α-([4'-hydroxy-6'-methoxy-quinolinoyl-3']-carboxamido)- α-phenylacetamido]-penicillanic acid.

6-[D-(-)-α-([4'-hydroxy-6'-bromo-quinolinoyl-3']-carboxamido)- α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6'-isopropyl-quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-benzo/1,2n/quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanic acid, 6-tD-(-)-a-([4 '-isobutoxycarbonyloxy-5 ' -propionyl-quinolinoyl-3 '] carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α;-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-morpholino-methylene- quinollnoyl-3 ']-carboxamido)-α-phenylacetamido]-penici llanic acid, 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-(4"-acetyl)-phenoxy- methylene-quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanic acid, 6-fD-(-)-a-((4'-isobutoxyearbonyloxy6' -ethyl-7' -(4 "-methyl)- phenylmarcaptomethylene-quinolinoyl-3']-carboxamido)-α-phenyl-cetamido]- penicillanic acid, 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-(3"-methyl-4"-chloro)phenoxymethylene-quinolinoyl-3']-carboxamido)-α-phenyl-acetamido]-penicillanic acid, 6-[D-(-)-α;-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-methoxy-methylene- quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanic acid, ~. 6-tD-(-)-a-([4'-isobutoxycarbonyloxy-8'-methoxy-quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α-([4'-isobutoxycarbonyloxy-6',7'-dimethoxy-quinolinoyl-3']- carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α;-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-isopropoxy-methylene- quinolinoyl-3'-]warboxamido)-a-phenylacetamido]-penicillanic acid, 6-[D-(-)-a-(t4 '-isobutoxycarbonyloxy-6' '-ethyl-7'-sec. butoxy-methylene- quinolinoyl-3']-carboxamido)-a-phenylacetamido]- penicillanic acid, 6-[D-(-)-([4'-isobutoxycarbonyloxy-6'-ethyl-7'-isobutoxy-methylene quinolinoyl-3']-carboxamido)-α-phenylacetamido]-penicillanic acid, 6-[D-(-)-α ;-([4'-isobutoxycarbonyloxy-8'-methoxy-quinolinoyl-3']- carboxamido)-a-phenylacetamido]- penici llanic acid, or (D-(-)-a-((4 '-isobutoxycartonyloxy-7 ',8' -dichloro-quinolinoyl-3 ']- carboxamido)-α-phenylacetamido]-penicillanic acid, or a sodium, potassium, calcium, dialkylammonium or trialkylammonium salt thereof, in which the alkyl groups have 1-6 carbon atoms and are straight chain or branched, or an ester thereof.

11. A pharmaceutical composition, for antibacterial use, comprising a compound as claimed in any of the preceding claims, in admixture with a pharmaceutical carrier or carriers.

12. A pharmaceutical composition comprising two or more of the compounds, as claimed in any of claims 1-10, preferably in admixture with a pharmaceutical carrier.

13. A pharmaceutical composition comprising from 0.0002 - 0.025 millimols of a compound as claimed in any of claims 1-10, preferably in admixture with a pharmaceutical carrier.

14. A quinoline-3-carboxylic acid or derivative of the formula II:

wherein R7 is hydrogen, a reactive cation or another reactive group, 6 R6 are as defined in claim 1 and, preferably, R2 and R7 are not simultaneously hydrogen.

15. A quinoline-3-carboxylic acid derivative as claimed in claim 14, wherein R7 is a halogen, an azide group, an alkoxycarbonyl group or, is such that said derivative is an acid anhydride or a mixed acid anhydride.

16. A quinoline-3-carboxylic acid or derivative as 2 6 claimed in claim 14 or 15, wherein R2 - R6 are as defined in claim 1 and any one or a combination of claims 3-9.

17. A process for preparing a quinoline-3carboxylic acid mixed anhydride, as claimed in claim 14, 15 or 16, comprising reacting a compound of formula II, in which R7 is hydrogen, with at least one halocarbonic alkyl ester.

18. A process for preparing a quinoline-3carboxylic acid derivative, as claimed in claim 14, 15 or 16, wherein a compound of formula II, in which R7 is hydrogen, is reacted with a halocarbonyl-5 norbornene-2 , 3-dicarboximidester, or with N-N'-bis-(5-norbornene-2,3-dicarboximidoyl)-carbonate, to provide a reactive ester of formula II.

19. A process as claimed in claim 17 or 18, wherein a compound of formula II, in which R2 and R7 are hydrogen, is reacted with a halocarbonic alkyl ester and the product is a mixed anhydride of formula II, in which R2 and R7 are both alkoxycarbonyl groups.

20. A process as claimed in any of claims 17-19, wherein the halogen in any halogenated or halo compound is chlorine.

21. A process as claimed in claims 17 and 19, wherein the halocarbonic alkyl ester is chlorocarbonic ethyl ester or chlorocarbonic isobutyl ester and R2 and R7, in the product mixed anhydride, are ethoxycarbonyl or isobutoxycarbonyl groups.

22. A process as claimed in any of claims 17-21, wherein the reaction is carried out in a water free solvent.

23. A process as claimed in any of claims 17-21, wherein the solvent is a chlorinated hydrocarbon, a cyclic ether, or dimethylformamide and the reaction is carried out at a temperature of betwee OOC and -400C in the presence of a tertiary amine.

24. A process as claimed in claim 23, wherein the chlorinated hydrocarbon is dichloromethane, the cyclic ether is tetrahydrofuran or dioxane, the reaction is carried out at a temperature of between -100C and -20 and the tertiary amine is triethylamine.

25. A process for preparing an a-aminoguinolinoyl-(3)-penicillin, as claimed in claim 1, comprising acylating an a-aminobenzylpenicillin of formula III:

or a derivative, with a quinoline-3-carboxylic compound, as claimed in any of claims 14-16 or as prepared by a process as claimed in any of claims 17-24.

26. A process as claimed in claim 23, wherein the derivative is a sodium, potassium or calcium salt, a dialkylammonium or trialkylammonium salt, in which the alkyl groups are straight chain or branched and have 1-6 carbon atoms, or an ester.

27. A process as claimed in claim 26, wherein said ester is a trialkylsylilester having 1-4 carbon atoms in the alkyl groups.

28. A process as claimed in any of claims 25-27, wherein the acylation reaction is carried out in a water free organic solvent and at a temperature of between 400C and -400C.

29. A process as claimed in claim 28, wherein the water free solvent is dichloromethane, a cyclic ether, preferably tetrahydrofuran or dioxane, or dimethylformamide, and the reaction temperature is between 100C and -20 C.

30. A process as claimed in any of claims 25-29, wherein the compound of formula I is produced as an acid and is converted to a pharmaceutically acceptable salt.

31. A process as claimed in claim 30, wherein the salt is a sodium salt.

32. A process as claimed in claim 31, wherein the sodium salt is produced by reacting the acid of formula I with sodium 2-ethylhexanoate.

33. An a-aminoquinolinoyl-(3)-penicillin, as hereinbefore described in any of the examples.

34. A quinoline-3-carboxylic acid or derivative, substantially as hereinbefore described as an intermediate in any of the examples.

35. A process for preparing a quinoline-3carboxylic intermediate, substantially as hereinbefore described in the examples.

36. A process for preparing an a-amino quinolinoyl-(3)-penicillin, substantially as hereinbefore described in any of the examples.