CA1070295A - Penicillins and their preparation - Google Patents

Abstract

NOVEL PENICILLINS AND THEIR PREPARATION

Abstract of the Disclosure:
Penicillins of the formula:

Description

~0~95 ~ -The present invention relates to novel penicillins and their preparation.
It is well known that 6~ aminoacylamido)penicillanic acid derivatives such as 6-(a-amino phenylacetamido)penicillanic - acid tAmpicillin), 6-(~-amino-p-hydroxyphenylacetamido)peni-cillanic acid (Amoxycillin), 6-(~-amino-thienylacetamido)peni-cillanic acid, 6~ aminocyclohexanecarboxamido)penicillanic acid (Cyclacillin), 6-(a-amino-isothiazolylacetamido)penicillanic acid and 6-~-amino-2-(1,4-hexadienylacetamido)]penicillanic acid ~Epicillin) inhibit the growth of various Gram-positive and Gram-nega~ive bacteria. Particularly, ampicillin is an excellent chemotherapeutic. These compounds, however, do not exert any appreciable antimicrobial activity against Pseudomonas. On the other hand, there is a tendency that infections caused by Pseudomonas are increasing.
Recently, some penicillin antibiotics effective in the treatment of infections with Pseudomonas such as "Carbenicillin" and "Sulfocillin" have appeared on the market, ;
but their anti-Pseudomonas activity is not particularly strong.
In U.S. Patent 3,433,784, there are disclosed some N-acyl derivatives of aminobenzylpenicillin (Ampicillin). Their anti-Pseudomonas activity is, however, not very high and their ~-antimicrobial actlvity against other Gram-negative bacteria -~
is quite low. In German Patent (Offen.) No. 2,165,462, there are disclosed some N-acyl derivatives of aminobenzylpenicillin.
, However, groups other than phenyl are not disclosed for the b/,c~f,~ C~ " n~ ~ ~
~symbol R (in formula I below). In Japanese Patent Applicati-en 9 ~ 3 - No. ~ , there are disclosed penicillins analogous to those of the formula (I). However9 the symbol A (in formula I
below) is limited to a monocyclic nitrogen-containing he~ero~
- aromatic ring.
One aspect of the invention provides a process for -- 1 -- . . . .

-``` 1~7~?Z95 producing penicillins of the formula:
HO-A-CONH-CH-CONH ~H 3 ( I ) - R o N COOH
wherein R represents cyclohexadienyl, cyclohexenyl, cyclohexyl or isobutyl and A represents a quinoline, isoquinoli.ne, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine or pyridopyrimidine ring optionally substituted with lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylthio, mercapto, lower alkoxymethyl, halogen, hydroxyl, cyano, nitro, lower alkylsulfonyl, arylsulfonyl, sulfamoyl, carbamoyl, aryloxy-carbonylamino, acetoacetylamino, lower alkylamino, di(lower)-alkylamino, halo(lower)alkyl, lower alk~nyl, aryl, cyclo(lower)~
alkyl and/or condensed cyclo(lower~alkylene; esters thereof and their non-toxic pharmaceutically acceptable salts, which comprisesreacting a carboxylic acid of the formula:
HO-A-COOH (II) wherein A is as defined above, or a reactive derivative thereof, with a compound of the formula:
H2N-CH-CONH ~ ~ HH3 (III) R ~ - N COOH

wherein R is as defined above, or a derivative thereof, and if necessary, converting a free acid product to a non tox.ic pharmaceutically acceptable salt thereof or vlce versa, and, if necessary, hydrolyzing an ester to the corresponding free acid.
Another aspect of the invention provides a penicillin of the formula:
HO-A-CONH-CH-CONH ~ ~ H (I) ~ -R N COOH
O :

`~ ~

- 2 - ~:

~ ~07~2~5 wherein R represents cyclohexadienyl, cyclohexenyl, cyclohexyl - or isobutyl and A represents a quinoline, isoquinoline, cinnoline, naphthyridine, quinoxalinel pyrazolopyridine or pyridopyrimidine ring optionally substituted with lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylthio, mercapto, lower alkoxymethyl, halogen, hydroxyl, cyano, nitro, lower alkylsulfonyl, arylsulfonyl, sulfamoyl, carbamoyl, aryloxycar-bonylamino, acetoacetylamino, lower alkylamino, di(lower)-alkylamino, halo(lower)alkyl, lower alkenyl, aryl, cyclo(lower)-alkyl and/or condensed cyclo(lower)alkylene; esters thereof, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process above or an obvious chemical equivalent thereof.
The penicillins (I) of the invention are characteristic in that a hydroxyl group is attached to the polycyclic hetero-aromatic ring represented by the symbol A, preferably at the position adjacent to the carbon atom to which the 6-(~ amino-acylamino)penicillanic acid moiety of the formula~

-CONH--CH-CON~ ,~C~3 (IA) o N COOH
20 wherein R is as defined above is linked. In the case of the ~.'t' ~ "'' "
hydroxyl group being capable of taking a tautomeric form such as a keto-enol form, it may be present in a keto form (O=C~
As stated above, the ring A may be quinoline, iso-quinoline, cinnoline, naphthyridine, quinoxaline, pyrazolo-pyridine and pyridopyrimidine. Of these a naphthyridine ring is preferred.
The ring A may bear, in addition to the hydroxyl group as stated above, any other substituent(s), of which examples are as follows: lower alkyl, lower alkoxy, lo~er ~ - 3 ~

~1:)7()29S

alkanoyl, lower alkoxycarbonyl, lower alkylthio, mercapto, lower alkoxymethyl, halogen, hydroxyl, cyano, nitro, lower alkyi-sulfonyl, arylsulfonyl, sulfamoyl, carbamoyl, aryloxycarbonyl-amino, acetoacetylamino, lower alkylamino, di(lower)alkylamino, halo(lower)alkyl, lower alkenyl, aryl, cyclo(lower)alkyl and condensed cyclo(lower)alkylene.
Non-toxic, pharmaceutically acceptable salts of the penicillins (I) include, ~or instance, inorganic salts such as sod~um, potassium, ammonium, calcium and magnesium salts and organic salts such as diethylamine, triethylamine, N,N'-dibenzylethylenediamine, diethanolamine, pyrrolidine, morpholine and procaine saltsO
The term "lowerl' used herein in connection with a hydrocarbon moiety, particularly alkyl, is intended to indicate a moiety having not more than 8 carbon atoms.

i~ ~

;"' ' - 3a -preferably not more than 5 carbon atoms, more preferably not more than 3 carbon atoms Typical examples of the term "aryl" are phenyl and naphthyl. The term "halogen" covers chlorine, bromine, iodine and fluorine~
The ~-carbon atom of the penicillin side chain (to which the acyl group is attached) is an asymmetric carbon atom and the compounds {I) can therefor~ exist in two optically active isomeric f~rms (i.e. the D- and L-diastereoisomers) as well as in the DL form which is a mixture of the two opt-lcally active forms. All such isomeric forms of the compounds (I) are lncluded wîthin the scope of the present invention, but the D~-) form is preferred. Also included within the scope of the present invention are esters of the compounds (I) which can be easily hydrolyzed to the corresponding free acids by chemicals or enzymatic hydrolysis.
Compared to the antibacterial activity of the penicillins in the above~mentioned Japanese application, the antibacterial activity of the penicillins (I) is more potent, especially against Escherichia coli, Proteus vulgaris and Klebsiella pneumoniae.
The penicillins (I) exert an e~cellent antibacterial activity against Gram-yositive and Gram-negative bacteria, particularly against Pseudomonas aeruginosa. Thus, they are useful as antibacterial agents, especially in treatment of infections caused by Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.
The reaction between the compound (II) or its -reactive deriva~ive and the compound (III) or its derivative is usually carried out in an inert solvent such as a polar solvent (e.g. dichloromethane, chloroform, acetone, tetra-hydrofuran, dioxane, acetonitrile, methylisobutylketone, ~C)7029S

ethanol, dimcthylformamide, dimethylacetamlde, dimethylsulfo~i~le, sulfonc, hexamethylphosphor-lc tr-lamide or water), a non-po].;lr solvent (e.g. benzene, toluene, petroleum ether or n-hexane) or a mlxture thereof. In some cases, there may be used arl aqueous medium. The reaction temperature is not limitative and is usually below 50 C.
Tbe react~ve derivative (~ubs~ituted on the carboxyl group) of the carboxylic acid (II) may be, for instance, the acid halide, acid anhyd~ide, mixed acid anhydride, acid a~olide, acid a~.ide or active ester~. Examples of acid a~olidcs include those prepared from imidazole, substituted imidazole, dimethylpyrazole, triazole and tetrazole. The active esteræ ~ ~-are exemplified by cyanomethyl ester, p-nitrophellyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonyi ester, l-hydroxy-2(1H)pyridone, N-hydroxysuccinimide and N-hydroxydiphthalimide.
When the carboxylic acid (Il) is used in the form of a ~ree acid, amidation with the compound (III) or its derivative can preferably be carried out in the presence of a coupling reagent such as N,~'-dicyclnhexylcarbodiimide, N-cyclohexyl-N'- -morpholinoethylcarbodiimide, triphenylphosphine, 2-ethyl-5-(m~sulfonyl)-isoxazoliu~ hydroxide inner salt or cnrbonyldilmidazole.
When the mixed acid anhydride is prepared for activatiorl of the carboxylic acid (II), the following procedllre is recommended. Thus, one molar amount of the carboxylic acid (II) is reacted with about 2 moles o a lower alkoxycarbonyl halide (~.~. ethyl chloroformate9 isobutyl chloroformnte) or a lower alkanoyl halide (e.~. pivaloyl chloride) in the presence of about 2 moles of a base to gi~e a mixed acid nnhydrLde of the formula:
Z-0-A-COOZ (IY) -- : - .' : ' ` ' . ~ . , ~7~ ~5 :

whereLn Z is an acyl group and A i9 as defined above. The ;-product of the amidation using such a mixed anhydride is representable by the formula:

Z--O-A-CONH--CH-CONH r ~ ~ CH3 (V~ '' ~ ~ COOH

wherein A, R and Z are each as defined above, which may be ~, converted into the corresponding penicillin (I) by treatment with an organic or inorganic base (e.g. sodium carbonate, potassium carbonate, sodium hydroxide, ammonia water, triethylamine, dimethylamine or potassium 2-ethylhexanoate).
The conversion can be also accomplished under acidic conditions, / ;~
although basic conditions are usually preferred.
A derivative of compound (III) ~lay be, for example, a salt, ester or N-substituted compound thereof. Examples of salts are salts of alkali metals (e.g. sodium and potassium), alkaline earth metals (e.g. calcium and barium), organic bases 5e.g. trimethylamine and triethylamine) and organic sulfonic acids (e.g. toluenesulfonic acid, naphthalenesulfonic acid and tetrahydronaphthalenesulfonic acid). Examples of esters and N-substituted compounds are as follows:

2N fH CONH ~ ~ CH3 R
o~ oosi--R

R213 SiNH-fH-coNH ~ ~ 3 / R

N-fN-CON ~ ~ ~ C~
R N COOSn\ R

70;~9S

CH - CO
Nd N ~ ~ CH3 / \O -COOH
R4 ~5 R-CH - CO
N~l N ~ ~ ~ CCH3 ~-~ \RO COOSi~ R2 H~N-fH-CONH ~ ~ OEI3 O COON=~

wherein R is as defined above, Rl, R2 and R3 are each lower alkyl or lower alkoxy, R4 and R5 are each lower alkyl and R6 is lower alkyl, aryl or a hetero ring.
Further examples of the ester unit in the esters of the compound (III) are toluenesulfonylethyl ester, p-nitrobenzyl ester, benzyl eseer~ phenacyl ester, diphenylmethyl ester, substituted diphenylmethyl ester, trityl ester, : .
benzoyloxymethyl ester, lower alkanoyloxymethyl ester, dimethylmethyleneamino ester, p-nitrophenyl ester, methylsulfonyl- `
phenyl ester, methylthiophenyl ester, t-butyl ester, 3,5-di-t-butyl-4-hydroxybenzyl ester and trichloroethyl ester. These ester units are all conventionally employed in related art fields as groups protecting a carboxylic acid radical.
These esters may be employed in salt form, such as those obtained by the use of;organic sulfonic acids (e.g.
toluenesulfonic acid or tetrahydronaphthalenesulfonic acid).
~fter amidation with the compound (II) or its reactive derivative, the.ester groups can be eliminated using - a per se conventional procedure such as reduction or hydrolysis .

: - 7 ~

-`` 1070~95 ;

under mild conditionP so as not to affect the ,B- lactam ring of the penicillln nucleus.
The following Examples illustrate the lT~vention. ~ ;
Example l Preparation of 6-[D-2-(4-hydroxy-7-methyl-1,8-naphthyridine-3-carbonamido)-~-cyclohexylacetamido]peni-cillanic acid~
0~
~ CONH - C H- CONH ~/~CH 3 N ~ N ~ ~ O ~ COOH
C
To a solution of 2.16 g of 6-aminopenicillanic 0 acid, 2.02 g of triethylamine and 1.33 g of dimethylaniline in 40 ml of dichloromethane was added dropwise 2.16 g of trimethylchlorosilane. After refluxing for 50 minutes, the mixture was cooled to -20C. To this mixture was added 2.33 g of D-~-cyclohexylglycyl chloride hydrochloride, and the mixture was stirred for 1 hour while maintaining the temperature at -20C. After addition of 3.01 g of 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid N- ;
hydroxysuccinimide ester, 2.26 g of triethylamine and 55 ml of dimethylformamide, the mixture was stirred at room temperature for 4 hours. Insolubles were removed bv filtra-tion, ether was added to the filtrate and the precipitated crystals were collected by filtration. The thus obtained crystals were suspended in 100 ml of dichloromethane with stirring, and the suspension was filtered to give 3.5 g o the triethylamine salt of the objective compound.
Example 2 Preparation of 6~[D-2-t4-hydroxy-1,5-naphthyri-dine-3-carbonamido)-2-(1 cyclohexenyl)acetamido]penicil1anic ~L~7~295 acid:-OH
N ~ CONH-CEI-CONH ~ / ~ CH3 ~ o~~~ COOEI
To a solution of 5.07 g of phenacyl 6-[D-2-amino-2-(1-cyclohexenyl)acetamidolpenicillanate hydro-chloride and 2.02 g of triethylamine in 50 ml of dimethyl-formamide was added 3.00 g of 4-hydroxy-1,5-naphthyridine-

3-carboxylic acid N-hydroxysuccinimide ester, and the mix-ture was stirred at room temperature for 3 hours. The reac-tion mixture was poured i~to 250 ml of ice-cooled 1% sodium bicarbonate aqueous solution while stirring. The precipi-tated white crystals were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 5.60 g of phenacyl 5-[D-2-(4-hydroxy-1,5-naphthyridine-3-carbonamido)-2~ cyclohexenyl)acetamido]-penicillanate. The thus obtained phenacyl ester of the ob-jective compound was added to 150 ml of dimethylformamide, 2.3 g of sodium thiophenoxide was added thereto and then ~;
stirring was continued at room temperature for 1 hour. To this mixture was added 500 ml of acetone, and the precipitated solid was collected by filtration and washed with acetone and ether in order to give 4~28 g of the sodium salt of the o~jective compound.
Example 3 Preparation of 6-1D-2-(4-hydrox~-1,5-naphthyri-dine-3-carbonamido)-2-isobutylacetamido~penicillanic acid:-. ::

.
. .. . . ~ , .

295 ;: :
, ~

N ~ ~ CONH-fH-CONH ~ ~ CU3 CH2 N COOH `
/' \

To a cooled solution of 3.29 g of 6-(D-2 amino-2-isobutylacetamido)penicillanic acid and 2.02 g of tri-ethylamine in 60 ml of dichloromethane were added 2.45 g 0~ 4-hydroxy-l,S-naphthyridine-3-car~onyl chloride h~dro-chloride and then 1.01 g of triethylamine with stirring.
The mixture was stirred for 3 hours with cooling in an ice bath and a further 1 hour at room temperature. The pre- -cipitated crystals were collected by filtration, washed With dichloromethane and dried under reduced pressure to gi~e 3.76 g of the triethylamine salt of the objective compound.
- Example 4 Preparation of 6-[~-2-(3-hydroxyauinoxaline-2-carbonamido)-2-(1-cyclohexenyl)acetamido]penicillanic acid~
N COMH-CH-CONH ~ ~ CH3 ~ N ~ OH b ~ N COOH

To a solution of 1.90 g of 3-hydroxy-quinoxaline-2-carboxylic acid in 30 ml of dimethylformamide was added 1.78 g of carbonyldiimida201e, and the mixture was stirred ~t room temperature for 30 minutes. To this r~actlon mixture was added a solution of 4.54 g of 6-[D-2-amino-2-(1-cyclohexenyl)acetamido]penicillanic acid triethyl-amine salt in 30 ml of dichloromethane, and stlrring was ' ~Lal7~295 continued at room temperature for 6 hours. After addi-tion of 3.64 g of 50 ~ n-butanolic solution of potasSium 2-ethylhexanoate followed by ether, the precipitated crystals were collected by filtration, washed with acetone and dissolved i~ water. This aqueous solution was ad-justed to p~I 2 with lN hydrochloric acid while stirring and cooling. The precipitated crystals were collected by filtration, washed well with cold water and dried over phosphorus pentoxide under reduced pressure to give 3.32 g of the objective compound.
Example 5 Preparation of 6-[D-2-(4-hydroxy~1,5-naphthyri-dine-3-carbonamido)-2-(1,4-cyclohexadienyl)acetamido]-penicillanic acid:-OE~
N ~ CON~-fH-CONH ~ / ~ C~3 ~ N ~ ~ ~ N COOH

To 100 ml of dried dimethylformamide, there were added 1.8 g of 6-[D-2-amino-2-(1,4-cyclohexadienyl)acet-amido]penicillanic acid and 0.92 g of triethylamine, and the mixture was stirred at room temperature for a while.
After addition of 1.44 g of powdered 4-hydroxy-1,5-naphthyxidine-3-carboxylic acid N-hydroxysuccinimide ester ~ ;~
and then 20 ml of dimethylformamide, the mixture was stirred at room temperature for 3 hours. The mixture was poured into 1000 ml of acetone to give 1.48 g of the tri-ethylamine salt of the objective compound as precipitated ;

crystals~

~ , 91 ~7~)Z9S

Example 6 Preparation of 6-~D-2-(6-dimethylamino-4-hydroxy-1,5-naphthyridine-3-carbonamido)-2-(1,4-cyclo-hexadienyl)acetamido]penicillanic acid:-OEI
H3C~N ~ ~CONH~fH-CONHn/~CH 3 :
W\ N J ~ ~ N COOE~

To a suspension of 3.49 g of 6-dimethylamino-4-hydroxy-1,5-naphthyridine-3 carboxylic acid and 3 o 03 g of triethylamine in 80 ml o~ dichloromethane cooled to -15 to -20C was added dropwise 3.24 g of ethyl chlorocarbonate, and the mixture was stirred at -15 to-20C for 30 minutes.
A cooled solution of 6.80 g of 6~[D-2-amino-2-(1,4-cvclo-hexadienyl)acetamido~penicillanic acid triethvlamine salt in 40 ml of dichloromethane was added thereto, and the resultant mixture was stirred fox 2 hours. After addition of a solution of 3.40 g of sodium bicarbonate in 200 ml of water, the mixture was shaken with 600 ml of ethyl acetate, . and the aqueous layer was separated. The aqueous layer was adjusted to pH 2 with lN hydrochloric acid while stirring and cooling. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 8.70 g of the ethyl pyrocarbonate derivative o~ the objective compound. This product was dissolved in a mixture of 20 ml of dimethylformamide and 220 ml of acetone. After removal of insolubles by filtration, 5.45 g of 50 ~ n-butanolic solution of potassium 2-ethylhexanoate was - added to the filtrate and stirred. Addition of 500 ml of ether to the mixture resulted in precipitation of crystals, which were collected by filtration, washed with ether and `:

- ~71~1Zg~

dried under xeduced p.ressure to give 8.3 g of the potassium salt of the objective compound.
When determined according to the agar dilution .
method, the penicillins (I) prepared in the above Examples af~orded minimal inhibitory concentrations against specified microorganisms as shown in Table 1.

Table 1 Exam- Minimal inhibitory concentration ~g/ml) ¦ .
Ple No. Staphylo Escheri- Proteus Proteus !Klebsie- Pseudo-coccus chia mirabilis vulgarisllla monas ~ :`
aureus coli GN2425 HV19 lpneumo- aerugi-203P NIHJ niae nosa PCI602 104 : :
_ . i - ~ .
1 1.56 3.13 6.25 0.39 6.25 ~.25 2 0.78 1.56 6.25 0.05 ? 6.25 3.13 3 1.56 3.13 12.5 0.2 12.5 3.13

4 0.78 ~.25 12.5 0.78 12.5 3~13 0.39 1.56 3.13 0.05 > 3.13 1.56 ~ ~

6 ~ _ _ 1.56 1.56 0.05 1.5~ 3.13 ~ :
'~

, . . ,~ . .

.. . .
:~ , - ,~ : ~ . '

Claims (25)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for producing penicillins of the formula:

(I) wherein R represents cyclohexadienyl, cyclohexenyl, cyclohexyl or isobutyl and A represents a quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine or pyridopyrimidine ring optionally substituted with lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylthio, mercapto,.
lower alkoxymethyl, halogen, hydroxyl, cyano, nitro, lower alkylsulfonyl, arylsulfonyl, sulfamoyl, carbamoyl, aryloxy-carbonylamino, acetoacetylamino, lower alkylamino, di(lower)-alkylamino, halo(lower)alkyl, lower alkenyl, aryl, cyclo(lower)-alkyl and/or condensed cyclo(lower)alkylene; esters thereof and their non-toxic pharmaceutically acceptable salts, which comprises reacting a carboxylic acid of the formula:
HO-A-COOH (II) wherein A is as defined above, or a reactive derivative thereof, with a compound of the formula:

(III) wherein R is as defined above, or a derivative thereof, and, if necessary, converting a free acid product to a non-toxic pharmaceutically acceptable salt thereof or vice versa, and, if necessary, hydrolizing an ester to the corresponding free acid.

2. A process according to claim 1 wherein R represents cyclohexenyl, cyclohexyl or isobutyl.

3. A process according to claim 1, wherein the reaction is carried out in an inert solvent.

4. A process according to claim 3, wherein the inert solvent is dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, methylisobutylketone, ethanol, dimethyl-formamide, dimethylacetamide, dimethylsulfoxide, sulfone, hexamethylphosphoric triamide, water, benzene, toluene, petroleum ether or n-hexane, or a mixture of two or more thereof.

5. A process according to claim 1, wherein the reaction is carried out at a temperature below 50°C.

6. A process according to claim l, wherein the reactive derivative of the carboxylic acid is the acid halide, acid anhydride, acid azolide, acid azide or active ester.

7. A process according to claim 1, wherein the derivative of the compound of formula (III) is a salt, ester or N-substituted derivative thereof.

8. A process according to claim 2, wherein ring A represents a naphthyridine ring or a quinoxaline ring.

9. A process according to claim 8, wherein the ring A optionally bears one or more hydroxyl, 1 to 3 carbon atom alkyl or dimethylamine substituents.

10. A process according to claim 1, wherein the objective penicillin is 6-[D-2-(4-hydroxy-1,5-naphthyridine-3-carbonamido)-2-(1-cyclohexenyl)acetamido]penicillanic acid, which comprises reacting 4-Hydroxy-1,5-naphthyridine-3-carboxylic acid or a reactive derivative thereof and 6-[D-2-Amino-2-(1-cyclohexenyl)-acetamido]penicillanic acid or a derivative thereof.

11. A process according to claim 1, wherein the objective penicillin is 6-[D-2-(4-hydroxy-1,5-naphthyridine-3-carbonamido)-2-isobutylacetamido]penicillanic acid, which comprises reacting 4-Hydroxy-1,5-naphthyridine-3-carboxylic acid or a reactive derivative thereof and 6-(D-2-Amino-2-isobutylacetamido)-penicillanic acid or a derivative thereof.

12. A process according to claim 1, wherein the objective penicillin is 6-[D-2-(3-hydroxyquinoxaline-2-carbonamido)-2-(1-cyclohexenyl)acetamido]penicillanic acid, which comprises reacting 3-Hydroxyquinoxaline-2-carboxylic acid or a reactive derivative thereof and 6-[D-2-Amino-2-(1-cyclohexenyl)acetamido]-penicillanic acid or a derivative thereof.

13. A process according to claim 1, wherein the objective penicillin is 6-[D-2-(4-hydroxy-7-methyl-1,8-naphthyridine-3-carbonamido)-2-cyclohexylacetamido]penicillanic acid, which comprises reacting 4-Hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid or a reactive derivative thereof and 6-(D-2-Amino-2-cyclohexylacetamido)penicillanic acid or a derivative thereof.

14. A process according to claim 1, wherein the objective penicillin is6-[D-2-(4-hydroxy-1,5-naphthyridine-3-carbonamido))-2-(1,4-cyclohexadienyl)acetamido]penicillanic acid, which comprises reacting 4-Hydroxy-1,5-naphthyridine-3-carboxylic acid or a reactive derivative thereof and 6-[D-2-Amino-2-(1,4-cyclohexadienyl)acetamido]penicillanic acid or a derivative thereof.

15. A process according to claim 1, wherein the objective penicillin is6-[D-2-(6-dimethylamino-4-hydroxy-1,5-naphthyridine-3-carbonamido)-2-(1,4-cyclohexadienyl)acetamido]penicillanic acid, which comprises reacting 6-Dimethylamino-4-hydroxy-1,5-naphthyridine-3-carboxylic acid or a reactive derivative thereof and6-[D-2-Amino-2-(1,4-cyclohexadienyl)acetamido]penicillanic acid or a derivative thereof.

16. A penicillin of the formula:

(I) wherein R represents cyclohexadienyl, cyclohexenyl, cyclohexyl or isobutyl and A represents a quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine or pyridopyrimidine ring optionally substituted with lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylthio, mercapto, lower alkoxy-methyl, halogen, hydroxyl, cyano, nitro, lower alkylsulfonyl, arylsulfonyl, sulfamoyl, carbamoyl, aryloxycarbonylamino, acetoacetylamino, lower alkylamino, di(lower)alkylamino, halo-(lower)alkyl, lower alkenyl, aryl, cyclo(lower)alkyl and/or condensed cyclo(lower)alkylene; esters thereof, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.

17. A penicillin according to claim 16, wherein A is a naphthyridine ring or a quinoxaline ring, whenever prepared by the process claimed in claim 8, or by an obvious chemical equivalent thereof.

18. A penicillin according to claim 16, wherein the ring optionally bears one or more substituents selected from hydroxyl, alkyl having 1 to 3 carbon atoms and dimethylamino, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.

19. 6-[D-2-(4-Hydroxy-1,5-naphthyridine-3-carbonamido)-2-(1-cyclohexenyl)acetamido]penicillanic acid and its non-toxic, pharmaceutically acceptable salts, whenever prepared by the process claimed in claim 10, or by an obvious chemical equivalent thereof.

20. 6-[D-2-(4-Hydroxy-1,5-naphthyridine-3-carbonamido)-2-isobutylacetamido]penicillanic acid and its non-toxic, pharmaceutically acceptable salts, whenever prepared by the process claimed in claim 11, or by an obvious chemical equivalent thereof.

21. 6-[D-2-(3-Hydroxyquinoxaline-2-carbonamido)-2-(1-cyclohexenyl)acetamido]penicillanic acid and its non-toxic, pharmaceutically acceptable salts, whenever prepared by the process claimed in claim 12, or by an obvious chemical equivalent thereof.

22. 6-[D-2-(4-Hydroxy-7-methyl-1,8-naphthyridine-3-carbonamido)-2-cyclohexylacetamido]penicillanic acid and its non-toxic, pharmaceutically acceptable salts, whenever prepared by the process claimed in claim 13, or by an obvious chemical equivalent thereof.

23. 6-[D-2-(4-Hydroxy-1,5-naphthyridine-3-carbonamido))-2-(1,4-cyclohexadienyl)acetamido]penicillanic acid and its non-toxic, pharmaceutically acceptable salts, whenever prepared by the process claimed in claim 14, or by an obvious chemical equivalent thereof.

24. 6-[D-2-(6-Dimethylamino-4 hydroxy-1,5-naphthyridine-3-carbonamido)-2-(1,4-cyclohexadienyl)acetamido]penicillanic acid and its non-toxic pharmaceutically acceptable salts, whenever prepared by the process claimed in claim 15, or by an obvious chemical equivalent thereof.

25. A penicillin according to claim 16 wherein R
represents cyclohexenyl, cyclohexyl or isobutyl, whenever prepared by a process according to claim 2 or by an obvious chemical equivalent thereof.