Esters of amidinepenicillins

Methylacetic esters of amidinepenicillins have a powerful antibacterial effect in relation to a number of pathogenic gram-negative bacterias and to pathogenic strains of Pseudomonas. Their superiority resides in their considerably higher absorpticity in relation to that of the free acids. This invention also includes a method for the preparation of these esters by acting with chloroacetone on salts of the corresponding amidinepenicillanic acids.

This invention relates to new methylacetic esters of amidinepenicillins 
with the general formula 1, wherein R.sub.1 and R.sub.2 are identical or 
different, and denote analkyl with normal or branched chain containing 1-6 
carbon atoms; an alkyl containing 3-6 carbon atoms; a monocyclic or 
bicyclic aryl or aralkyl, preferably phenyl, benzyl, naphthyl, 
diphenylmethyl, phenylethyl, or naphthylmethyl; and an aralken, preferably 
cinnamyl, a cycloalkyl with a heterocyclic system; a heterocyclic system, 
preferably furyl, thienyl, pyrrolidyl, piperidyl, or morpholyl; or R.sub.1 
and R.sub.2 together with nitrogen atom form a system of 
heptamethyleneimine, hexamethyleneimine, piperidine, pyrrolidine, or 
morpholine, non-substituted or substituted with aminoalkyl group or 
azidoalkyl wherein alkyl contains 1-4 carbon atoms. 
The invention relates also to new addition salts of methylacetic esters of 
amidinepenicillins having the general formula 2, wherein R.sub.1 and 
R.sub.2 have the meaning as specified above, and Z denotes a 
pharmaceutically admissible organic acid, preferably tartaric, citric, 
oxalic, p-toluenesulphonic, or ethanedisulphonic-1,2 acid, or an anorganic 
acid, preferably hydrochloric, nitric, sulphuric, or phosphoric acid. 
The specified amidinepenicillins in form of free acids having the general 
formula 3, wherein R.sub.1 and R.sub.2 have the meaning as specified 
above, are featured with very powerful antibacterial effect in relation to 
a number of pathogenic Gram-negative bacteriae, especially in relation to 
pathogenic strains of Escherichia coli, Salmonella, and Shigella (British 
Patent Specifications Nos. 1,293,590; 1,315,560; 1,312,050). Moreover, 
amidinepenicillins in form of free acids with the general formula 3, 
wherein R.sub.1 and R.sub.2 together with the nitrogen atom denote a 
piperidine or hexamethyleneimine system, substituted with aminoalkyl or 
azidoalkyl group, are featured with very powerful antibacterial effect 
also in relation to pathogenic strains of Pseudomonas (Belgian Patent 
Specification No. 856 278). 
Said compounds, however, on administering per os show weak absorptivity, 
what considerably restricts the possibility of employing them in 
therapeutics. 
On the other hand, it has been found that new methylacetic esters of 
amidinepenicillins, having the general formula 1, and addition salts 
thereof, having the general formula 2, manifest an absorptivity 
consideraby higher than that of said amidinepenicillins in form of free 
solids. In the blood and in constitutional liquids said esters undergo to 
rapid hydrolysis to free acids, and being administered per os they give 
both in the serum and in organs maximum levels of antibiotic, higher than 
those on administering equivalent doses of free acids of 
amidinepenicillins. 
To the most active methylacetic esters of amidinepenicillins there belong 
methylacetic esters of 6-/N,N-1', 6'-hexyleneformamidine/-penicillanic 
acid having the general formula 6, and hydrochloride thereof. 
By the way of example there were determined levels of free 
6-/N,N,1',6'-hexyleneformamidine/-penicillanic acid in the blood serum of 
rats on administering per os equivalent doses (in terms of free 
acid):-methylacetic ester of 6-/N,N-1', 
6'-hexyleneformamidine)-pencillanic acid, having the formula 6; 
hydrochloride of methylacetic ester of 6-/N, N-1', 
6'-hexyleneformamidine/-penicillanic acid, or hydrochloride of 
pivaloyl-oxymethyl ester of 6-/N,N-1',6'-hecylaneformamidine/-penicillanic 
acid, introduced today to the therapeutics under the name Pivmecillinam 
(Table 1). From comparison of these data it results that the highest 
levels of free 6-/N, N-1', 6'-hexyleneformamidine/-penicillanic acid in 
the serum of rats is obtained on administering of methylacetic ester of 
6/-N, N-1', 6'-hexyleneformamidine/-penicillanic acid, having the formula 
6. The maximum levels are then over twenty times higher than those on 
administering of equivalent dose of corresponding free acid, and over two 
times higher than those on administering of equivalent dose of 
Pivmecillinam. 
Also comparative mesurement were performed of the levels of 6-/N,N-1', 
6'-hexyleneformamidine/-penicillanic acid in the blood serum, and in 
livers, lungs, and kidneys of rats after administration per os of 
equivalent doses of methylacetic ester having the formula 6 and of 
penicillinic preparation in form of Pivmecillinam. The results of the 
measurements, expressed in .mu.g/ml are specified in Table 2. 
TABLE 1 
__________________________________________________________________________ 
Time 
3 4 5 
Compound 5' 10' 
15' 
30' 
45' 
1 hr 
2 hrs 
hrs 
hrs 
hrs 
6 hrs 
__________________________________________________________________________ 
Methylacetic ester of 
6-N,N-1', 6'-hexylene- 
formamidine/- penicillanic 
acid 29.3 
35.0 
42.7 
21.1 
21.2 
16.9 
4.9 
1.6 
0.8 
0.6 
0.3 
Hydrochloride of methyl- 
acetic ester of 6-/N, 
N1', 6'-hexyleneformami- 
dine/-penicillanic acid 
12.9 
14.3 
16.4 
16.1 
18.9 
14.4 
9.1 
2.1 
1.0 
0.8 
0.1 
Pivmecillinam 
6.3 
12.7 
15.5 
19.2 
16.3 
14.7 
7.9 
2.1 
1.8 
1.5 
1.1 
6-/N,N-1', 6'-hexylene- 
formamidine/- 
penicillanic acid 
0.3 
0.9 
1.7 
1.8 
1.9 
1.9 
1.6 
1.3 
0.8 
0.6 
0.5 
__________________________________________________________________________ 
TABLE 2 
______________________________________ 
Time Preparation 
Kidneys Lungs Liver Serum 
______________________________________ 
15 min. 
A 35.7 20.3 114.1 42.7 
B 9.9 23.1 38.3 42.7 
30 min. 
A 32.2 14.2 78.6 21.2 
B 11.8 5.7 43.6 19.2 
45 min. 
A 34.1 16.5 83.0 21.2 
B 9.8 7.0 50.5 16.3 
1 hr A 33.2 11.8 74.2 16.9 
B 4.7 8.3 37.2 14.7 
2 hrs A 6.7 3.9 38.1 4.9 
B 1.5 4.4 25.6 7.9 
3 hrs A 2.7 1.5 11.3 1.6 
B 0.29 0.76 6.6 2.1 
4 hrs A 0.5 1.2 4.3 0.8 
B 0.27 1.19 8.4 1.8 
6 hrs A 0.3 0.7 1.4 0.3 
B 0.36 0.8 3.1 1.1 
______________________________________ 
A = methylacetic ester of 6/N, N1', 6'- hexyleneformamidine/ penicillanic 
acid 
B = Pivmecillinam 
The presented data prove that after administration of methylacetic ester of 
6-/N, N-1', 6'-hexyleneformamidine/-peniccilinic acid, having the formula 
6, high levels of free acid are obtained both in the blood serum and in 
the investigated organs. Maximum levels are considerably higher than those 
observed after administration of equivalent dose of Pivmecillinam, that is 
in kidneys three times, and in the liver over two times higher. The 
maximum levels in the lungs, instead, on administering equivalent doses of 
both preparations are approximate ones. 
Also after administration per os of dihydrochloride of methylacetic ester 
of 6-{N, N-[3'-(.gamma.-aminopropylo/-1', 
5'-pentyleneformamidine)]}-penicillanic acid the levels of free acid are 
obtained in the serum and in organs of rats, being multiply higher than 
those on administering an equivalent dose of corresponding free acid. 
Moreover, methylacetic esters of amidinepenicillins, having the general 
formula 1, and addition salts, having the formula 2, are featured with 
very low toxicity. For instance the methylacetic ester of 6-(N,N-1', 
6'-hexyleneformamidine)-penicillanic acid, having the formula 6, and 
addition salts thereof, show a toxicity lower than that of Pivascillinam. 
After administration per os of the ester having the formula 6 the value 
LD.sub.50, as determined on mice, amounts to over 3 g/kg of the body 
weight, and LD.sub.50 of the hydrochloride of said ester amounts over 5 
g/kg of the body weight, whereas LD.sub.50 determined under the same 
conditions for Pivascillinam amounts to 2,6 g/kg of the body weight. 
An additional advantage consists therein that said methylacetic ester with 
the formula 6 and hydrochloride thereof, on the contrary to Pivmecillinam, 
show no effect onto the arterial pressure of experimental animals. The 
subject of the invention there are also processes of production of new 
methylacetic esters of amidinepenicillins with the formula 1, wherein 
R.sub.1 and R.sub.2 have the meaning as specified above, and of addition 
salts thereof with pharmaceutically admitted acids having the formula 2. 
Said compounds are produced by acting with chloroacetone onto the salts of 
corresponding amidinepenicillanic acids, having the general formula 3, 
wherein R.sub.1 and R.sub.2 have the meaning as specified above, with 
organic or anorganic bases, for instance onto sodium salts, potassium 
salts, or salts with tertiary amine. As tertiary amine preferably 
triethylamine, N-ethylpiperidine, or N-methylmorpholine. The reaction is 
conducted in a neutral organic solvent, for instance in dimethylformamide, 
dimethyl sulphoide, or dimethyl acetamide. As substrate isolated 
amidinepenicillins are employed, or a reaction mixture containing salts of 
amidinepenicillins. Such mixture can be obtained for instance in results 
of reaction of corresponding salt of 6-aminopenicillanic acid with active 
derivates of amides (British Patent Specification No. 1,417,099). The 
obtained product is isolated from the mixture after the reaction in form 
of free ester or its addition salt with acid. In case of obtaining of free 
ester it can be subsequently converted into addition salt. An advantage of 
this method is a simplicity of chemical operations with simultaneous 
achieving of high product yields. 
The compounds having the general formula 1 and addition salts thereof, with 
the general formula 2, can be also obtained in result of condensation of 
methylacetic ester of 6-amidinepenicillanic acid having the formula 4 with 
corresponding active derivate of N-formylamine having the general formula 
5, wherein R.sub.1 and R.sub.2 have the meaning as specified above, in the 
presence of tertiary amine in an inert organic solvent. The initial 
methylacetic ester of 6-aminepenicillanic acid can be obtained in the 
process disclosed in the British Patent Specification No. 1,164,457. This 
ester is employed in free form or in form of an addition salt with organic 
acid, especially p-toluenesulphonic acid. An active derivate of 
N-formylamine having the general formula 5 constitutes a suitable 
chloroformiminic chloride, a complex with dimethyl sulphate, or acetal. 
Said compounds are known and described in the literature. 
The condensation reaction is conducted in the presence of tertiary amine, 
preferably triethylamine, N-Methylpiperidine, N-ethylpiperidine, or 
N-methylpirolidine. 
As inert organic solvent especially chloroform or methylene chloride are 
used. The obtained product gets isolated from the reaction mixture in form 
of free ester or in form of addition salt with acid. In case of free ester 
it can be subsequently converted into its addition salt. 
An advantage of production of methylacetic esters of amidinepenicillins is 
a considerably lower cost and easier accessibility of the 
substrate/methylacetic ester of 6-aminepenicillanic acid with the formula 
4/, and thus lower cost of the final compound. 
For obtaining addition salts of methylacetic esters of amidinepenicillins 
with the general formula 2 as organic acids there are employed 
advantageously tartaric, citric, exalic, acetic, p-toluenesulphonic, or 
ethanedisulphonic-1,2 acid, and as anorganic acids -hydrochloric, 
sulphuric, nitric, or phosphoric acid. The addition salts are produced in 
the medium of an organic solvent, especially of an alcohol containing 1-5 
carbon atoms, or of ether, for instance diethyl, dipropyl, diisobutyl, or 
dibutyl ether. The obtained salt is then isolated after known methods. 
With respect to interesting pharmacological properties thereof, and 
simplicity of their production, the compounds according to the invention 
can find a broad application in the therapy for controlling the infections 
caused by Gram-negative bacterise.

The methods of obtaining of new methylacetic esters of amidinepenicillins 
and of their addition salts are explained by following examples, which do 
not restrict the scope of the invention. 
EXAMPLE I 
7.52 g/0.02 mole/ of 6-/N,N-1',6'-hexyleneformamidine/-penicillanic acid is 
suspended in 30 ml of dry N,N-dimethylformamide. After cooling down to the 
temperature of 0.degree. C. 2.8 ml /0.02 mole/ of triethylamine are added, 
and under intensive stirring 3.4 ml (0.04 mole) of chloroacetone are added 
drop by drop, whereafter the mixture is stirred for 5 hours at the 
temperature of 0.degree. C. and allowed to stay by night in a 
refrigerator. Then the reaction mixture is poured, under intensive 
stirring, into 400 ml of water with salt at the temperature of 
0.degree.-5.degree. C., brought to the pH-value of 8.0-8.5, the isolated 
deposit is then filtered, washed with cold water (3.times.50 ml) and dried 
above P.sub.2 O.sub.5. There are obtained 6.6 g of raw methylacetic ester 
of 6-/N,N-1', 6'-hexyleneformamidine/-penicillanic acid, what corresponds 
with 86% of theoretical yield. The raw ester is crystallized from n-amyl 
alcohol, resulting in a preparation having the form of white glittering 
needles having the melting point of 79.degree.-80.degree. C. The spectrum 
in infrared shows characteristic bands at 1770 cm.sup.-1 (C.dbd.O 
.beta.-lactam), 1740 and 1720 cm.sup.-1 (C.dbd.O, ester), 1620 cm.sup.-1 
(C.dbd.N). 
In the NMR spectrum, recorded in DMSO at 60 MHz, the following bands are 
observed--(in ppm) 
1.47 s, (3H), 1.59 s (3H), two groups CH.sub.3 at C-2 
1.3-1.7 m, (8H), --(CH.sub.2).sub.4 --from the hexamethyleneimine system. 
2.06 s, (3H), group CH.sub.3 --from CH.sub.3 COCH.sub.2 --3.1-3.4 m, (4H), 
--CH.sub.2 --N--CH.sub.2 --, 
4.18 s, (H), C-3 
4.76 s, (2H) group CH.sub.2 --from CH.sub.3 COCH.sub.2 -- 
4.9 d, (H), C-6, J=4 
5.3 d, (H),C-5,=JH=4 
7.4 s, (H), --N=CH--N--. 
EXAMPLE II 
Conducting the reaction as in Example I, but using an equivalent amount of 
dimethylsulphoxide instead of dimethylformamide, raw methylacetic ester of 
6-/N,N-1',6'-hexyleneformamidine/-penicillanic acid is obtained with a 
yield of 84% of theoretical yield. 
EXAMPLE III 
3.8 g /0.01 mole/ of methylacetic of 
6-/N,N-1',6'-hexyleneformamidine/-penicillanic acid is suspended in 13 ml 
of anhydrous isopropyl alcohol, and at the temperature of 
0.degree.-5.degree. C. in course of 2-3 min there are added drop by drop 4 
ml (0.01 mole) 2.5 n solution of HCl in isopropanol. Then 30 ml of ether 
are added and allowed to stay in a refrigerator for 18 hours. 
The isolated deposit is filtered, washed two times with ether, dried above 
P.sub.2 O.sub.5, and crystallized from anhydrous isopropanol. 
Hydrochloride of the initial ester is obtained in form of white glittering 
needles with a yield amounting to 85% in terms of used ester. 
The infrared spectrum shows characteristic bands at 1780 cm.sup.-1 
(C.dbd.O, .beta.-lactam), 1755, 1730 cm.sup.-1 (C.dbd.O, ester), 1665 
cm.sup.-1 (C.dbd.N). 
In the NMR spectrum recorded in D.sub.2 O at 60 MHz following bands are 
observed (in .delta.ppm): 
1.52 s (3H), 1.76 s (3H), two groups CH.sub.3 at C-2 1.4-2.0 m, (8H), 
--(CH.sub.2 /.sub.4)--from the hexamethylene--imine system 
2.26 s, (3H), group CH.sub.3 --from CH.sub.3 COCH.sub.2 -- 
3.5-4.0 m, (4H), --CH.sub.2 --N--CH.sub.2 -- 
4.15 s, (H), C-3 
5.55 d, (H), C-6, J=4 
5.73 d, (H), C-5, J=4 
8.13 s, (H), --N=CH--N--. 
EXAMPLE IV 
Proceeding similarly as in Example III, but using equivalent amounts of 
sulphuric acid solution, sulphate of methylacetic ester of 
6-/N,N-1',6'-hexyleneformamidine/-penicillanic acid is obtained, with an 
yield of 78%. 
The infrared spectrum shows characteristic bands at 1775 cm.sup.-1 
(C.dbd.O, .beta.-lactam), 1760, 1735 cm.sup.-1 (C.dbd.O, ester), 1665 
cm.sup.-1 (C.dbd.N). 
EXAMPLE V 
Proceeding similarly as in Example III, but using an equivalent amount of 
phosphoric acid solution, phosphate of methylacetic ester of 
6/N,N-1',6'-hexyleneformamidine/-penicillanic acid is obtained with a 
yield of 81%. 
The infrared spectrum shows characteristic bands at 1780 cm.sup.-1 
(C.dbd.O, .beta.-lactam), 1755, 1730 cm.sup.-1 (C.dbd.O, ester), 1670 
cm.sup.-1 (C.dbd.N). 
EXAMPLE VI 
Proceeding similarly as in Example III, but using an equivalent amount of 
the solution of ethanedisulphonic-1,2 acid, ethanedisulphonate-1,2 of 
methylacetic ester of 6-/N,N-1',6'-hexyleneformamidine/-penicillanic acid 
is obtained with a yield of 73%. 
The infrared spectrum shows characteristic bands at 1775 cm.sup.-1 
(C.dbd.O, .beta.-lactam), 1755, 1730 cm.sup.-1 (C.dbd.O, ester), 1675 
cm.sup.-1 (C.dbd.N). 
EXAMPLE VII 
Proceeding similarly as in Example I, but using an equivalent amount of 
6-/N,N-diethylformamidine/-penicillanic acid, methylacetic ester of 
6-/N,N-diethylformamidine/-penicillanic acid is obtained with a yield of 
55%. 
The infrared spectrum shows characteristic bands at 1775 cm.sup.-1 
(C.dbd.O, .beta.-lactam), 1735, 1720 cm.sup.-1 (C.dbd.O, ester), 1625 
cm.sup.-1 (C.dbd.N). 
In the NMR spectrum registered in DMSO at 60 MHz following bands are 
observed (in .delta. ppm): 
1.48 s, (3H), 1.60 s, (3H), two groups CH.sub.3 --at C-2 
1.0-1.7 (multiplet covering the bands of groups CH.sub.3 --at C-2) (6H), 
two groups CH.sub.3 from CH.sub.3 CH.sub.2 NCH.sub.2 CH.sub.3 
3.7-3.9, (4H), two groups CH.sub.2 --from CH.sub.3 CH.sub.2 NCH.sub.2 
CH.sub.3 
4.4 s, (H), C-3 
4.88 s, (2H), group CH.sub.2 --from CH.sub.3 COCH.sub.2 -- 
5.1 d, (H), C-6, J=4 
5.5 d, (H), C-5, J=4 
7.85 s, (H), N=CH--N. 
EXAMPLE VIII 
21.6 g (0.1 mole) of 6-aminopenicillanic acid are suspended in 100 ml of 
methylene chloride, then 32.8 ml (0.23 mole) of triethylamine are added 
and stirred for 1.5 hour at room temperature. Then the mixture is cooled 
down to the temperature of 0.degree.-5.degree. C., and slowly 32 g (0.12 
mole) of a complex of N-formylhexamethyleneimine with dimethyl sulfate are 
added drop by drop and stirred for further 2 hours, increasing the 
temperature gradually up to 20.degree. C. After throrough evaporation of 
the solvent, to the remainder 60 ml of dimethylformamide are added, cooled 
down to 0.degree. C. 16.8 ml (0.2 mole) of chloroacetone are added drop by 
drop, the mixture is stirred 3 hours, and then is allowed to stand for 
further 18 hours at the temperature of 0.degree.-5.degree. C. The reaction 
mixture is dropped into 600 ml of cold brine and stirred for 0.5 hour. The 
isolated deposit of ester, of cream colour, is filtered, and washed with 
cold water and petroleum benzin. After drying in the air there are 
obtained 24 g of methylacetic ester of 
6-/N,N-1',6'-hexyleneformamidine/-penicillanic acid, what makes 63% of 
theoretical yield in terms of 6-aminopenicillanic acid. 
After crystallization from n-amyl alcohol the ester is obtained in form of 
white glittering needles having the melting point of 79.degree.-80.degree. 
C. 
The infrared and NMR spectrum show a good conformity with those of the 
ester obtained after the method specified in example I. 
EXAMPLE IX 
Proceeding similarly as in Example VIII but using an equivalent amount of 
complex of N-formyl-N-methyl-benzylamine with dimethyl sulphate 
methyl-acetic ester of 6-/N-methyl-N-benzyloformamidine/-penicillanic 
acidins obtained with a yield of 58% in terms of 6-aminopenicillanic acid. 
The infrared spectrum shows characteristic bands at 1765 cm.sup.-1 
(C.dbd.O, .beta.-lactam), 1740, 1720 cm.sup.-1 (C.dbd.O, ester), 1625 
cm.sup.-1 (C.dbd.N). 
In the NMR spectrum recorded in DMSO at 60 MHz there are observed the 
following bands (in .delta.ppm): 
1.58 s, (3H), 1.62 s, (3H), two groups CH.sub.3 --at C-2 
2.16 s, (3H) group CH.sub.3 13 from CH.sub.3 COCH.sub.2 -- 
2.76 s, (3H), group CH.sub.3 --from CH.sub.3 N-- 
4.38 s, (H), C-3 
4.45 s, (2H), group CH.sub.2 --from C.sub.6 H.sub.5 CH.sub.2 -- 
4.90 s, (2H), group CH.sub.2 --from CH.sub.3 COCH.sub.2 -- 
5.15 d, (H), C-6, J=4 
5.50 d, (H), C-5, J=4 
7.2-7.6 m, (5H), C.sub.6 H.sub.5 -- 
7.88 s, (H), N=CH--N. 
EXAMPLE X 
Proceeding similarly as in Example VIII, but using an equivalent amount of 
the complex of N-formyl-N-methylcyclohexylamine with dimethyl sulphate 
methyl acetic ester of 6-/N-methyl-N-cyclohexylformamidin/-penicillanic 
acid with a yield of 55% in terms of 6-aminopenicillanic acid. 
The infrared spectrum shows characteristic bands at 1770 cm-.sup.-1 
(C.dbd.O, .beta.-lactam), 1745, 1720 cm.sup.-1 (C.dbd.O, ester), 1625 
cm.sup.-1 (O.dbd.N). 
In the NMR spectrum registered in DMSO at 60 MHz there are observed the 
following characteristic bands (in .delta. ppm): 
1.60 s, (3H), 1.72 s, (3H), two groups CH.sub.3 --at C-2 
1.0-2.0 m, protons of cyclohexyl system 
2.18 s, (3H), group CH.sub.3 --from CH.sub.3 COCH.sub.2 -- 
2.92 s, (3H), group CH.sub.3 --from CH.sub.3 N-- 
3.65 m, (H), CHN--from the cyclohexyl system 
4.48 s, (H), C-3 
4.96 s, (2H), group CH.sub.2 --from CH.sub.3 COCH.sub.2 -- 
5.38 d, (H), C-6, J=4 
5.55 d, (H), C-5, J=4 
8.0 s, (H), N=CH--N 
EXAMPLE XI 
Proceeding similarly as in Example I, but using an equivalent amount of 
6-{N,N-[3'-(.gamma.-azidopropyl)-1',5'-pentyleneformamidine]}-penicillanic 
acid, it is obtained methylacetic ester of 
6-{N,N-[3'-(.gamma.-azidopropyl)-1',5'-pentileneformamidine]}-penicillanic 
acid, with a yield of 65%. 
After reduction with hydrogen, using a palladium catalyst in a acidic 
medium, it is obtained the dihydrochloride of ester methylacetic of 
6-{N,N-[3'-(.gamma.-aminopropyl)-1',5'-pentileneformamidine]}-penicillanic 
acid. 
The infrared spectrum shows characteristic bands at 1770 cm.sup.-1 
(C.dbd.O, .beta.-lactam), 1745, 1715 cm.sup.-1 (C.dbd.O, ester) 1685 
cm.sup.-1 (C.dbd.N). 
In the NMR spectrum recorded in D.sub.2 O at 60 MHz the following 
characteristic bands are observed (in d ppm): 
1.59 s, (3H), 1.75 s, (3H), two groups CH.sub.3 - at C-2 1.0-2.0 m, (9H), 
-CH.sub.2 -CH-CH.sub.2 from the piperidine system and -CH.sub.2 -CH.sub.2 
from the group NH.sub.2 -CH.sub.2 -CH.sub.2 -CH) 2.23 s, (3H), group 
CH.sub.3 - from CH.sub.3 COCH.sub.2 - 2.9-4.1 m, (6H), group CH.sub.2 from 
NH.sub.2 -CH.sub.2 - an -CH.sub.2 -N-CH.sub.2 - 
4.66 s, (H), C-3 5.02 s, (2H), group CH.sub.2 - from CH.sub.3 COCH.sub.2 - 
5.51 d, (H), C-6, J=4 
5.68 d, (H), C-5, J=4 
8.0 s, (H), -N-CH=N-. 
EXAMPLE XII 
8.8 g (0.02 mole) of p-toluenesulphonate of methylacetyl ester of 
6-aminepenicillanic acid are added to 100 ml of chloroform (dry) and after 
cooling down to the temperature of -30.degree. C. a solution of 0.02 mole 
of (N,N-1,6-hexylene/chloroforminiate chloride in 20 ml of chloroform is 
added drop by drop under stirring. Then 8.4 ml (0.06 mole) of 
triethylamine is added and stirred for 2 hours, increasing the temperature 
gradually up to 0.degree. C. The obtained solution is washed two times 
with water, then dried by means of Na.sub.2 SO.sub.4, and thickened. The 
obtained remainder is washed three times with petroleum benzine and dried 
in the air. The raw product is crystallized from n-amyl alcohol, what 
results in obtaining of 4.1 g of pure methylacetyl ester of 
6-/N,N-1',6'-Hexyleneformamidine/-penicillanic acid, what constitutes 
53.9% of theoretical yield. The melting point equals to 
78.degree.-79.degree. C. 
The infrared and NMR spectra show a conformity with these of the ester 
received after the method specified in Example I. 
EXAMPLE XIII 
Proceeding analogically as in Example XII, but using an equivalent amount 
of /N,N-diethyl/-chloroformiminiate chloride methylacetyl ester of 
6/N,N-diethylformamidine/-penicillanic acid is obtained. 
The infrared and NMR spectra show a conformity with these of the ester 
obtained after the method specified in Example VII. 
EXAMPLE XIV 
Proceeding analogically as in Example XII, but using an equivalent amount 
of /N-methyl-N-cyclohexyl/-chloraformiminic chloride methylacetyl ester of 
6-/N-methyl-N-cyclohexylformamidine/-penicillanic acid is obtained. The 
infrared and NMR spectra show a conformity with those of the ester 
obtained after the method specified in Example X. 
EXAMPLE XV 
Proceeding analogically as in Example XII, but using an equivalent amount 
of /N-methyl-N-benzyl/-chloroformiminic chloride methylacetyl ester of 
6-/N-methyl-N-benzylformamidine/-penicillanic acid is obtained. 
The infrared and NMR spectra show a conformity with those of the ester 
obtained after the method specified in Example IX. 
EXAMPLE XVI 
Proceeding analogically as in Example XII, but using an equivalent amount 
of {N,N-[3'-(.gamma.-azidepropyl/-1',5'-pentylene]}-chloroformiminic 
chloride methylacetyl ester of 
6-{N,N-[3'-(.gamma.-azidepropyl)-1',5'-pentyleneformamidine]}-penicillanic 
acid is obtained. 
After reduction with hydrogen, using palladium catalyst in acidic medium, 
dihydrochloride of methylacetyl ester of 
6-N,N-[3'-(.gamma.-aminopropyl)-1', 5'-pentyleneformamidine]-penicillanic 
acid is obtained. 
The infrared and NMR spectra show a conformity with those of the ester 
obtained after the method specified in Example XI. 
##STR1##