Oleandomycin oximes ##STR1## wherein R.sup.1 stands for hydrogen or --CH.sub.3, R.sup.2 stands for --CH.sub.3 or hydrogen or R.sup.1 and R.sup.2 stand together for an epoxide group or for .dbd.CH.sub.2, R.sup.3 stands for --OH, whereas the line stands for a single or a double bond, a process for the preparation thereof and their use in antimicrobial agents.

The present invention relates to oleandomycin oximes, to a process for the 
preparation of oleandomycin oximes and to their use in antimicrobial 
agents. 
Oleandomycin is a 14-membered macrolide antibiotic possessing an activity 
spectrum similar to that of erythromycin. It was described for the first 
time in U.S. Pat. No. 2,757,123. The structural representation of 
oleandomycin shows a 14-membered lactone ring, comprising a keto group in 
C-9 position and bearing two sugar moieties (desosamine in C-5 position; 
and oleandrose in C-3 position) and three --OH groups (cf. formula IIa, 
hereinafter). 
It differs from other polyoxo macrolides by the presence of an exocyclic 
epoxide ring on the C-8 atom. Hitherto, there have been described numerous 
chemical transformations of the above-mentioned functional groups. It has 
been known that the dehydration of the --OH group in position C-11 under 
slightly alkaline conditions results in a double bond between the C-10 and 
C-11 atoms of the aglycone ring, upon formation of the anhydro 
oleandomycin (J. Am. Chem. Soc., 82, 3225, 1960) (cf. formula IIb, 
represented hereinafter). 
It has been known as well (U.S. Pat. No. 4,069,379) that the epoxide group 
may be converted into the methylene group by conducting the reaction with 
CrCl.sub.2 in reaction-inert solvents, yielding a compound of formula IIc 
(represented hereinafter). 
Furtheron, it has been known that the catalytical reduction of the 
exocyclic methylene group in position C-8 yields a mixture of 
8-methyl-oleandomycin anomers of formulae IId and IIe (W. D. Celmer, Pure 
Appl. Chem., 28, 413, 1971). 
The currently most suitable technical and preparative method of preparing 
oximes has been the reacting of aldehydes and ketones with an excess of 
hydroxylamine hydrochloride in the presence of inorganic or organic bases, 
e.g. BaCO.sub.3, NaHCO.sub.3, triethylamine and pyridine, in a solvent 
chosen from alcohols or an excess of an organic base (Methoden der Org. 
Chem., 4.sup.th Ed., Vol. X/4, p. 55). 
Conventional oximation reactions are not applicable to oleandomycin in 
virtue of the known sensitivity of the oleandomycin molecule. The 
performance of the reaction in acidic medium and at elevated temperatures 
results in the breaking up of the epoxide, the elimination of the sugar 
moieties, and the trans-lactonization, whereas an alkaline medium causes 
dehydration. On the other hand, somewhat severe oximation conditions, e.g. 
increased temperature, in some cases increased pressure, strong bases, 
prolonged reaction times are indicated owing to the steric hindrance of 
the C-9 keto group (J. Org. Chem., 28, 1557, 1963). 
There was a need to provide oleandomycin oximes and a process which would 
fulfill all the aforesaid rather contradictory requests and ensure the 
performance of the reaction in the desired position, leaving the remaining 
part of the molecule unaltered. 
The present invention provides oleandomycin oximes of formula I 
##STR2## 
wherein R.sup.1 stands for hydrogen or --CH.sub.3, R.sup.2 stands for 
--CH.sub.3 or hydrogen or R.sup.1 and R.sup.2 stand together for an 
epoxide group or for .dbd.CH.sub.2, R.sup.3 stands for --OH, whereas the 
line stands for a single or a double bond. 
Particular compounds of formula (I) are compounds Ia-Ie: 
##STR3## 
Oleandomycin oximes of formula (I) are deemed to be novel. 
As a further feature of the present invention there is provided a process 
for the preparation of oleandomycin oximes (I), comprising the reaction of 
oleandomycin of formula (II) 
##STR4## 
wherein R.sup.1, R.sup.2, R.sup.3 and the line have the hereinabove 
mentioned meanings, with an excess of hydroxylamine hydrochloride. 
In particular, the compounds (Ia)-(Ie) as cited hereinabove can be obtained 
by reacting compounds (IIa)-(IIe): 
##STR5## 
with an excess of hydroxylamine hydrochloride. 
Said reaction can be carried out with a 4-6 molar excess of hydroxylamine 
hydrochloride, in the presence of an excess of pyridine serving 
additionally as a solvent, in a nitrogen stream, at ambient temperature, 
within of 2-40 hours. 
The completion of the reaction was determined by thin layer chromatography 
(TLC) on silicagel plates 60 F.sub.254 in the following systems: 
A) CHCl.sub.3 /CH.sub.3 OH/conc. NH.sub.4 OH(6:1:0.1) 
B) CH.sub.2 Cl.sub.2 /CH.sub.3 OH/conc. NH.sub.4 OH(90:9:1.5) 
The isolation of the products was performed by extraction with halogenated 
solvents, e.g. chloroform or methylene chloride, within a pH range of 
7.0-8.5, and finally by evaporation of the organic extract to dryness. 
The preparation of 8-methyl-oleandomycin oximes of formulae (Id) and (Ie) 
started from a mixture of 8-methyl-oleandomycin anomers of formulae (IId) 
and (IIe), which was without prior separation directly subjected to the 
oximation reaction. There was obtained a crude product, comprising a 
mixture of anomer oximes of formulae (Id) and (Ie), which was separated by 
chromatography on a silica gel column; elution with a mixture of CH.sub.2 
Cl.sub.2 /CH.sub.3 OH (85:15). 
The antibacterial in vitro activity was evidenced on a series of standard 
and clinically isolated strains. The results are expressed as Minimal 
Inhibitory Concentration (MIC; .mu.g/mL) and represented hereinbelow in 
Tables 1 and 2. 
TABLE 1 
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Antibacterial in vitro activity of 8-methyl-oleandomycin 
oxime (Ie) in comparison with oleandomycin phosphate 
against standard strains 
Minimal Inhibitory Concentrations 
(MIC in .mu.g/mL) 
Test Organism oleandomycin phosphate 
Ie 
______________________________________ 
Staph. aureus 0.4 0.2 
ATCC 6538-P 
Strept. faecalis 
0.8 0.2 
ATCC-8043 
Sarcina lutea 0.2 0.2 
ATCC-9341 
E. coli 25 6.2 
ATCC 10536 
Klebsiella pneum. 
&gt;50 50 
NCTC-10499 
Pseud. aerug. &gt;50 50 
NCTC-10490 
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TABLE 2 
______________________________________ 
Antibacterial in vitro activity of 8-methyl-oleandomycin 
oxime (Ie) in comparison with oleandomycin phosphate 
against clinical isolates 
Minimal Inhibitory Concentrations 
(MIC in .mu.g/mL) 
Test Organism oleandomycin phosphate 
Ie 
______________________________________ 
Staph. aureus 0.8 0.4 
10099 
Staph. saprophyt. 
1.6 1.6 
3947 
Strept. faecalis 
3.1 0.8 
10390 
Staph. aureus 0.8 0.4 
10097 
Strept. pneumoniae 
1.6 0.4 
4050 
H. Influenze -- 0.4 
4028 
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