Erythromycin derivatives

All possible stereoisomeric forms and mixtures thereof of a compound of the formula ##STR1## wherein the substituents are as defined in the specification and their non-toxic, pharmaceutically acceptable acid addition salts having antibiotic properties.

OBJECTS OF THE INVENTION 
It is another object of the invention to provide novel compounds of formula 
I and their non-toxic, pharmaceutically acceptable acid addition salts and 
a process for their preparation. 
It is another object of the invention to provide novel antibiotic 
compositions and a novel method of combatting bacterial infections in 
warm-blooded animals. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel compounds of the invention are selected from the group consisting 
of all possible stereoisomeric forms and mixtures thereof of a compound of 
the formula 
##STR2## 
wherein X and Y are hydrogen or together form 
##STR3## 
R is --(CH.sub.2).sub.m -- 
##STR4## 
m is an integer from 0 to 20, n is 0, 1, 2 or 3, A and B are individually 
selected from the group consisting of hydrogen, halogen, alkyl of 1 to 8 
carbon atoms and aryl of 6 to 8 carbon atoms with the double bond geometry 
being E or Z or a mixture of E and Z or A and B form a third bond between 
the carbons to which they are attached, X.sub.A is selected from the group 
consisting of alkyl, alkenyl and alkynyl of 6 to 20 carbon atoms 
optionally interrupted with at least one heteroatom and optionally 
substituted with at least one halogen, cycloalkyl of 3 to 8 carbon atoms 
optionally substituted by a carbocyclic aryl, halogen, --CN, --OR.sub.3, 
COR.sub.4, --COOR.sub.5, --SR.sub.6, --SOR.sub.7, --SO.sub.2 R.sub.8, 
##STR5## 
--OC(Ar).sub.3 and a carbocyclic aryl and heterocyclic aryl optionally 
substituted, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and 
R.sub.9 are individually selected from the group consisting of hydrogen, 
alkyl of 1 to 8 carbon atoms optionally interrupted by at least one 
heteroatom and optionally substituted by at least one halogen, carbocyclic 
and heterocyclic aryl and aralkyl of up to 14 carbon atoms optionally 
substituted with at least one member of the group consisting of free, 
salified, esterified or amidified carboxy, --OH, halogen, --NO.sub.2, --CN 
, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, 
alkenylthio, alkynylthio, --SO-alkyl, --SO-alkenyl, --SO-alkynyl, 
--SO.sub.2 -- alkyl, --SO.sub.2 -alkenyl and --S.sub.2 -alkynyl of up to 
12 carbon atoms, all optionally substituted with at least one halogen, 
carbocyclic and heterocyclic aryl O-aryl and --S-aryl of up to 14 carbon 
atoms, R'.sub.1 and R'.sub.2 are individually selected from the group 
consisting of hydrogen and alkyl of 1 to 12 carbon atoms, R.sub.1 and 
R.sub.2 are individually selected from the group consisting of hydrogen, 
alkyl of 1 to 20 carbon atoms, --COAlk and --COO-Alk, aryl, --CO-aryl, 
--COO-aryl, aralkyl, --CO-aralkyl and --COO-aralkyl of up to 14 carbon 
atoms, Alk is alkyl of 1 to 8 carbon atoms, or R.sub.1 and R.sub.2 
together with the nitrogen to which they are attached form ring of 3 to 8 
members optionally containing a second heteroatom and optionally 
substituted with the above aryl substituents, Ar is a carbocyclic aryl 
optionally substituted with at least one of the above aryl substituents, Z 
is hydrogen or aryl of an organic carboxylic acid of up to 18 carbon atoms 
and their non-toxic, pharmaceutically acid addition salts. 
The compounds of formula I can exist in all their possible stereoisomeric 
forms, as well as their mixtures. The oxime in position 9, for example can 
be of E or Z geometry and includes the E oximes, the Z oximes as well as 
their E+Z mixtures. 
Examples of the acids to form the non-toxic, pharmaceutically acceptable 
acid addition salts are acetic acid, propionic acid, trifluoroacetic acid, 
maleic acid, tartaric acid, methane-sulfonic acid, benzene-sulfonic acid, 
p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic 
acid, sulfuric acid, phosphoric acid and stearic acid. 
When X.sub.A is alkyl of 6 to 20 carbon atoms, it is preferably hexyl, 
heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 
pentadecyl and hexadecyl, as well as their isomers. 
In the definition of the substituents: halogen is preferably fluorine or 
chlorine or bromine, alkyl, alkenyl or alkynyl are preferably methyl, 
ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, 
vinyl, allyl, ethynyl, propynyl or propargyl. Examples of cycloalkyl are 
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
When alkyl is optionally interrupted by one or more heteroatoms, it is 
preferably one or more oxygen atoms. Carbocyclic aryl is preferably phenyl 
or naphthyl. By heterocyclic aryl is meant either a monocyclic heteroaryl 
of 5 or 6 ring members containing one or more heteroatoms, or a condensed 
polycyclic system, each ring containing 5 or 6 ring members and optionally 
one or more heteroatoms. Heterocyclic aryl may contain one or more 
heteroatoms preferably chosen from oxygen, sulfur and nitrogen. 
Examples of monocyclic heteroaryl with 5 members are thienyl, furyl, 
pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or 
isoxazolyl. Examples of monocyclic heteroaryl with 6 members are pyridyl, 
pyrimidinyl, pyridazinyl or pyrazinyl. Examples of condensed polycyclic 
heteroaryl are indolyl, benzofuryl, benzothienyl or quinolinyl, or the 
remainder of a purine base such as adenine. 
The alkyl, alkenyl or alkynyl are preferably methyl, ethyl, propyl, 
isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, 
ethynyl, propynyl, propargyl, cyclobutyl, cyclopentyl or cyclohexyl and 
the carboxylic acid remainder is preferably acetyl, propionyl, butyryl, 
isobutyryl, n-valeryl, iso-valeryl, tert-valeryl or pivalyl. 
Among the preferred compounds of the invention are the compounds of formula 
I in which X and Y are hydrogen, those in which Z is hydrogen, those in 
which R is 
##STR6## 
m and n are 0, and X.sub.A is saturated or unsaturated alkyl of 8 to 16 
carbon atoms optionally substituted by at least one halogen, or cycloalkyl 
of 3 to 6 carbon atoms, for example those in which R is undecyl, dodecyl, 
3,7,11-trimethyl-2,6,10-dodecatrienyl or 3-cyclohexylpropyl, as well as 
their addition salts with acids. 
Other preferred compounds of formula I are those wherein R is 
##STR7## 
in which X.sub.A is phenyl optionally substituted by one of the radicals 
mentioned above as substituents of the aryl radicals, m, n, A and B are as 
defined above and preferably n is 0 or 1, or is an integer of 2 to 6 and 
those in which X.sub.A is phenyl optionally substituted by at least one 
member of the group consisting of halogen, methyl, trifluoromethyl, 
hydroxy, methoxy, phenyl or phenoxy optionally substituted by at least one 
halogen. 
Also preferred are the compounds in which R is --(CH.sub.2).sub.3 Ar, 
--(CH.sub.2).sub.4 --Ar or --CH.sub.2 --CH.dbd.CH--Ar, Ar is optionally 
substituted phenyl, as well as their addition salts with acids and those 
wherein X.sub.A is 
EQU --O--C(C.sub.6 H.sub.5).sub.3 
in which phenyl is optionally substituted by at least one of the 
substituents indicated above as well as their addition salts with acids. 
Among the compounds of the invention, there can also be mentioned the 
compounds of formula I wherein X.sub.A is 
##STR8## 
in which R.sub.1 and R.sub.2 are individually hydrogen or alkyl of up to 
12 carbon atoms and particularly dodecylamino. 
A more particular subject of the invention are the compounds of Examples 1, 
2, 4, 5, 21, 25, 26, 33, 37, 38, 42, 48, 51, 54, 57, 64, 65 and 66. 
The novel antibiotic components of the invention are comprised of an 
antibiotically effective amount of at least one compound of formula I and 
their non-toxic, pharmaceutically acceptable acid addition salts and an 
inert pharmaceutical carrier. The compositions may be in the form of 
tablets, dragees, capsules, granules, suppositories, ointments, creams, 
gels, and injectable solutions or suspension. 
Examples of suitable inert pharmaceutical carriers are talc, gum arabic, 
lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous 
vehicles, fatty substances of animal or vegetable origin, paraffin 
derivatives, glycols, various wetting, dispersing or emulsifying agents 
and preservatives. The compositions can also be in the form of a powder 
intended to be dissolved extemporaneously in an appropriate vehicle, for 
example apyrogenic sterile water. 
The compositions have a very good antibiotic activity on gram positive 
bacteria such as staphylococci, streptococci and pneumococci and therefore 
can be used for the treatment of infections caused by sensitive germs and, 
particularly, staphylococcia such as staphylococcal septicemias, malignant 
staphylococcia of the face or skin, pyodermatitis, septic or suppurating 
wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia 
such as acute primary or post-influenzal angina, bronchopneumonia, 
pulmonary suppuration, streptococcia such as acute anginas, otitis, 
sinusitis, scarlet fever, pneumococcia such as pneumonia, bronchitis; 
brucellosis, diptheria, gonococcal infection. The compositions are also 
active against infections caused by germs such as Haemophilus influenzae, 
Rickettsies, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, 
Toxoplasma, Listeria, Campylobacter and Meningococcus. 
The novel method of the invention for combatting bacterial infections in 
warm-blooded animals comprising administering to warmblooded animals an 
anti-bacterially effective amount of at least one compound of formula I 
and their non-toxic, pharmaceutically acceptable acid addition salts. The 
compounds may be administered rectally, orally or parenterally as well as 
topically to the skin or mucous membrane. The usual useful daily dose is 
0.70 to 4 mg/kg depending on the condition treated, the compound used and 
the method of administration. 
The process for the preparation of the compounds of formula I comprises 
reacting all possible stereoisomers and mixtures thereof of a compound of 
the formula 
##STR9## 
wherein X, Y and Z have the above definitions with a compound of the 
formula 
EQU RCHO III 
wherein R has the above definition to obtain the corresponding compound of 
formula I which is optionally reacted with an esterification agent to 
esterify the 2 '-hydroxyl or with an acid to form the acid addition salt. 
Preferably, the compounds of formulae II and III are reacted in the 
presence of NaBH.sub.3 CN or in the presence of hydrogen and a suitable 
catalyst such as palladium on activated charcoal. The optional 
esterification of the 2'-hydroxyl may be effected with known procedures 
and the salification may be effected with the appropriate acid. 
The compounds of formula II in all their stereoisomeric forms as well as 
their mixtures are described in European Patent Application 0487411. The 
compounds of formula II in which the 9-oxime is of E geometry can be 
obtained by chromatography starting with R+S diastereosiomer mixtures at 
the level of the 3-carbon of the piperidine, or can be obtained by using 
chiral (S) 3-hydroxy piperidine obtained by resolution using as active 
ingredient a chiral acid by the process described in European Patent 
Application 487411 (cf preparation of Example 27). 
The compounds of formula III are known in a general manner and can be 
prepared by the reaction scheme 
EQU RCO.sub.2 H.fwdarw.RCH.sub.2 OH.fwdarw.RCHO 
using standard processes. 
In the following examples, there are described several preferred 
embodiments to illustrate the invention. However, it is to be understood 
that the invention is not intended to be limited to the specific 
embodiments. 
The compounds prepared hereafter are prepared according to one of the 
following 3 general operating methods: In what follows, 3-de 
[(2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribohexopyranosyl)-oxy]-6-O- 
methyl-3-oxo-erythromycin (R) (E) 9-O-(3-piperidinyl)oxime is called 
Product A. 
Operating method 1 
0.5 mM of product A, 0.5 mM of aldehyde were dissolved in 4 ml of methanol 
or 3 ml of methyl cyanide+1 ml of methanol and 0.1 ml of glacial acetic 
acid was added thereto. The mixture was stirred for 5 to 10 minutes and 
0.55 mM of NaBH.sub.3 CN were added all at once. The mixture was stirred 
at ambient temperature for 15 to 60 minutes and then the solution was 
concentrated under reduced pressure. After taking the residue up in 10 ml 
of water and 30 ml of ethyl acetate, the pH was adjusted to about 8 with 
sodium hydroxide, followed by decanting, extracting, washing the aqueous 
phase with 10 ml of ethyl acetate, then washing the organic phases with a 
saturated solution of sodium chloride. After drying over magnesium 
sulfate, the product was purified by chromatographing on silica, eluting 
with mixtures of the following type: ethyl acetate-triethylamine; 
isopropyl ether-triethylamine-methanol; methylene chloride-methanol; 
methylene chloride-methanol-ammonium hydroxide; 
chloroform-methanol-ammonium hydroxide; ethyl acetate-methanol; ethyl 
acetate-methanol-triethylamine to obtain the desired product. 
Operating method 2 
0.4 mM of product A, 0.45 mM of aldehyde were dissolved in 10 ml of 
methanol and 30 .mu.l of glacial acetic acid and 50 mg of palladium on 
activated charcoal were added. The mixture was stirred under 1.5 
atmospheres of hydrogen for 2 to 24 hours. The solution was filtered on 
clarcel, rinsed with 20 ml of methanol and the solution was concentrated. 
Purification was carried out by chromatographing on silica, eluting with 
one of the eluant systems in operating method 1 to obtain the desired 
product. 
Operating method 3 
0.2 mM of product A and 0.3 mM of aldehyde were dissolved in 0.6 ml of 
methyl cyanide and 0.5 ml of a solution of sodium acid phosphate and the 
mixture was stirred for 5 minutes. Then, 30 mg (0.48 mM) of NaBH.sub.3 CN 
were added and the pH was adjusted to approx. 4.5 by adding a hydrochloric 
acid solution dropwise. The reaction was completed in 5 to 60 minutes and 
5 ml of water were added. The pH was adjusted to 8 with sodium hydroxide 
and extraction was carried out with 2.times.10 ml of chloroform. The 
organic phases were dried over magnesium sulfate and purification was 
carried out by chromatographing on silica using one of the eluant systems 
in operating method 1 to obtain the desired product.