U.S. patent number RE39,743 [Application Number 10/302,324] was granted by the patent office on 2007-07-24 for 2-halogenated derivatives of 5-0 desosaminyl-erythronolide a, their preparation process and their antibiotic use.
This patent grant is currently assigned to Aventis Pharma S.A.. Invention is credited to Constantin Agouridas, Francois Bretin, Alexis Denis, Claude Fromentin.
United States Patent |
RE39,743 |
Agouridas , et al. |
July 24, 2007 |
2-halogenated derivatives of 5-0 desosaminyl-erythronolide a, their
preparation process and their antibiotic use
Abstract
Novel compounds of the formula ##STR00001## wherein the
substituents are defined as in the application having antibiotic
properties.
Inventors: |
Agouridas; Constantin (Nogent
sur Marne, FR), Bretin; Francois (Ozoir la Ferriere,
FR), Denis; Alexis (Paris, FR), Fromentin;
Claude (Paris, FR) |
Assignee: |
Aventis Pharma S.A. (Paris,
FR)
|
Family
ID: |
26234600 |
Appl.
No.: |
10/302,324 |
Filed: |
November 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
09416022 |
Oct 8, 1999 |
06352983 |
Mar 5, 2002 |
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Foreign Application Priority Data
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Oct 15, 1998 [FR] |
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98 12937 |
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Current U.S.
Class: |
514/220; 536/7.4;
514/375; 540/556; 548/218; 514/29 |
Current CPC
Class: |
C07H
17/08 (20130101); A61P 31/04 (20180101) |
Current International
Class: |
A61K
31/55 (20060101); A61K 31/42 (20060101); C07D
243/00 (20060101); C07D 498/00 (20060101); A61P
31/04 (20060101) |
Field of
Search: |
;540/556 ;548/218
;514/29,220,375 ;536/7.4 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 487 411 |
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May 1992 |
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EP |
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2 742 757 |
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Jun 1997 |
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FR |
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WO 99/21871 |
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May 1999 |
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WO |
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Primary Examiner: Coleman; Brenda
Attorney, Agent or Firm: Gupta; Balaram
Claims
What we claim is:
1. A compound selected from the group consisting of the formula
##STR00019## wherein A is nitrogen or N.fwdarw.O, R.sub.1 and
R.sub.2 are individually selected from the group consisting of
hydrogen and alkyl of 1 to 18 carbon atoms, R is
--(CH.sub.2).sub.mOB, Hal is halogen, m and n are individually an
integer from 1 to 8, B is hydrogen or ##STR00020## or
--(CH.sub.2).sub.n--Ar, Ar is mono- or polycyclic aryl or
heteroaryl, Z is hydrogen or acyl of an organic carboxylic acid of
up to 18 carbon atoms and its non-toxic, pharmaceutically
acceptable acid addition salts.
2. A compound of claim 1 wherein R.sub.1 and R.sub.2 are
hydrogen.
3. A compound of claim 1 wherein A is nitrogen.
4. A compound of claim 1 wherein Hal is fluorine.
5. A compound of claim 1 wherein R is --CH.sub.2OH.
6. A compound of claim 1 which is (3aS, 4R*, 7S*, 9R*, 10R*, 11R*,
13R*, 15R*, 15aR*,
18S*)-4-ethyl-7-fluoro-3a,4,10,11,12,13,15,15a-octahydro-18-(hydroxymethy-
l)-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,4,6-trideoxy-3-(dimethylam-
ino)-.beta.-D-xylo-hexopyranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetr-
adecino[4,3-d]oxazole-2,6,8(7H,9H)-trione.
7. An antibiotic composition comprising an antibiotically effective
amount of a compound of claim 1 and an inert pharmaceutical
carrier.
8. An antibiotic composition comprising an antibiotically effective
amount of a compound of claim 6 and an inert pharmaceutical
carrier.
9. A method of treating bacterial infections in warm-blooded
animals comprising administering to warm-blooded animals in need
thereof an antibiotically effective amount of a compound of claim
1.
10. A method of treating bacterial infections in warm-blooded
animals comprising administering to warm-blooded animals in need
thereof an antibiotically effective amount of a compound of claim
6.
11. A process for the preparation of a compound of claim 1
comprising reacting a compound of the formula ##STR00021## wherein
Hal is halogen and OM is a protected hydroxyl with a compound of
the formula ##STR00022## wherein m is an integer from 1 to 8 to
obtain a compound of the formula ##STR00023## deprotecting the
2'-hydroxyl to obtain a compound of the formula ##STR00024##
reacting the latter with a debenzylating agent to obtain a compound
of the formula ##STR00025## reacting the latter with a cyclization
agent to form a compound of the formula ##STR00026## corresponding
to a compound of Formula I of claim 1 wherein R is
--(CH.sub.2).sub.m--OH and optionally subjecting the latter to an
aralkylating or acylating agent to obtain a compound of formula I
of claim 1 wherein B is --(CH.sub.2).sub.n--Ar or ##STR00027##
12. A compound selected from the group consisting of ##STR00028##
.[.where the substituents are defined as in claim 11.].
.Iadd.wherein m, R.sub.1, R.sub.2, and Hal are as defined in claim
1; and OM is a protected hydroxyl.Iaddend..
Description
SUMMARY OF THE INVENTION
Novel 2-halogenated derivatives of 5-0-desosaminyl-erythronolide A
and their use.
OBJECTS OF THE INVENTION
It is an object of the invention to provide the novel compounds of
formula I and their acid addition salts and a process for their
preparation.
It is another object of the invention to provide novel antibiotic
compositions and a method of treating 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 products of the invention are compounds selected from the
group consisting of a compound of the formula ##STR00002## wherein
A is nitrogen or N.fwdarw.O, R.sub.1 and R.sub.2 are individually
selected from the group consisting of hydrogen and alkyl of 1 to 18
carbons atoms, R is selected from the group consisting of hydrogen
and --(CH.sub.2).sub.mOB, Hal is halogen, m and n are individually
an integer from 1 to 8, B is hydrogen or ##STR00003## Ar is a mono-
or polycyclic aryl or heteroaryl, Z is hydrogen or acyl of an
organic carboxylic acid of up to 18 carbon atoms and its non-toxic,
pharmaceutically acceptable acid addition salts.
Examples of acids for the acid addition salts are acetic acid,
propionic acid, trifluoroacetic acid, maleic acid, tartaric acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
and particularly stearic acid, ethylsuccinic acid or laurylsulfonic
acid.
Examples of alkyl are methyl, ethyl, propyl, isopropyl, n-butyl,
isobutyl, terbutyl, decyl and dodecyl.
Examples of aryl are phenyl or naphthyl and examples of heteroaryl
are thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl,
thiadiazolyl, pyrazolyl or isopyrazolyl, pyridyl, pyrimidyl,
pyridazinyl and pyrazinyl and also indolyl, benzofurannyl,
benzothiazyl and quinolinyl.
Examples of substituents are at least one of hydroxyl, halogen,
--NO.sub.2, --C.ident.N, alkyl, alkenyl or alkynyl, O-alkyl,
O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl and
N-alkyl, N-alkenyl or N-alkynyl of up to 12 carbon atoms optionally
substituted by at least one halogen, ##STR00004## R.sub.a and
R.sub.b individually being hydrogen or alkyl of up to 12 carbon
atoms, ##STR00005## R.sub.3 being alkyl of up to 12 carbon atoms,
or an optionally substituted aryl or heteroaryl radical,
carbocyclic aryl, O-aryl or S-aryl, or heterocyclic aryl, O-aryl or
S-aryl with 5 or 6 members comprising at least one heteroatom,
optionally substituted by one or more of the above
substituents.
Hal is halogen, preferably fluorine or chlorine. When one of the
substituents is halogen, it is preferably fluorine, chlorine or
bromine.
Among the preferred compounds of formula I are those wherein
R.sub.1 and R.sub.2 are hydrogen, those wherein A is nitrogen,
those wherein Hal is fluorine, those wherein R is hydrogen and
those wherein R is --CH.sub.2OH.
The process for the preparation of a compound of formula I
comprises reacting a compound of the formula ##STR00006## wherein
Hal is halogen and OM is a protected hydroxyl with a compound of
the formula ##STR00007## wherein m is an integer from 1 to 8 to
obtain a compound of the formula ##STR00008## deprotecting the
2'-hydroxyl to obtain a compound of the formula ##STR00009##
reacting the latter with a debenzylating agent to obtain a compound
of the formula ##STR00010## reacting the latter with a cyclization
agent to form a compound of the formula ##STR00011## wherein R is
--(CH.sub.2).sub.m--OH and optionally subjecting the latter to
aralkylating or acylating agent to obtain a compound of claim 1
wherein B is --(CH.sub.2).sub.n--Ar or ##STR00012##
The starting compounds of formula II are described in French patent
application 98-04366 filed Apr. 8, 1998 and a detailed description
of the process for the preparation of compounds of formula II
wherein Hal is fluorine is described herein.
The process comprises reacting a compound of the formula
##STR00013## wherein --OZ is --OH or a protected hydroxyl with a
fluorination agent to obtain a compound of the formula ##STR00014##
which is then reacted with carboxyldiimidazole to obtain the
compound of formula II. Other products can be prepared in an
analogous manner.
Preferably, OZ is acetyl or benzoyl and the protected hydroxyl can
be released by methanolysis. The debenzylation may be effected by
hydrogenation such as with palladium on carbon in the presence of
ammonium formate at methanol reflux and cyclization may be effected
at ethanol reflux in the presence of acetic acid. The acylation or
arylation can be carried out by standard procedures.
The compound S of formulae IV, V and VI are novel and are part of
the invention.
In a variation of the process to prepare the compounds of formula
I, a compound of the formula ##STR00015## wherein A, R, R.sub.1 and
R.sub.2 are defined as above and --OM is a protected hydroxyl is
reacted with a halogenation agent to obtain a compound of the
formula ##STR00016## which is optionally reacted with an agent to
free the 2'-hydroxyl to obtain the compound of formula I wherein in
Z is hydrogen and optionally with an esterification agent to obtain
the 2'-acylated compound or with an acid to form the acid addition
salt.
The preferred halogenation agent is bisphenyl sulfonylimide of the
Formula ##STR00017##
The novel antibiotic compositions of the invention are comprised of
an antibiotically effective amount of a compound of formula I and
its non-toxic, pharmaceutically acceptable acid addition salts and
an inert pharmaceutical carrier. The compositions may be in the
form of plain or sugar-coated tablets, gelatin capsules, granules,
suppositories, injectable preparations, ointments, creams,
gels.
Examples of the 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 present 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 .sym.
bacteria such as staphylococcis, streptococcis, pneumococcis and
therefore are useful in the treatment of germ-sensitive infections
and particularly in that of staphylococcia such as staphylococcal
septicaemias, malignant staphylococcia of the face or skin,
pyodermitis, septic or suppurant wounds, boils, anthrax, phlegmons,
erysipelas and acne, staphylococcia such as primitive or
post-influenzal acute angina, bronchopneumonia, pulmonary
suppuration, streptococcia such as acute angina, otitis, sinusitis,
scarlatina, pneumococcia such as pneumonia, bronchitis;
brucellosis, diphtheria, gonococcal infection.
The compositions are also active against infections caused by germs
such as Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae,
Chlamydia, Legionella, Ureaplasma, Toxoplasma, or germs of the
Mycobacterium genus.
The method of treating bacterial infections in warm-blooded animals
comprises administering to a warm-blooded animal an antibiotically
effective amount of a compound of formula I or its acid addition
salt. The compounds can be administered buccally, rectally,
parenterally or by topical application on the skin and mucous
membranes, but the preferred administration route is the buccal
route. The usual effective daily dose is 2 to 15 mg/kg depending on
the method of administration and the active compound.
In the following examples, there are described various 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.
EXAMPLE 1
[3as-(3aR*,4S*,7R*,9S*,10S*,11S*,13S*,15S*,15aS)*]-4-ethyl-7-fluoro-3a,4,1-
0,11,12,13,15,15a-octahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,4-
,6-trideoxy-3-(dimethyl-amino)-.beta.-D-xylo-hexopyranosyl]oxy]-14,1-(nitr-
iloethano)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(9H)-trione
Stage A:
[3aS-(3aR*,4S*,7S*,9S*,10S*,11S*,13S*,15S*,15aS*)]-4-ethyl-3a,4-
,10,11,12,13,15,15a-octahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3-
,4,6-trideoxy-3-(dimethyl-amino)-2-0-(trimethylsilyl)-.beta.-D-xylo-hexopy-
ranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetradecino[4,3-oxazole-2,6,8-
(7H, 9H)-trione
A mixture of 0.9835 g of
[3aS-(3aR*,4S*,7S*,9S*,10S*,11S*,13S*,15S*,15aS*)]-4-ethyl-3a,4,10,11,12,-
13,15,15a-octahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,4,6-tride-
oxy-3-(dimethyl-amino)-.beta.-D-xylo-hexopyranosyl]oxy]-14,1-(nitriloethan-
o)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(7H,9H)-trione (EP
0638585) and 9.8 ml of THF were stirred for 5 minutes and then 105
mg of imidazole and 0.327 ml of hexamethylsilylamine
[(CH.sub.3).sub.3Si].sub.2NH were added. The mixture was stirred
for 5 days during which twice 0.2 eq of 3-pyrazolamine and twice
0.2 eq of hexamethylsilylamine were added followed by drying and
taking up in methylene chloride. 30 ml of a solution of sodium
dihydrogen phosphate were added and the mixture was stirred for 15
minutes followed by decanting. The aqueous phase was extracted with
methylene chloride and the chloromethylenic phases were combined,
dried, filtered and evaporated to obtain 1.2259 g of the desired
product. Stage B:
[3aS-(3aR*,4S*,7S*,9S*,10S*,11S*,13S*,15S*,15aS*)]-4-ethyl-7-fluoro-3a,4,-
10,11,12,13,15,15a-octahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,-
4,6-trideoxy-3-(dimethylamino)-2-0-(trimethylsilyl)-.beta.-D-xylo-hexopyra-
nosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetra-decino[4,3-d]oxazole-2,6,-
8(7H,9H)-trione
A solution of 1.1003 g of the product of Stage A and 11 ml of THF
was cooled to -10.degree. C. and 1.86 ml of potassium terbutylate
in THF were added. The mixture was stirred for 5 minutes and 0.588
g of ##STR00018## were added. The mixture was stirred for 10
minutes at -10.degree. C. and the reaction medium was allowed to
return to ambient temperature. The mixture was stirred at ambient
temperature for 1 hour 30 minutes followed by filtration. The
precipitate was rinsed with ethyl acetate and the filtrate was
concentrated and taken up to 10 ml of ethyl acetate, 10 ml of water
and 5 ml of a 20% aqueous solution of ammonium hydroxide. The
mixture was stirred for 10 minutes followed by decanting, washing
with water and extracting with ethyl acetate. The organic phases
were combined, dried, filtered and evaporated to dryness to obtain
1.1067 g of the desired product. Stage C:
[3aS-(3aR*,4S*,7S*,9S*,10S*,11S*,13S*,15S*,15aS*)]-4-ethyl-7-fluoro-3a,4,-
10,11,12,13,15,15a-octahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,-
4,6-trideoxy-3-(dimethylamino)-.beta.-D-xylo-hexopyranosyl]oxy]-14,1-(nitr-
iloethano)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(9H)-trione
1.13 ml of a solution of tetrabutylammonium fluoride in THF were
added to a solution of 0.55 g of the product of Stage A and 5.5 ml
of THF and the mixture was stirred for 4 hours 30 minutes. The
solvent was evaporated off and the residue was taken up in 5 ml of
ethyl acetate, 5 ml of water and 2 ml of a 20% solution of ammonium
hydroxide. The mixture was stirred for 15 minutes followed by
decanting. The aqueous phase was extracted with ethyl acetate
followed by washing with water. The aqueous phase was re-extracted
and the organic phases were combined, dried, filtered and
evaporated to dryness to obtain 0.4134 g of the desired
product.
EXAMPLE 2
(3aS,4R,7S,9R,10R,11R,13R,15R,15aR,18S)-4-ethyl-7-fluoro-3a,4,10,11,12,13,-
15,15a-octahydro-18-(hydroxymethyl)-11-methoxy-3a,7,9,11,13,15-hexamethyl--
10-[[3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-xylo-hexopyranosyl]oxy]-14,-
1-(nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(7H,
9H)-trione
State A:
11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.-L-
-ribo-hexopyranosyl)oxy]-2-fluoro-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[(2R-
)-1-hydroxy-3-[(phenylmethyl)amino]-2-propyl]imino]-2'-acetoxy
6.7 g of the product of Preparation I were introduced into a
solution of 8.33 g of
(R)-2-amino-3-[(phenyl-methyl)amino]-1-propanol, 67 ml of
acetonitrile and 6.7 ml of water and after the is reaction mixture
was taken to 55.degree., it was maintained at this temperature for
21 hours. The reaction mixture was then poured into a water-ethyl
acetate mixture followed by decanting, extracting with ethyl
acetate, drying, filtering and evaporating to obtain 10.7 g of the
desired product. Stage B:
11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.-L-ribo-hexo-
pyranosyl)oxy]-2-fluoro-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[(2R)-1-hydrox-
y-3-[(phenylmethyl)amino]-2-propyl]imino]-erythromycin
107 ml of methanol were added to 10.7 g of the product of Stage A
and the mixture was stirred for 15 hours at ambient temperature.
The methanol was evaporated off followed by drying to obtain 9.47 g
of crude sought product which was purified by 2 successive
chromatographies eluting with a methylene
chloride/methanol/ammonium hydroxide mixture (96-4-0.4), then
eluting with an ethyl acetate/triethylamine mixture to obtain 2.66
g of the desired product. Stage C:
11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.-L-ribo-hexo-
pyranosyl)oxy]-2-fluoro-6-0-methyl-3-oxo-12,11-[oxycarbonyl[(2R)-1-amino-3-
-hydroxy-2-propyl)imino]]-erythromycin
0.8 g of the product of Stage B, 8 ml of methanol, 315 mg of
ammonium formate and 800 mg of palladium on carbon were mixed
together and the reaction mixture was refluxed for 4 hours and 30
minutes under hydrogen. The reaction medium was allowed to return
to ambient temperature and then was filtered. The filtrate was
concentrated under reduced pressure to obtain 660 mg of product
which was taken up in 20 ml of ethyl acetate followed by pouring
into a 20% solution of ammonium hydroxide. The mixture was stirred
followed by decanting and extracting with ethyl acetate, drying and
filtering to obtain 660 mg of the desired product. Stage D:
3aS,4R,7S,9R,10R,11R,13R,15R,15aR,18S)-4-ethyl-7-fluoro-3a,4,10,-
11,12,13,15,15a-octahydro-18-hydroxymethyl)-11-methoxy-3a,7,9,11,13-15-hex-
amethyl-10-[[3,4,6-tridsexy-3-(dimethylamino)-.beta.-D-xylo-hexopyranosyl]-
oxy]-14,1-(nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(7H,9H-
)-trione
0.3795 g of the product of Stage C, 4 ml of ethanol and 62 .mu.l of
acetic acid were refluxed with stirring for 6 days and then was
allowed to return to ambient temperature, followed by concentrating
under reduced pressure. The residue was taken up in ethyl acetate
and the solution was poured into a 20% solution of ammonium
hydroxide. The mixture was stirred for 15 minutes followed by
decanting, extracting with ethyl acetate, drying, filtering,
rinsing and evaporating to obtain 0.304 g of product which was
purified by chromatography on silica eluting with a
chloroform/isopropanol/ammonium hydroxide mixture (90-10-0.4) to
obtain 88 mg of the desired product.
Preparation 1
12-(oxycarbonylimidazol)-11-deoxy-10,11-didehydro-3-de[-2,6-dideoxy-3-C-me-
thyl-3-0-methyl-.alpha.-L-ribohexopyranosyl)oxy]6-0-methyl-3-oxo-erythromy-
cin 2'-acetoxy 2.alpha.-fluoro
Stage A: 11-deoxy 10,11-dedehydro-3-de[(2,6-dideoxy 3-0-methyl
.alpha.-L-ribohexopyranosyl)oxy]6-0-methyl 3-oxoerythromycin.
A mixture of 8.722 g of
11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-.alpha.-L-ribohexop-
yranosyl)-oxy]-6-0-methyl-3-oxo-erythromycin (EP 596802) 2'-acetate
and 350 ml of anhydrous methanol was stirred for 44 hours. The
reaction medium was evaporated, taken up with methylene chloride
and dried to obtain 8.794 g of the desired product. Stage B:
11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-.alpha.-L-ribohexop-
yranosyl)-oxy]-6-0-methyl-3-oxo-erythromycin-2'-trimethylsilyloxy.
A mixture of 3.08 g of the product of Stage A, 340 mg of imidazole,
32 ml of anhydrous THF and 1.06 ml of hexamethyl-disilylazane was
stirred at ambient temperature for 4 days. The reaction medium was
then evaporated to dryness and the residue was taken up in a
mixture of 60 ml of methylene chloride and 60 ml of a 0.5 M aqueous
solution of sodium acid phosphate. The mixture was stirred for 15
minutes followed by decanting, extracting with is methylene
chloride, drying and evaporating to dryness to obtain 3.345 g of
the desired product. Stage C: 11-deoxy 10,11-didehydro
3-de[(2,6-dideoxy 3-0-methyl
.alpha.-L-ribohexopyranosyl)oxy]6-0-methyl 3-oxo erythromycin
2'-trimethylsilyloxy 2.alpha.-fluoro. p 1.24 ml of a sodium
potassium terbutylate in 0.97M THF was added at -12.degree. C.,
under an argon atmosphere, to a solution of 668 mg of
11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-.alpha.-L-ribohexop-
yranosyl)-oxy]-6-0-methyl-3-oxo-erythromycin-2'-trimethylsilyloxy
and 6.7 ml of anhydrous THF. The mixture was stirred for 5 minutes
and 378 mg of N-fluoro-dibenzenesulfonimide were added followed by
stirring for 10 minutes at -12.degree. C. The mixture was allowed
to return to ambient temperature over 90 minutes. Isolation and
purification operations were carried out to obtain 695 mg of the
desired product. Stage D:
11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.--
L-ribohexopyranosyl)-oxy]-6-0-methyl-3-oxo-erythromycin-2.alpha.-fluoro.
A mixture of 5.476 g of the product of Stage c, 50 ml of THF and
11.2 ml of 1M tetrabutylammonium fluoride in THF was stirred for 3
hours 30 minutes and the solvent was evaporated off. 37 ml of ethyl
acetate, 37 ml of water and 7.5 ml of ammonium hydroxide at 20%
were added and the mixture was stirred for 10 minutes followed by
decanting, extraction with ethyl acetate, drying and filtering. The
filtrate was concentrated to dryness and the product was
chromatographed on silica eluting with an ammoniated
CH.sub.2Cl.sub.2--MeOH mixture 99-1, then 98-2, 97-3, 96-4, 95-5 to
obtain 2.452 g of the desired product. Stage E: 11-deoxy
10,11-didehydro 3-de[(2,6-dideoxy
3-C-methyl-3-O-methyl-.alpha.-L-ribohexopyrasonyl)oxy]6-O-methyl
3-oxo erythromycin 2'-acetoxy 2.alpha.-fluoro.
1.02 g of the product of Stage D, 10 ml of methylene chloride and
241 .mu.l of acetic anhydride were stirred for 3 hours followed by
evaporation. Then, 10 ml of water and 10 ml of ethyl acetate were
added and the reaction medium stood for 1 hour at ambient
temperature with stirring, followed by decanting, drying and
evaporating to obtain 1.01 g of the desired product. Stage F:
12-(oxycarbonylimidazol)-11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-C-m-
ethyl-3-0-methyl-.alpha.-L-ribohexopyranosyl)-oxy]-6-0-methyl-3-oxo-erythr-
omycin-2'-acetoxy-2.alpha.-fluoro.
0.388 g of carbonyldiimidazole and 24 .mu.l of DBU were added at
0.degree. C. to a solution of 1.01 g of the product of Stage E and
10 ml of anhydrous THF and the mixture was stirred at 0.degree. C.
for 19 hours. The THF was evaporated off and 10 ml of water and 10
ml of ethyl acetate were added. The reaction mixture was stirred
for 10 minutes followed by extracting, drying and evaporating to
obtain 0.902 g of the crude sought product which was
chromatographed eluting with an ethyl acetate-triethylamine mixture
96-4 to obtain 0.573 g of the desired product.
EXAMPLE 3
(3aS,4R,7S,9R,10R,11R,13R,15R,15aR,18S)-4-ethyl-7-fluoro-3a,4,10,11,12,13,-
15,15a-octahydro-18-[[[(4-quinoleinyl)carbonyl]oxy]methyl]-11-methoxy-3a,7-
,9,11,13,15-hexamethyl-10-[[3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-xylo-
-hexopyranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxaz-
ole-2,6,8(7H,9H)-trione
Stage A:
(3aS,4R,7S,9R,10R,11R,13R,15R,15aR,18S)-4-ethyl-7-fluoro-3a,4,1-
0,11,12,13,15,15a-octahydro-18-(hydroxymethyl)-11-methoxy-3a,7,9,11,13,15--
hexamethyl-10-[[2-O-acetyl-3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-xylo--
hexopyranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxazo-
le-2,6,8(7H,9H)-trione
299 mg of the product of Example 2, 3 ml of ethyl acetate and 46
.mu.l of acetic anhydride were stirred at ambient temperature for
20 hours and then was poured into a 20% saturated solution of
ammonium hydroxide followed by stirring for 20 minutes, decanting
and extracting with ethyl acetate, drying, filtering and
evaporating to obtain 0.3296 g of the desired product. Stage
B:(3aS,4R,7S,9R,10R,11R,13R,15R,15aR,18S)-4-ethyl-7-fluoro-3a,4,10,11,12,-
13,15,15a-octahydro-18-[[[(4-quinoleinyl)carbonyl]oxy]methyl]-11-methoxy-3-
a,7,9,11,13,15-hexamethyl-10-[[2-O-acetyl-3,4,6-trideoxy-3-(dimethylamino)-
-.beta.-D-xylo-hexopyranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetradec-
ino[4,3-d]oxazole-2,6,8(7H,9H)-trione
A mixture of 180 mg of the product of Stage A, 6 ml of methylene
chloride, 137 .mu.l of TEA, 0.142 g of acid chloride and 33.2 mg of
DMAP was refluxed for 5 hours 30 minutes and the reaction mixture
was then poured into a 10% aqueous solution of ammonium hydroxide
followed by decanting. The organic phase was washed with a
saturated aqueous solution of sodium chloride and the aqueous phase
was extracted with ethyl acetate. The organic phases were combined,
dried, filtered and evaporated to obtain 0.23 g of the crude sought
product which was purified by chromatography on silica eluting with
a chloroform, isopropyl alcohol, ammonium hydroxide mixture
96-4-0,1%. Stage C:
(3aS,4R,7S,9R,10R,11R,13R,15R,15aR,18S)-4-ethyl-7-fluoro-3a,4,10,11,12,13-
,15,15a-octahydro-18-[[[(4-quinoleinyl)carbonyl]oxy]methyl]-11-methoxy-3a,-
7,9,11,13,15-hexamethyl-10-[[3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-xyl-
o-hexopyranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxa-
zole-2,6,8(7H,9H)-trione.
A mixture of 0.135 g of the product of Stage B and 2 ml of methanol
was stirred for 24 hours followed by evaporating to dryness. The
residue was taken up in ethyl acetate and 20 ml of 10% ammonium
hydroxide were added. The mixture was stirred for 10 minutes
followed by decanting, extracting with ethyl acetate, drying,
filtering and evaporating. The residue was taken up in ether,
filtered and dried to obtain the desired product with a rf=0.40
(CHCl.sub.3, MeOH, NH.sub.4OH=96-4-0.4, and with a mass spectrum
MH.sup.+=683.sup.+.
Example of Pharmaceutical Composition
Tablets containing 150 mg of the Product of Example 1 and
sufficient excipient of starch, talc, magnesium stearate for 1 g
tablets.
PHARMACOLOGICAL STUDY
Method of Dilutions in Liquid Medium
A series of tubes were prepared in which the same quantity of
nutritive sterile medium was distributed. Increasing quantities of
the product to be studied were distributed into each tube and then
each tube was seeded with a bacterial strain. After incubation for
twenty-four hours in an oven at 37.degree. C., the growth
inhibition was evaluated by transillumination, which allowed the
minimal inhibitory concentrations (M.I.C.) to be determined,
expressed in micrograms/ml. The following results were obtained:
(reading after 24 hours)
TABLE-US-00001 TABLE 1 Example Example GRAM* bacterial strains 1 3
S. aureus 011UC4 0.150 0.040 S. aureus 011UC4 + 50% serum 0.040
0.040 S. aureus 011GO251 0.600 0.040 S. epidermidis 012GO111 0.300
0.150 S. pyogenes 02A1UC1 0.040 #0.02 S. agalactine 02B1HT1 #0.02
0.02 S. foccolis 02D2UC1 0.040 0.02 S. faccium 02D3HT1 #0.02 0.02
Streptococcus gr. G02GOGR5 0.040 0.02 S. mitis 02MitCB1 0.040 0.02
S. agalactine 02B1S11c 1.200 0.02 S. pneumoriae 032UC1 0.080 0.02
S. pneumoriae 030GR20 #0.02 0.02
Moreover, the product of Example 1 showed a useful activity on the
following Gram bacterial strains: Haemophillus Influenzae 351HT3,
351CB12 and 351CA1.
Various modifications of the products of the invention may be made
without departing from the spirit or scope thereof and it is to be
understood that the invention is intended to be limited only as
defined in the appended claims.
* * * * *