U.S. patent application number 09/734162 was filed with the patent office on 2002-03-07 for new derivatives of erythromycin, their preparation process and their use as medicaments.
This patent application is currently assigned to Hoechst Marion Roussel. Invention is credited to Agouridas, Constantin, Denis, Alexis, Fromentin, Claude.
Application Number | 20020028781 09/734162 |
Document ID | / |
Family ID | 9532584 |
Filed Date | 2002-03-07 |
United States Patent
Application |
20020028781 |
Kind Code |
A1 |
Agouridas, Constantin ; et
al. |
March 7, 2002 |
New derivatives of erythromycin, their preparation process and
their use as medicaments
Abstract
A subject of the invention is, as new chemical products, the
compounds of formula (I) 1 in which X represents a hydrogen atom or
a halogen atom and Z represents a hydrogen atom or the remainder of
an acid as well as their addition salts with acids. The compounds
of formula (I) have antibiotic properties.
Inventors: |
Agouridas, Constantin;
(Nogent Sur Marne, FR) ; Denis, Alexis; (Paris,
FR) ; Fromentin, Claude; (Paris, FR) |
Correspondence
Address: |
Charles A. Muserlian
c/o Bierman, Muserlian and Lucas
600 Third Avenue
New York
NY
10016
US
|
Assignee: |
Hoechst Marion Roussel
|
Family ID: |
9532584 |
Appl. No.: |
09/734162 |
Filed: |
December 11, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09734162 |
Dec 11, 2000 |
|
|
|
09433146 |
Nov 3, 1999 |
|
|
|
Current U.S.
Class: |
514/29 ;
536/7.4 |
Current CPC
Class: |
C07D 233/64 20130101;
A61P 31/04 20180101; A61P 31/00 20180101; C07H 17/08 20130101 |
Class at
Publication: |
514/29 ;
536/7.4 |
International
Class: |
A61K 031/7048; C07H
017/08 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 10, 1998 |
FR |
98 14145 |
Claims
1. As new chemical products, the compounds of formula (I) 6in which
X represents a hydrogen atom or a halogen atom and Z represents a
hydrogen atom or the remainder of an acid as well as their addition
salts with acids.
2. The compounds of formula (I) in which X represents a fluorine
atom.
3. The compounds of formula (I) defined in claim 1 or 2 in which Z
represents a hydrogen atom.
4. As a new chemical product defined in claim 1, the following
compound:
11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyr-
anosyl)oxy]6-0-methyl 3-oxo
12,11-[oxycarbonyl[[4-[4-(4-aminophenyl)-1H-im-
idazol-1-yl]-butyl]imino]]-erythromycin.
5. As a new chemical product defined in claim 1, the following
compound:
2-fluoro-11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ri-
bohexopyranosyl)oxy]6-0-methyl 3-oxo
12,11-[oxycarbonyl[[4-[4-(4-aminophen-
yl)-1H-imidazol-1-yl]-butyl]imino]]-erythromycin.
6. Preparation process for the compounds of formula defined in any
one of claims 1 to 5 characterized in compound of formula (II). 7in
which X retains its previous meaning and OM represents the
remainder of an acyl radical is subjected to the action of a
compound of formula (III). 8in order to obtain the corresponding
compound of formula (IA) then if desired the compound,of formula
(IA) is subjected to the action of an agent of the hydroxyl
function in position 2' and/or if appropriate, to the action of an
acid in order form the salt.
7. As a new chemical product, the compound of formula (III) defined
in claim 5.
8. As a medicament, the compounds of formula (I) defined in any one
of claims 1 to 5 as well as their addition salts with
pharmaceutically acceptable acids.
9. The pharmaceutical compositions containing at least one
medicament according to claim 8 as active ingredient.
Description
[0001] The present invention relates to new derivatives of
eryrthromycin, their preparation process and their use as
medicaments.
[0002] A subject of the invention is, as new chemical products, the
compounds of formula (I) 2
[0003] in which X represents a hydrogen atom or a halogen atom and
Z represents a hydrogen atom or the remainder of an acid as well as
their addition salts with acids.
[0004] Among the addition salts with acids, the salts formed with
acetic, propionic, trifluoroacetic, maleic, tartaric,
methanesulphonic, benzenesulphonic, p-toluenesulphonic acids and
particularly stearic, ethylsuccinic or laurylsulphonic acids, can
be mentioned.
[0005] The halogen atom is for example a chlorine or fluorine atom
and preferably a fluorine atom.
[0006] A more particular subject of the invention is the compounds
of formula (I) in which Z represents a hydrogen atom.
[0007] A more particular subject of the invention is the compounds,
the preparation of which is given hereafter in the experimental
part.
[0008] The products of general formula (I) have a very good
antibiotic activity on gram .sup..sym. bacteria such as
staphylococci, streptococci, pneumococci.
[0009] The products are particularly active on strains which are
resistant to erythromycin such as for example Streptococcus
pyogenes and Streptococcus pneumoniae and S. aureus which have an
inducible resistance to erythromycin.
[0010] The compounds of the invention can therefore be used as
medicaments in the treatment of germ-sensitive infections and in
particular, in that of staphylococcia such as staphylococcal
septicaemias, malignant staphylococcia of the face or skin,
pyodermitis, septic or suppurating 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, and
diphtheria. The products of the present invention are also active
against infections caused by germs such as Haemophilus
influenzae
[0011] Therefore a subject of the invention is the compounds of
formula (I) as medicaments.
[0012] More especially a subject of the invention is, as
medicaments, the compounds indicated above as preferred
compounds.
[0013] A subject of the invention is also the pharmaceutical
compositions containing at least one of the medicaments defined
above, as active ingredient.
[0014] These compositions can be administered by buccal, rectal,
parenteral route, or by local route as a topical application on the
skin and mucous membranes, but the preferred administration route
is the buccal or injectable route. They can be solids or liquids
and be presented in the pharmaceutical forms commonly used in human
medicine, such as for example, plain or sugar-coated tablets,
gelatin capsules, granules, suppositories, injectable preparations,
ointments, creams, gels; they are prepared according to the usual
methods. The active ingredient or ingredients can be incorporated
with the excipients usually used in these pharmaceutical
compositions such as 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,
preservatives.
[0015] These compositions can also be presented in the form of a
powder intended to be dissolved extemporaneously in an appropriate
vehicle, for example, apyrogenic sterile water.
[0016] The dose administered is variable according to the affection
treated, the patient in question, the administration route and the
product considered. It can be, for example, comprised between 50 mg
and 3000 mg per day by oral or injectable route for an adult for
the preferred products.
[0017] A subject of the invention is also a preparation process
characterized in that a compound of formula (II): 3
[0018] in which X retains its previous meaning and OM represents
the remainder of an acyl radical is subjected to the action of a
compound of formula (III) 4
[0019] in order to obtain the corresponding compound of formula
(IA) then if desired the compound of formula (IA) is subjected to
the action of an agent of the hydroxyl function in position 2'
and/or if appropriate, to the action of an acid in order to form
the salt.
[0020] the reaction of the compound of formula (II) with the
compound of formula (III) takes place in a solvent such as for
example acetonitrile, dimethylformamide or also tetrahydrofuran,
dimethoxy ethane or dimethylsulphoxide,
[0021] the hydrolysis of the ester function in position 2' is
carried out using methanol or aqueous hydrochloric acid,
[0022] the salification is carried out using acids according to
standard processes.
[0023] The compounds of formula (II) in which X represents a
hydrogen atom, which are used as starting products are described
and claimed in European Patent Application 0 596 802.
[0024] The compounds of formula (II) which are used as starting
products in which X represents a fluorine atom can be prepared as
indicated hereafter in the experimental part.
[0025] Compound III is a new product and is itself a subject of the
present invention.
EXAMPLE 1
[0026]
11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-riboh-
exopyranosyl)oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl-[[4-[4-(4-aminopheny-
l)-1H-imidazol-1-yl]butyl]imino]]-eryrthromycin
[0027] A mixture containing 0.690 g of the product of Preparation
1, 14 ml of THF, 14 ml of isopropanol, 1.41 g of 2'-acetate and
12-[(1H-imidazol-1-yl)carboxylate]of 10,11-didehydro-11-deoxy-3-de
[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl)oxy]-6-0-me-
thyl-3-oxo-erythromycin and 60 .mu.l of DBU is agitated for 48
hours at ambient temperature. The reaction medium is poured into
water, extracted with ethyl acetate, washed with water, dried,
filtered and concentrated. 1.54 g of product is obtained which is
taken up in 15 ml of methanol with 0.015 ml of DBU added to it. The
methanol is driven off under reduced pressure and 1.44 g of product
is obtained which is chromatographed on silica eluting with a
methylene chloride, methanol, ammonium hydroxide mixture 93-7-0.4.
0.84 g of product is obtained which is taken up in ethyl acetate,
water and ammonium hydroxide, followed by extracting, drying,
filtering and concentrating. 0.8 g of product is obtained which is
chromatographed on silica eluting with an ethyl acetate methanol
triethylamine mixture. 0.4 g of product is obtained which is
crystallized from ether, separated and dried. 0.270 g of sought
product is obtained. M.p.=188.about.190.degree. C.
[0028] Mass spectrum MH.sup.+=826.sup.+
[0029] NMR CDCl.sub.3 ppm
1 Number & 'H Number & 'H 1 1' 4.28 (d) 2 3.86 q 2' 3.18
(m) 3 3' 2.45 (m) 4 3.07 (m) 4' 1.24-1.68 (m) 5 4.24 (d) 5' 3.53
(m) 6 5' Me 1.25 (d) 7 1.60-1.82 (m) N (Me).sub.2 2.26 (s) 8 2.60
masked NCH.sub.2 3.64-3.72 (m) 9 CH.sub.2 1.65 (m) 10 3.13 (m)
CH.sub.2 1.85 (m) 11 3.57 (s) CH.sub.2N 3.95 (t) 12 N imidazole
7.10-7.45 13 4.94 (dd) 5 6.70 (d) 7.56 (d) 14 1.54-1.92 (m)
NH.sub.2 13.53 15 0.84 (t) 2Me 1.38 (d) 4Me 1.30 (d) 6Me 1.34, or,
1.48 (s) 8Me 1.17 (d) 10Me 1.00 (d) 12Me 1.34 or 1.48 (s) 60Me 2.63
(s)
Preparation 1
[0030] 4-(4-aminophenyl)-1H-imidazole-1-butanamine
[0031] Stage A: 4-(4-nitrophenyl)-1H-imidazole
[0032] 9.7 g of 2-bromo-1-(4-nitrophenyl)-ethanone and 30 ml of
formamide are agitated for 1 hour at 180.degree. C. The reaction
medium is cooled down and poured into water. The pH of the reaction
medium is adjusted to 1 using a solution of hydrochloric acid and
extracted with ethyl acetate. The aqueous phase has concentrated
ammonium hydroxide added to it, followed by saturating with sodium
chloride and extracting with ethyl acetate. The organic phase is
dried, filtered and concentrated under reduced pressure. 7.09 g of
product is obtained which is impasted in the ethyl ether, separated
and dried. 4.74 g of product is obtained melting at 216-218.degree.
C.
[0033] Stage B:
2-[4-[4-(4-nitrophenyl)-1H-imidazole-1-yl]butyl]-1H-isoind-
ole-1,3(2H)-dione.
[0034] A solution containing 4.7 g of the product of the preceding
stage and 15 ml of DMF is introduced into a mixture containing 1.44
g of sodium hydride and 12.5 ml of DMF. A solution containing 7.05
g of N-(4-bromobutyl)phthalimide and 17.5 ml of DMF is added.
Agitation is carried out for 3 hours at ambient temperature. The
reaction medium is poured into a mixture of water and ice,
extracted with ethyl acetate, washed with water, dried, filtered
and concentrated. 6.77 g of product is obtained which is
chromatographed on silica eluting with an ethyl acetate
triethylamine mixture 95-5. 2.29 g of product is obtained melting
at 170-172.degree. C.
[0035] Stage C:
2-[4-[4-(4-aminophenyl)-1H-imidazole-1-yl]butyl]-1H-isoind-
ole-1,3(2H)-dione.
[0036] A mixture of 2 g of product of the preceding stage, 41 ml of
a methanol, methylene chloride mixture (20.5 ml-20.5 ml) and 200 mg
of 10% palladium on carbon is agitated at ambient temperature under
hydrogen pressure for 3 hours. The reaction medium is filtered,
washed with a methylene chloride methanol mixture 50-50 and
concentrated under reduced pressure. 1.6 g of product is obtained
which is used as it is in the following stage.
[0037] Stage D: 4-(4-aminophenyl)-1H imidazole-1-butanamine
[0038] A mixture containing 1.6 g of product of the preceding
stage, 1.1 ml of hydrazine hydrate and 35.5 cm.sup.3 of absolute
ethanol is taken to reflux for 24 hours. The reaction medium is
cooled down to ambient temperature, filtered, rinsed with ethanol,
concentrated under reduced pressure, taken up in methylene
chloride, filtered and concentrated. 0.71 g of sought product is
obtained.
EXAMPLE 2
[0039]
2-fluoro-11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alph-
a-L-ribohexopyranosyl)oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(4-am-
inophenyl) -1H-imidazol-1-yl]butyl]imino]]-eryrthromycin
[0040] By operating as previously starting with the product of
Preparation 2, the sought product is obtained. TLC: ethyl
acetate/triethylamine 90-10. Rf 0.20
[0041] Preparation 2
[0042] 2'-acetoxy 2.alpha.-fluoro of
12-(oxycarbonylimidazol)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.
[0043] Stage A: 11-deoxy 10,11-didehydro 3-de[(2,6-dideoxy
3-0-methyl .alpha.-L-ribohexopyranosyl) oxy]6-0-methyl 3-oxo
eryrthromycin.
[0044] A mixture of 8.722 g of 2'-acetate of 11-deoxy
10,11-didehydro 3-de[(2,6-dideoxy 3-0-methyl .alpha.
L-ribohexopyranosyl)oxy]6-0-methyl 3-oxo eryrthromycin (EP 596802)
and 350 ml of anhydrous methanol is agitated for 44 hours. 8.794 g
of sought product is obtained.
[0045] Stage B: 2'-trimethylsilyloxy of 11-deoxy 10,11-didehydro
3-de [(2,6-dideoxy 3-0-methyl .alpha.-L-ribohexopyranosyl)oxy]
6-0-methyl 3-oxo eryrthromycin.
[0046] A mixture containing 3.08 g of the product of the preceding
stage, 340 mg of imidazole, 32 ml of THF anhydre and 1.06 ml of
hexamethyl-disilylazane is agitated at ambient temperature for 4
days, followed by evaporating to dryness, taking up in a mixture of
60 ml of methylene chloride and 60 ml of 0.5M sodium acid
phosphate. The reaction mixture is maintained under agitation for
15 minutes, decanted, extracted with methylene chloride, dried and
evaporated to dryness. 3.345 g of sought product is obtained.
[0047] Stage C: 2'-trimethylsilyloxy 2.alpha.-fluoro of 11-deoxy
10,11-didehydro 3- de [(2,6-dideoxy 3-0-methyl
.alpha.-L-ribohexo-pyranos- yl)oxy]6-0-methyl 3-oxo
eryrthromycin.
[0048] 1.24 ml of a solution of potassium terbutylate in THF 0.97M
is added at -12.degree. C. under an argon atmosphere to a solution
containing 668 mg of 2'-trimethylsilyloxy of 11-deoxy
10,11-didehydro 3-de [(2,6-dideoxy 3-0-methyl
.alpha.-L-ribohexopyranosyl)oxy]6-0-methyl 3-oxo eryrthromycin and
6.7 ml of anhydrous THF. The reaction medium is agitated for 5
minutes and 378 mg of N-fluoro dibenzenesulphonimide is added.
Agitation is carried out for 10 minutes at -12.degree. C. and the
reaction medium is left for 1 hour 30 minutes to return to ambient
temperature. Isolation and purification operations are carried out
and 695 mg of sought product is obtained.
[0049] Stage D: 2.alpha.-fluoro of 11-deoxy 10,11-didehydro 3- de
[(2,6-dideoxy 3-0-methyl 3-0-methyl
.alpha.-L-ribohexopyranosyl)oxy] 6-0-methyl 3-oxo eryrthromycin
[0050] A mixture of 5.476 g of the product of the preceding stage,
50 ml of THF and 11.2 ml of 1M tetrabutylammonium fluoride in THF
is agitated for 3 hours 30 minutes. The solvent is evaporated off
and 37 ml of ethyl acetate, 37 ml of water and 7.5 ml of 20%
ammonium hydroxide are added. Agitation is carried out for 10
minutes, followed by decanting, extracting with ethyl acetate,
drying, filtering and concentrating the filtrate to dryness. The
product obtained is 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. 2.452 g of sought product is obtained.
[0051] Stage E: 2'-acetoxy 2.alpha.-fluoro of 11-deoxy
10,11-didehydro 3-de[(2,6-dideoxy 3'-0-methyl
.alpha.-L-ribohexopyranosyl)oxy] 6-0-methyl 3-oxo eryrthromycin
[0052] 1.02 g of the product of Stage D, 10 ml of methylene
chloride and 241 .mu.l of acetic anhydride are maintained under
agitation for 3 hours. After evaporation is carried out, 10 ml of
water and 10 ml of ethyl acetate are added. The reaction medium is
left under agitation for 1 hour at ambient temperature, decanted,
dried and evaporated. 1.01 9 of sought product is obtained.
[0053] Stage F: 2'-acetoxy 2.alpha.-fluoro of
12-(oxycarbonyllimidazol) 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 eryrthromycin
[0054] 0.388 g of carbonyldiimidazole and 24 .mu.l of DBU is added
at 0.degree. C. to a solution containing 1.01 g of the product of
the preceding stage and 10 ml of anhydrous THF. The THF is
evaporated off and 10 ml of water and 10 ml of ethyl acetate are
added. The reaction mixture is maintained under agitation for 10
minutes, extracted, dried and evaporated. 0.902 g of crude sought
product is obtained which is chromatographed eluting with an ethyl
acetate-triethylamine mixture 96-4. 0.573 9 of sought product is
obtained.
Examples of Pharmaceutical Compositions
[0055]
2 Tablets were prepared containing: Product of Example 1 150 mg
Excipient s.q.f. 1 g
[0056]
3 Detail of excipient: starch, talc, magnesium stearate Product of
Example 2 150 mg Excipient s.q.f. 1 g
[0057] Detail of excipient: starch, talc, magnesium stearate
Injectable solutions were also prepared from salif compounds.
Pharmacological Study of the Products
[0058] A--Method of dilutions in liquid medium
[0059] A series of tubes were prepared in which the same quantity
of nutritive sterile medium is distributed. Increasing quantities
of the product to be studied are distributed into each tube, then
each tube is sown with a bacterial strain. After incubation for 24
hours in a heating chamber at 37.degree. C., the growth inhibition
is evaluated by transillumination, which allows the minimal
inhibitory concentrations to be determined, expressed in
micrograms/cm.sup.3. The following results were obtained
4 EX. 1 EX. 2 Streptococcus pyogenes 2.5 0.3 Streptococcus
pneumoniae 1.2 0.150
* * * * *