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Claims  |
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I claim:
1. A compountd of the formula I or a pharmaceutically acceptable ester of
acid addtion salt thereof:
##STR13##
wherein one of R.sup.1 and R.sup.2 is hydrogen, and the other of R.sup.1
and R.sup.2 is amino unsubstituted or substitued by one or two alkyl
moieties of 1 to 6 carbon atoms, or the other of R.sup.1 and R.sup.2
together with R.sup.5, is a group of the formula III below, or R.sup.1 and
R.sup.2 together are oxo, oxime unsubstituted or substituted by alkyl,
cycloalkyl or alkenyl of up to 6 carbon atoms, phenyl,
hydrocarbon-carbonyl or hydrocarbonoxy-carbonyl wherein the gydrocarbon is
alkyl of up to 6 carabon atoms or phenyl each of which is unsubstituted or
substituted by alkyl of 1 to 6 carbon atoms, heterocyclyl, amino,
alkanoylamino of 1 to 6 carbon atoms, mono-, di- or tri-alkylamino of 1 to
6 carbon atoms in each alkyl moiety, hydroxy, alkoxy of 1 to 6 carbon
atoms, mercapto, sulphamoyl, carbamoyl, amindino, guanidino, nitro,
chloro, bromo, fluoro carboxy or salt or ester thereof, alkanoyloxy of 1
to 6 carbon atoms, arylcarbonyl, heterocyclylcarbonyl or --S(O).sub.n
R.sup.12 wherein n is 0, 1 or 2 and R.sup.12 is alkyl of 1 to 6 carbon
atoms, heterocyclyl or aryl, or an imino; R.sup.3 is carbamoyl or
N-substituted carbamoyl of the formula --O--CO--NH--X--R.sup.15 wherein X
is --CO-- or --SO.sub.2 -- and R.sup.15 is alkyl of 1 to 6 carbon atoms,
haloalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 1 to 6 carbon atoms in
each of the alkoxy and alkyl moieties, phenyl, alkylphenyl of 1 to 6
carbon atoms in the alkyl moiety or halophenyl;
R.sup.4 is hydrogen or hydroxy, and
R.sup.5 is hydroxy, or etherified hydroxy, or R.sup.5 together with R.sup.1
or R.sup.2 is a group of the formula III below as defined above, or
R.sup.4 and R.sup.5 together are a group of the formula II or III:
##STR14##
is which R.sup.A and R.sup.B are the same of different, and each is
hydrogen, phenyl, or alkyl of 1 to 6 carbon atoms, said alkyl being
unsubstituted or substituted by heterocyclyl, amino, alkanoylamino of 1 to
6 carbon atoms, mono-, di-, or tri-alkylamino of 1 to 6 carbon atoms in
each alkyl moiety, hydroxy, alkoxy of 1 to 6 carbon atoms, mercapto,
alkylthio of 1 to 6 carbon atoms, heterocyclylthio, arylthio, sulphamoyl,
carbamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, carboxyl or a
salt or ester thereof, alkanoyloxy of 1 to 6 carbon atoms,
arylcarbonyloxy, heterocyclylcarbonyloxy or acyl;
R.sup.6 is hydrogen, fluorine or hydroxy;
R.sup.7 is hydrogen or methyl;
one of R.sup.8 and R.sup.9 is hydrogen, hydroxy, alkoxy, alkanoyloxy,
amino, substituted amino of the formula XII or XIII:
--NHCOR.sup.16 XII
or
--NHSO.sub.2 R.sup.16 XIII
wherein
R.sup.16 is alkyl of 1 to 6 carbon atoms or phenyl, unsubstituted or
substituted by heterocyclyl, amino, alkanoylamino of 1 to 6 carbon atoms,
mono-, di-, or tri-alkylamino of 1 to 6 carbon atoms in each alkyl moiety,
hydroxy, alkoxy of 1 to 6 carbon atoms, mercapto, alkylthio of 1 to 6
carbon atoms, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino,
guanidino, nitro, chloro, bromo, fluoro, carboxyl or a salt or ester
thereof, alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyloxy,
heterocyclylcarbonyloxy or acyl, or a group of the formula R.sup.C
SO.sub.2 --O--, in which R.sup.C is, alkyl of 1 to 6 carbon atoms, alkenyl
of 2 to 6 carbon atoms, phenyl, nitrophenyl, halophenyl, alkylphenyl of 1
to 6 carbon atoms in the alkyl moiety, benzyl, nitrobenzyl, halobenzyl,
alkylbenzyl of 1 to 6 carbon atoms in the alkyl moiety, phenoxyalkyl of 1
to 6 carbon atoms in the alkyl moiety, nitrophenoxyalkyl of 1 to 6 carbon
atoms in the alkyl moiety, halophenyoxyalkyl of 1 to 6 carbon atoms in the
alkyl moiety, alkylphenoxyalkyl of 1 to 6 carbon atoms in each alkyl
moiety or R.sup.17 --CH.sub.2 --CH.sub.2 --wherein R.sup.17 is amino,
carbamoyl, sulphamoyl, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6
carbon atoms, aryloxy, arylthio, benzyloxy or benzylthio and the other of
R.sup.8 and R.sup.9 is hydrogen, or R.sup.8 and R.sup.9 together are oxo,
oxime or acetyloxime.
2. A compound according to claim 1, wherein R.sup.11 is hydrogen or methyl.
3. A compound according to claim 1, wherein R.sup.4 is hydroxy.
4. A compound according to claim 1 wherein R.sup.7 is methyl.
5. A compound according to claim I wherein R.sup.8 is hydrogen and R.sup.9
is hydroxy.
6. A compound according to claim 1, wherein R.sup.5 is hydroxy.
7. A compound according to claim 1, wherein R.sup.5 is alkoxy of 1 to 6
carbon atoms or a group of the formula IX or X:
##STR15##
in which formulae Q is one of the following groups:
##STR16##
R.sup.D is alkyl, R.sup.E is hydrogen or alkyl of 1 to 6 carbon atoms,
R.sup.F is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms,
cycloalkyl of 3 to 7 carbon atoms or phenyl each of which is unsubstituted
or substituted by heterocyclyl, amino, alkanoylamino of 1 to 6 carbon
atoms, mono-, di-, or tri-alkylamino of 1 to 6 carbon atoms, in each alkyl
moiety, hydroxy, alkoxy of 1 to 6 carbon atoms mercapto, alkylthio of 1 to
6 carbon atoms, heterocyclylthio, arylthio, sulphamoyl, carbamoyl,
amidino, guanidino, nitro, chloro, bromo, fluoro, carboxyl or a salt or
ester thereof, alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyloxy,
heterocyclylcarbonyloxy or acyl;
R.sup.G is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon
atoms, aryl, aryloxy, cycloalkyl of 3 to 7 carbon atoms or cycloalkyloxy
of 3 to 7 carbon atoms unsubstituted or substituted by hydroxy, halo,
carboxy, alkoxy of 1 to 6 carbon atoms, aryloxy, formyl, acyloxy,
alkoxycarbonyl of 1 to 6 carbon atoms in the alkyl moiety,
alkanesulphonyloxy of 1 to 6 carbon atoms in the alkane moiety,
trialkylsilyloxy of 1 to 6 carbon atoms in each alkyl moiety, amino,
N-alkylamino or N, N-dialkylamino of 1 to 6 carbon atoms in each alkyl
moity, oxo, azido, diazo or heterocyclyl, each of R.sup.H and R.sup.J, is
the same or different, and each is hydrogen or alkyl of up to 6 carbon
atoms, cycloalkyl of 3 to 7 carbon atoms or phenyl each of which is
unsubstituted or substituted by alkyl of 1 to 6 carbon atoms,
heterocyclyl, amino, alkanoylamino of 1 to 6 carbon atoms, mono-, di-, or
tri-alkylamino of 1 to 6 carbon atoms in each alkyl moiety, hydroxy,
alkoxy of 1 to 6 carbon atoms, mercapto, sulphamoyl, carbamoyl, amidino,
guanidino, nitro, chloro, bromo, fluoro, carboxy or salt or ester thereof,
alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyl, heterocyclylcarbonyl or
-S(0).sub.n R.sup.12 wherein n is 0, 1 or 2 and R.sup.12 is alkyl of 1 to
6 carbon atoms, heterocyclyl or aryl, or any two of R.sup.F, R.sup.G,
R.sup.H and R.sup.J together form a 4- to 7-membered heterocyclic ring
together with the intervening atoms of the molecule.
8. The compound according to claim 1, which is
(i) erythromycin A 6-carbamate 9-oxime;
(ii) erythromycin A 6-carbamate 9-oxime 11, 12-carbonate;
(iii) erythromycin A 6-carbamate;
(iv) erythromycin A 6,11-dicarbamate 9-methoxime;
(v) erythromycin A 6-carbamate 9-methoxime 11,12-carbonate;
(vi) erythromycin A 6-carbamate 9-imine;
(vii) erythromycylamine 6-carbamate;
(viii) erythromycin A 6-carbamate 11,12-carbonate;
(ix) erythromycin A 6-carbamate 9-methoxime;
(x) erythromycin A 6, 12-dicarbamate 9-methoxime 11-formate;
(xi) erythromycin A 6-carbonate 9-(2-methoxyethoxymethoxime);
(xii) erythromycin A 6-benzoylcarbamate 9-oxime;
(xiii) erythromycin A 6-benzoylcarbamate 9-oxime 11,12-carbonate;
(xiv) erythromycin A 6-benzoylcarbamate 9-methoxime 11,12-carbonate;
(xv) erythromycin A 6-benzoylcarbamate 9-methoxime;
(xvi) erythromycin A 6, 12-bis-acetylcarbamate 9-methoxime 11-formate;
(xvii) erythromycin A 6-acetylcarbamate 9-methoxime 11,12-carbonate;
(xviii) 9-dihydro-9, 11-ethylidene-erythromycin A 6-carbamate;
(xix) erythromycin A 6-methoxyacetylcarbamate 9-methoxime 11,4"-diformate;
(xx) erythromycin A 6,12-methoxyacetylcarbamate 9-methtoxime
11,4"-diformate;
(xxi) erythromycin A 6-p-toluenesulphonylcarbamate 9-methoxime
11,4"-diformate;
(xxii) erythromycin A 6,12-bis-p-toluenesulphonylcarbamate 9-methoxime 11,
4"-diformate;
(xxiii) 11-O-(2-hydroxyethoxymethyl)-erythromycin A 6-carbamate 9-oxime;
(xxiv) 11-O-(2-hydroxyethoxymethyl)-erythromycin A 6,12-dicarbamate
9-oxmine;
(xxv) 11-O-(2-N,N-dimethylaminoethoxymethyl)-erythromycin A 6-carbamate
9-oxime;
(xxvi) 11-O-(2-N,N-dimethylaminoethoxymethyl)-erythromycin A 6-carbamate;
(xxvii) 11-O-ethoxymethyl-erythromycin A 6-carbamate 9-oxime;
(xxviii) 11-O-ethoxymethyl-erythromycin A 6,12-dicarbamate 9-oxime;
(xxix) 11-O-ethoxymethyl-erythromycin A 6-carbamate 9-methoxime; or
(xxx) erythromycin A 6-p-toluenesulphonylcarbamate 9-methoxime; or a
pharmaceutically acceptable ester or acid addition salt thereof.
9. A pharmaceutical composition useful for treating bacterial infections in
humans and animals which comprises an antibacterially effective amount of
the compound of the formula I or a pharmaceutically acceptable ester or
acid addition salt thereof:
##STR17##
wherein one of R.sup.1 and R.sup.2 is hydrogen, and the other of R.sup.1
and R.sup.2 is amino unsubstituted or substituted by one or two alkyl
moieties of 1 to 6 carbon atoms, or the other of R.sup.1 and R.sup.2,
together with R.sup.5, is a group of the formula III below, or R.sup.1 and
R.sup.2 together are oxo, oxime unsubstituted or substituted by alky,
cycloalkyl or alkenyl of up to 6 carbon atoms, phenyl,
hydrocarbon-carbonyl or hydrocarbonoxy-carbonyl wherein the hydrocarbon is
alkyl of up to 6 carbon atoms or phenyl each of which is unsubstituted or
substituted by alkyl of 1 to 6 carbon atoms, heterocyclyl, amino,
alkanoylamino of 1 to 6 carbon atoms, mono-, di- or trialkylamino of 1 to
6 carbon atoms in each alkyl moiety, hydroxy, alkoxy of 1 to 6 carbon
atoms, mercapto, sulphamoyl, carbamoyl, amidino, guanidino, nitro, chloro,
bromo, fluoro, carboxy or salt or ester thereof, alkanoyloxy of 1 to 6
carbon atoms, arylcarbonyl, heterocyclylcarbonyl or -S(0).sub.n R.sup.12
wherein n is 0, 1 or 2 and R.sup.12 is alkyl of 1 to 6 carbon atoms,
heterocyclyl or aryl, or an imino; R.sup.3 is carbamoyl or N-substituted
carbamoyl of the formula --O--CO--NH--X--R.sup.15 wherein X is --CO-- or
--SO.sub.2 and R.sup.15 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to
6 carbon atoms, alkoxyalkyl of 1 to 6 carbon atoms in each of the alkoxy
and alkyl moieties, phenyl, alkylphenyl of 1 to 6 carbon atoms in the
alkyl moiety or halophenyl;
R.sup.4 is hydrogen or hydroxy, and
R.sup.5 is hydroxy, or etherified hydroxy, or R.sup.5 together with R.sup.1
or
R.sup.2 is a group of the formula III below as defined above, or
R.sup.4 and R.sup.5 together are a group of the formula II or III:
##STR18##
in which R.sup.A and R.sup.B are the same or different, and each is
hydrogen, phenyl, or alkyl of 1 to 6 carbon atoms, said alkyl being
unsubstituted or substituted by heterocyclyl, amino, alkanoylamino of 1 to
6 carbon atoms, mono-, di-, or tri-alkylamino of 1 to 6 carbon atoms in
each alkyl moiety, hydroxy, alkoxy of 1 to 6 carbon atoms, mercapto,
alkylthio of 1 to 6 carbon atoms, heterocyclylthio, arylthio, sulphamoyl,
carbamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, carboxyl or a
salt or ester thereof, alkanoyloxy of 1 to 6 carbon atoms,
arylcarbonyloxy, heterocyclylcarbonyloxy or acyl;
R.sup.6 is hydrogen, fluorine or hydroxy;
R.sup.7 is hydrogen or methyl;
one of R.sup.8 and R.sup.9 is hydrogen, hydroxy, alkoxy, alkanoyloxy,
amino, substituted amino of the formula XII or XIII:
--NHCOR.sup.16 XII
or
--NHSO.sub.2 R.sup.16 XIII
wherein
R.sup.16 is alkyl of 1 to 6 carbon atoms or phenyl, unsubstituted or
substituted by heterocyclyl, amino, alkanoylamino of 1 to 6 carbon atoms,
mono-, di-, or tri-alkylamino of 1 to 6 carbon atoms in each alkyl moiety,
hydroxy, alkoxy of 1 to 6 carbon atoms, mercapto, alkylthio of 1 to 6
carbon atoms, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino,
guanidino, nitro, chloro, bromo, fluoro, carboxyl or a salt or ester
thereof, alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyloxy,
heterocyclylcarbonyloxy or acyl, or a group of the formula R.sup.C
SO.sub.2 --O--, in which R.sup.C is, alkyl of 1 to 6 carbon atoms, alkenyl
of 2 to 6 carbon atoms, phenyl, nitrophenyl, halophenyl, alkylphenyl of 1
to 6 carbon atoms in the alkyl moiety, benzyl, nitrobenzyl, halobenzyl,
alkylbenzyl of 1 to 6 carbon atoms in the alkyl moiety, phenoxyalkyl of 1
to 6 carbon atoms in the alkyl moiety, nitrophenoxyalkyl of 1 to 6 carbon
atoms in the alkyl moiety, halophenyoxyalkyl of 1 to 6 carbon atoms in the
alkyl moiety, alkylphenoxyalkyl of 1 to 6 carbon atoms in the alkyl moiety
or R.sup.17 --CH.sub.2 --CH.sub.2 -- wherein R.sup.17 is amino, carbamoyl,
sulphamoyl, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon
atoms, aryloxy, arylthio, benzyloxy or benzylthio and the other of R.sup.8
and R.sup.9 is hydrogen, or R.sup.8 and R.sup.9 together are oxo, oxime or
acetyloxime, in combination with a pharmaceutically acceptable carrier.
10. A composition according to claim 9, wherein R.sup.11 is hydrogen or
methyl.
11. A composition according to claim 9, wherein R.sup.4 is hydroxy.
12. A composition according to claim 9 wherein R.sup.7 is methyl.
13. A composition according to claim 9 wherein R.sup.8 is hydrogen and
R.sup.9 is hydroxy.
14. A composition according to claim 9, wherein R.sup.5 is hydroxy.
15. A composition according to claim 9, wherein R.sup.5 is alkoxy of 1 to 6
carbon atoms or a group of the formula IX or X:
##STR19##
in which formulae Q is one of the following groups:
##STR20##
R.sup.D is alkyl, R.sup.E is hydrogen or alkyl of 1 to 6 carbon atoms,
R.sup.F is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms,
cycloalkyl of 3 to 7 carbon atoms or phenyl each of which is unsubstituted
or substituted by heterocyclyl, amino, alkanoylamino of 1 to 6 carbon
atoms, mon-, di-, or tri-alkylamino or 1 to 6 carbon atoms in each alkyl
moiety, hydroxy, alkoxy of 1 to 6 carbon atoms, mercapato, alkylthio of 1
to 6 carbon atoms, heterocyclylthio, arylthio, sulphamoyl, carbamoyl,
amidino, guanidino, nitro, chloro, bromo, fluoro, carboxyl or a salt or
ester thereof, alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyloxy,
heterocyclylcarbonyloxy or acyl;
R.sup.G is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon
atoms, aryl, aryloxy, cycloalkyl of 3 to 7 carbon atoms or cycloalkyloxy
of 3 to 7 carbon atoms unsubstituted or substituted by hydroxy, halo,
carboxy, alkoxy of 1 to 6 carbon atoms, aryloxy, formyl, acyloxy,
alkoxycarbonyl of 1 to 6 carbon atoms in the alkyl moiety,
alkanesulphonyloxy of 1 to 6 carbon atoms in the alkane moiety,
trialkylsilyloxy of 1 to 6 carbon atoms in each alkyl moiety, amino,
N-alkylamino or N,N-dialkylamino of 1 to 6 carbon atoms in each alkyl
moiety, oxo, azido, diazo or heterocyclyl, each of R.sup.H and R.sup.J, is
the same or different, and each is hydrogen or alkyl of up to 6 carbon
atoms, cycloalkyl of 3 to 7 carbon atoms or phenyl each of which is
unsubstituted or substituted by alkyl of 1 to 6 carbon atoms,
heterocyclyl, amino, alkanoylamino of 1 to 6 carbon atoms, mono-, di- or
tri-alkylamino of 1 to 6 carbon atoms in each alkyl moiety, hydroxy,
alkoxy of 1 to 6 carbon atoms, mercapto, sulphamoyl, carbamoyl, amidino,
guanidino, nitro, chloro, bromo, fluoro, carboxy or salt or ester thereof,
alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyl, heterocyclylcarbonyl or
--S(0).sub.n R.sup.12 wherein n is 0, 1 or 2 and R.sup.12 is alkyl of 1 to
6 carbon atoms, heterocyclyl or aryl, or any two of R.sup.F, R.sup.G,
R.sup.H and R.sup.J together form a 4- to 7-membered heterocyclic ring
together with the intervening atoms of the molecule.
16. The composition according to claim 9, wherein the compound of formula I
is
(i) erythromycin A 6-carbamate 9-oxime;
(ii) erythromycin A 6-carbamate 9-oxime 11, 12-carbonate;
(iii) erythromycin A 6-carbamate;
(iv) erythromycin A 6,11-dicarbamate 9-methoxime;
(v) erythromycin A 6-carbamate 9-methoxime 11,12-carbonate;
(vi) erythromycin A 6-carbamate 9-imine;
(vii) erythromycylamine 6-carbamate,
(viii) erythromycin A 6-carbamate 11,12-carbonate;
(ix) erythromycin A 6-carbamate 9-methoxime;
(x) erythromycin A 6,12-dicarbamate 9-methoxime 11-formate;
(xi) erythromycin A 6-carbamate 9-(2-methoxyethoxymethoxime);
(xii) erythromycin A 6-benzoylcarbamate 9-oxime;
(xiii) erythromycin A 6-benzoylcarbamate 9-oxime 11,12-carbonate;
(xiv) erythromycin A 6-benzoylcarbamate 9-methoxime 11,12-carbonate;
(xv) erythromycin A 6-benzoylcarbamate 9-methoxime;
(xvi) erythromycin A 6,12-bis-acetylcarbamate 9-methoxime 11-formate;
(xvii) erythromycin A 6-acetylcarbamate 9-methoxime 11,12-carbonate;
(xviii) 9-dihydro-9, 11-ethylidene-erythromycin A 6-carbamate;
(xix) erythromycin A 6-methoxyacetylcarbamate 9-methoxime 11, 4"
-diformate;
(xx) erythromycin A 6,12-methoxyacetylcarbamate 9-methoxime
11,4"-diformate;
(xxi) erythromycin A 6-p-toluenesulphonylcarbamate 9-methoxime
11,4"-diformate;
(xxii) erythromycin A 6,12-bis-p-toluenesulphonylcarbamate 9-methoxime
11,4"-diformate;
(xxiii) 11-O-(2-hydroxyethoxymethyl)-erythromycin A 6-carbamate 9-oxime;
(xxiv) 11-O-(2-hydroxyethoxymethyl)-erythromycin A 6, 12-dicarbamate
9-oxime;
(xxv) 11-O-(2-N, N-dimethylaminoethoxymethyl)-erythromycin A 6-carbamate
9-oxime;
(xxvi) 11-O-(2-N, N-dimethylaminoethoxymethyl)-erythromycin A 6 -carbamate;
(xxvii) 11-O-ethoxymethyl-erythromycin A 6-carbamate 9-oxime;
(xxviii) 11-O-ethoxymethyl-erythromycin A 6,12-dicarbamate 9-oxime;
(xxix) 1-O-ethoxymethyl-erythromycin A 6-carbamate 9-methoxime; or
(xxx) erythromycin A 6-p-toluenesulphonylcarbamate 9-methoxime; or a
pharmaceutically acceptable ester or acid addition salt thereof.
17. A method of treating bacterial infections in humans and animals which
comprises administering to a human or animal in need thereof an
antibacterially effective amount of the compound of the formula I or a
pharmaceutically acceptable ester or acid addition salt thereof:
##STR21##
wherein one of R.sup.1 and R.sup.2 is hydrogen, and the other of R.sup.1
and R.sup.2 is amino unsubstituted or substituted by one or two alkyl
moieties of 1 to 6 carbon atoms, or the other of R.sup.1 and R.sup.2,
together with R.sup.5, is a group of the formula III below, or R.sup.1 and
R.sup.2 together are oxo, oxime unsubstituted or substituted by alkyl,
cycloalkyl or alkenyl of up to 6 carbon atoms, phenyl,
hydrocarbon-carbonyl or hydrocarbonoxy-carbonyl wherein the hydrocarbon is
alkyl of up to 6 carbon atoms or phenyl each of which is unsubstituted or
substituted by alkyl of 1 to 6 carbon atoms, heterocyclyl, amino,
alkanoylamino of 1 to 6 carbon atoms, mono-, di- or tri-alkylamino of 1 to
6 carbon atom in each alkyl moiey, hydroxy, alkoxy of 1 to 6 carbon atoms,
mercapto, sulphamoyl, carbamoyl, amidino, guanidino, nitro, chloro, bromo,
fluoro, carboxy or salt or ester thereof, alkanoyloxy of 1 to 6 carbon
atoms, arylcarbonyl, heterocyclylcarbonyl or --S(O).sub.n R.sup.12 wherein
n is 0, 1 or 2 and R.sup.12 is alkyl of 1 to 6 carbon atoms, heterocyclyl
or aryl, or an imino; R.sup.3 is carbamoyl or N-substituted carbamoyl of
the formula --O--CO--NH--X--R.sup.15 wherein X is --CO-- or --SO.sub.2 and
R.sup.15 is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon
atoms, alkoxyalkyl of 1 to 6 carbon atoms in each of the alkoxy and alkyl
moieties, phenyl, alkylphenyl of 1 to 6 carbon atoms in the alkyl moiety
or halophenyl;
R.sup.4 is hydrogen or hydroxy, and
R.sup.5 is hydroxy, or etherified hydroxy, or R.sup.5 together with R.sup.1
or
R.sup.2 is a group of the formula III below as defined above, or
R.sup.4 and R.sup.5 together are a group of the formula II or III:
##STR22##
in which R.sup.A and R.sup.B are the same or different, and each is
hydrogen, phenyl, or alkyl of 1 to 6 carbon atoms, said alkyl being
unsubstituted or substituted by heterocyclyl, amino, alkanoylamino of 1 to
6 carbon atoms, mono-, di-, or tri-alkylamino of 1 to 6 carbon atoms in
each alkyl moiety, hydroxy, alkoxy of 1 to 6 carbon atoms, mercapto,
alkylthio of 1 to 6 carbon atoms, heterocyclylthio, arylthio, sulphamoyl,
carbamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, carboxyl or a
salt or ester thereof, alkanoyloxy of 1 to 6 carbon atoms,
arylcarbonyloxy, heterocyclylcarbonyloxy or acyl;
R.sup.6 is hydrogen, fluorine or hydroxy;
R.sup.7 is hydrogen or methyl;
one of R.sup.8 and R.sup.9 is hydrogen, hydroxy, alkoxy, alkanoyloxy,
amino, substituted amino of the formula XII or XIII:
--NHCOR.sup.16 XII
or
--NHSO.sub.2 R.sup.16 XIII
wherein
R.sup.16 is alkyl of 1 to 6 carbon atoms or phenyl, unsubstituted or
substituted by heterocyclyl, amino, alkanoylamino of 1 to 6 carbon atoms,
mono-, di-, or tri-alkylamino of 1 to 6 carbon atoms in each alkyl moiety,
hydroxy, alkoxy of 1 to 6 carbon atoms, mercapto, alkylthio of 1 to 6
carbon atoms, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino,
guanidino, nitro, chloro, bromo, fluoro, carboxyl or a salt or ester
thereof, alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyloxy,
heterocyclylcarbonyloxy or acyl, or a group of the formula R.sup.C
SO.sub.2 --O--, in which R.sup.C is, alkyl of 1 to 6 carbon atoms, alkenyl
of 2 to 6 carbon atoms, phenyl, nitrophenyl, halophenyl, alkylphenyl of 1
to 6 carbon atoms in the alkyl moiety, benzyl, nitrobenzyl, halobenzyl,
alkylbenzyl of 1 to 6 carbon atoms in the alkyl moiety, phenoxyalkyl of 1
to 6 carbon atoms in the alkyl moiety, nitrophenoxyalkyl of 1 to 6 carbon
atoms in the alkyl moiety, halophenyoxyalkyl of 1 to 6 carbon atoms in the
alkyl moiety, alkylphenoxyalkyl of 1 to 6 carbon atoms in each alkyl
moiety or R.sup.17 --CH.sub.2 --CH.sub.2 -- wherein R.sup.17 is amino,
carbamoyl, sulphamoyl, alkoxy of 1 to 6 carabon atoms, alkylthio of 1 to 6
carbon atoms, aryloxy, arylthio, benzyloxy or benzylthio and the other of
R.sup.8 and R.sup.9 is hydrogen, or R.sup.8 and R.sup.9 together are oxo,
oxime or acetyloxime, in combination with a pharmaceutically acceptable
carrier.
18. A method according to claim 17, wherein R.sup.11 is hydrogen or methyl.
19. A method according to claim 17, wherein R.sup.4 is hydroxy.
20. A method according to claim 17, wherein R.sup.7 is methyl.
21. A method accroding to claim 17 wherein R.sup.8 is hydrogen and R.sup.9
is hydroxy.
22. A method according to claim 17, wherein R.sup.5 is hydroxy.
23. A method according to claim 17, wherein R.sup.5 is alkoxy of 1 to 6
carbon atoms or a group of the formula IX or X:
##STR23##
in which formulae Q is one of the following groups:
##STR24##
R.sup.D is alkyl, R.sup.E is hydrogen or alkyl of 1 to 6 carbon atoms,
R.sup.F is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms,
cycloalkyl of 3 to 7 carbon atoms or phenyl each of which is unsubstituted
or substituted by heterocyclyl, amino, alkanoylamino of 1 to 6 carbon
atoms, mono-, di- or tri-alkylamino of 1 to 6 carbon atoms in each alkyl
moiety, hydroxy, alkoxy of 1 to 6 carbon atoms, mercapto, alkylthio of 1
to 6 carbon atoms, heterocyclylthio, arylthio, sulphamoyl, carbamoyl,
amidino, guanidino, nitro, chloro, bromo, fluoro, carboxyl or a salt or
ester thereof, alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyloxy,
heterocyclylcarbonyloxy or acyl;
R.sup.G is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon
atoms, aryl, aryloxy, cycloalkyl of 3 to 7 carbon atoms or cycloalkyloxy
of 3 to 7 carbon atoms unsubstituted or substituted by hydroxy, halo,
carboxy, alkoxy of 1 to 6 carbon atoms, aryloxy, formyl, acyloxy,
alkoxycarbonyl of 1 to 6 carbon atoms in the alkyl moiety,
alkanesulphonyloxy of 1 to 6 carbon atoms in the alkane moiety,
trialkylsilyloxy of 1 to 6 carbon atoms in each alkyl moiety, amino,
N-alkylamino or N, N-dialkylamino of 1 to 6 carbon atoms in each alkyl
moiety, oxo, azido, diazo or heterocyclyl, each of R.sup.H and R.sup.J, is
the same or different, and each is hydrogen or alkyl of up to 6 carbon
atoms, cycloalkyl of 3 to 7 carbon atoms or phenyl each of which is
unsubstituted or substituted by alkyl of 1 to 6 carbon atoms,
heterocyclyl, amino, alkanoylamino of 1 to 6 carbon atoms, mono-, di- or
tri-alkylamino of 1 to 6 carbon atoms in each alkyl moiety, hydroxy,
alkoxy of 1 to 6 carbon atoms, mercapto, sulphamoyl, carbamoyl, amidino,
guanidino, nitro, chloro, bromo, fluoro, carboxy or salt or ester thereof,
alkanoyloxy of 1 to 6 carbon atoms, arylcarbonyl, heterocyclylcarbonyl or
--S(.sub.O).sub.n R.sup.12 wherein n is 0,1 or 2 and R.sub.12 is alkyl of
1 to 6 carbon atoms, heterocyclyl or aryl, or any two of R.sup.F, R.sup.G,
R.sup.H and R.sup.J together form a 4- to 7-membered heterocyclic ring
together with the intervening atoms of the molecule.
24. The method according to claim 17, wherein the compound of formula I is
(i) erythromycin A 6-carbamate 9-oxime;
(ii) erythromycin A 6-carbamate 9-oxime 11,12-carbonate;
(iii) erythromycin A 6-carbamate;
(iv) erythromycin A 6,11-dicarbamate 9-methoxime;
(v) erythromycin A 6-carbamate 9-methoxime 11,12-carbonate;
(vi) erythromycin A 6-dicarbamate 9-imine;
(vii) erythromycylamine 6-carbamate;
(viii) erythromycin A 6-carbamate 11, 12-carbonate;
(ix) erythromycin A 6-carbamate 9-methoxime
(x) erythromycin A 6, 12-dicarbamate 9-methoxime 11-formate;
(xi) erythromycin A 6-carbamate 9-(2-methoxy- ethoxymethoxime);
(xii) erythromycin A 6-benzoylcarbamate 9-oxime;
(xiii) erythromycin A 6-benzoylcarbamate 9-oxime 11,12-carbonate;
(xiv) erythromycin A 6-benzoylcarbamate 9-methoxime 11,12-carbonate;
(xv) erythromycin A 6-benzoylcarbamate 9-methoxime;
(xvi) erythromycin A 6, 12-bis-acetylcarbamate 9-methoxime 11-formate;
(xvii) erythromycin A 6-acetylcarbamate 9-methoxime 11,12-carbonate;
(xviii) 9-dihydro-9,11-ethylidene-erythromycin A 6-carbamate;
(xix) erythromycin A 6-methoxyacetylcarbamate 9methoxime 11,4"-diformate;
(xx) erythromycin A 6,12-methoxyacetylcarbamate 9-methoxime
11,4"-diformate;
(xxi) erythromycin A 6-p-toluenesulphonylcarbamate 9-methoxime
11,4"-diformate;
(xxii) erythromycin A 6,12-bis-p-toluenesulphonylcarbamate 9-methoxime 11,
4"-diformate;
(xxiii) 11-O-(2-hydroxyethoxymethyl)-erythromycin A 6-carbamate 9-oxime;
(xxiv) 11-O-(2-hydroxyethoxymethyl)-erythromycin A 6,12-dicarbamate
9-oxime;
(xxv) 11-O-(2-N, N-dimethylaminoethoxymethyl)-erythromycin A 6-carbamate
9-oxime;
(xxvi) 11-O-(2-N, N-dimethylaminoethoxymethyl)-erythromycin A 6-carbamate;
(xxvii) 11-O-ethoxymethyl-erythromycin A 6-carbamate 9-oxime;
(xxviii) 11-O-ethoxymethyl-erythromycin A 6,12-dicarbamate 9-oxime;
(xxix) 1-O-ethoxymethyl-erythromycin A 6-carbamate 9-methoxime; or
(xxx) erythromycin A 6-p-toluenesulphonylcarbamate 9-methoxime; or a
pharaceuticalIy acceptable ester or acid addtion salt thereof. |
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Claims |
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Description |
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The present invention relates to novel chemical compounds, their
preparation and their use, and in particular to a novel class of
erythromycin derivatives. These compounds have antibacterial properties,
in particular against Gram-positive bacteria but also against some
Gram-negative bacteria, and they are therefore of use in the treatment of
bacterial infections in humans and animals caused by a wide range of
organisms.
Erythromycin was first described in U.S. Pat. No. 2,653,899 (R. L. Bunch et
al; Eli Lilly). The structure of erythromycins can be represented as
follows:
##STR2##
in which R.sup.a denotes hydrogen or hydroxy and
R.sup.b denotes hydrogen or methyl.
The basic erythromycin structure comprises:
(i) a 14-membered lactone ring, referred to as the erythronolide ring,
numbered with unprimed digits as shown in the above formula,
(ii) a first sugar ring, known as the desosamine ring, numbered with
single-primed digits, and
(iii) a second sugar ring, known as the cladinose ring, numbered with
double-primed digits.
The erythronolide ring can exist in two forms:
erythronolide A (in which R.sup.a =OH)
erythronolide B (in which R.sup.a =H).
The four main naturally occurring erythromycins are as follows:
______________________________________
Erythromycin R.sup.a R.sup.b
______________________________________
A OH CH.sub.3
B H CH.sub.3
C OH H
D H H
______________________________________
of which erythromycin A is by far the most important. Erythromycins, and in
particular erythromycin A, are antibiotics widely employed clinically in
the treatment of infections caused by Gram-positive and some Gram-negative
bacteria. A major drawback of erythromycins is their poor acid stability,
resulting in poor and erratic oral absorption.
Numerous attempts have been made to modify erythromycin to produce
derivatives having improved acid stability without loss of the
antibacterial activity.
(9S)-9-Dihydroerythromycin A (which carries a 9-hydroxy group in place of
the 9-keto group) has been described, but has poor antibacterial activity
(P. F. Wiley et al, J. Amer. Chem. Soc., 1955, 77, 3676-3677; M. V. Sigal
et al, ibid, 1956, 78, 388-395; and T. Glabski et al, Roczniki Chem.,
1976, 50, 1281). Erythromycylamine and erythromycin oxime (in which the
9-keto group is replaced, respectively, by an amino or oxime group), as
well as various N-substituted derivatives of erythromycylamine have also
been described (GB 1 100 504 (Pliva Pharmaceutical); E. H. Massey et al,
Tetrahedron Letters, 1970, No. 2, 157-160; and G. H. Timms et al, ibid,
1971, No. 2, 195-198), as have various erythromycin oxime ethers (U.S.
Pat. No. 3,681,326 (A. M. Von Esch; Abbott Laboratories); U.S. Pat. No.
3,869,445 and 4,063,014 (both R. Hallas et al; Abbott Laboratories); U.S.
Pat. No. 4,349,545 (S. Gouin d'Ambrieres; Roussel-Uclaf)); and
Antimicrobial agents and chemotherapy, 1974, 6 479).
Certain aldehyde-erythromycylamine condensation products with a 9-N,6-O- or
9-N,11-O-cyclic substituent have previously been disclosed (U.S. Pat. No.
4,048,306 (R. Maier et al; Boehringer Ingelheim GmbH)).
4"-Deoxy-11-O-methylthiomethyl-4"-oxo-erythromycin B and its conversion to
(i) 4"-deoxy-9,11-O-(optionally substituted)methylene-4"-oxo-erythromycin
B 6,9-hemiacetal and the corresponding 4"-epi-hydroxy, 2',
4"-O-diacetyl-4"-epi, and 4"-O-acetyl-4"-epi derivatives, and (ii)
4"-deoxy-4"-oxo-, 4"-O-acetyl-4"-epi-, and 4"-epi-erythromycin B; as well
as 4"-O-formyl-11-O-methylthiomethyl-erythromycin B and its conversion to
11-O-methylthiomethyl-erythromycin B, 9,11-O-methylene-erythromycin B
6,9-hemiacetal, 11-O-methyl-erythromycin B and 11-O-n-butylerythromycin B;
and also 4"-deoxy-4"-oxo-erythromycin A are described in U.S. Pat. Nos.
3,842,069, 3,884,903 and 3,884,904 (all P. H. Jones et al; Abbott
Laboratories).
4"-Deoxy-4"-amino-erythromycin A, 4"-deoxy-4"-amino-erythromycin A
6,9-hemiketal, and 4"-deoxy-4"-oxo-erythromycin A 6,9-hemiketal, as well
as corresponding 11-O-acetyl and 11,12-cyclic carbonate derivatives, and
also 4"-deoxy-4"-amino-erythromycin B and 4"-deoxy-4"-oxo-erythromycin A
4"-O-oxime or 4"-O-acetyloxime, are described in U.S. Pat. No. 4,150,220
(F. C. Sciavolino; Pfizer).
Various 4"-O-sulhhonyl derivatives of erythromycin, erythromycin oxime, and
erythromycin oxime ethers are described in U.S. Pat. Nos. 3,836,519,
3,869,445 and 4,063,114 (all R. Hallas et al; Abbott Laboratories).
Certain further 4"-deoxy-erythromycin derivatives are described in JP No.
58-049396 (Toyo Jozo KK).
An 11,12-cyclic carbonate of 9-dihydroerythromycin has also been described
in T. Glabski et al; Roczniki Chem., 1976, 50, 1281 and
9-dihydro-11,12-O-isopropylidene-erythromycin A and the corresponding
4"-epi compound, as well as 4"-epi-erythromycin A and corresponding
9-dihydro, 11,12-carbonate, 9-dihydro-11,12-carbonate, and 2'-acetyl
compounds, have been described in U.S. Pat. Nos. 4,382,085 and 4,382,086
(both F. C. Sciavolino et al; Pfizer).
11,12-O-(optionally substituted)-methylene derivatives and
9,11,-O-(optionally substituted)-methylene derivatives of erythromycin are
described in WO No. 86/01513 and EP No. 0 184 921 A2, respectively (both
Beecham).
6-O-Methyl-, 6,11-di-O-methyl-, 11-O-methyl- and 11-O-ethyl-erythromycin A,
and also 6-O-methyl-6,4"-di-O-methyl-, and 6,11,4"-tri-O-methylo
erythromycin B are described in EP No. 0 041 355 Al, EP No. 0 080 818 Al,
EP No. 0 080 819 Al, and EP No. 0 158 467 A2 (all Taisho Pharmaceutical).
8-hydroxy-erythromycin A and 8-fluoro-erythromycin A have been described
(K. Krowicki et al, J. Antibiotics, XXVI 575-581 (1973), and L. Toscano et
al, ibid XXXVI 1439-1450 (1983), respectively). Various 6,9-ketal
derivatives of 8-fluoro-erythromycins have also been described (EP No. 0
158 102 A, Pierrel).
The present invention provides antibacterially active 6-carbamate
derivatives of erythromycin, and corresponding 9-(optionally
substituted)oxime, 9-(optionally substituted)amino, and 9-imino compounds.
In particular, the present invention provides a compound of the general
formula I or a pharmaceutically acceptable ester or acid addition salt
thereof:
##STR3##
wherein
one of R.sup.1 and R.sup.2 denotes hydrogen, and the other of R.sup.1 and
R.sup.2 denotes an amino group or a substituted amino group, or the other
of R.sup.1 and R.sup.2, together with R.sup.5, denotes a group of the
formula III below, or
R.sup.1 and R.sup.2 together denote an oxo group, an oxime group, a
substituted oxime group, or an imino group;
R.sup.3 denotes a carbamoyl group or an N-substituted carbamoyl group;
R.sup.4 denotes hydrogen or hydroxy, and
R.sup.5 denotes hydroxy, or an etherified hydroxy group, or together with
R.sup.1 or R.sup.2 denotes a group of the formula III below as defined
above, or
R.sup.4 and R.sup.5 together denote a group of the formula II or III:
##STR4##
in which
each of R.sup.A and R.sup.B, which may be identical or different, denotes
hydrogen or a hydrocarbon group;
R.sup.6 denotes hydrogen, fluorine or hydroxy;
R.sup.7 denotes hydrogen or methyl;
one of R.sup.8 and R.sup.9 denotes hydrogen, hydroxy, alkoxy, alkanoyloxy,
amino, substituted amino, or a group of the formula R.sup.C --SO.sub.2
--O--, in which R.sup.C denotes an organic group, and the other of R.sup.8
and R.sup.9 denotes hydrogen, or
R.sup.8 and R.sup.9 together denote an oxo group, an oxime group, or a
substituted oxime group.
The term `hydrocarbon` as used herein includes groups having up to 18
carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon
atoms. Suitable hydrocarbon groups include (C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, C.sub.2-6)alkynyl, (C.sub.3-7)cycloalkyl, aryl,
(C.sub.3-7)cycloalkyl(C.sub.1-6)alkyl, aryl(C.sub.1-6)alkyl,
(C.sub.1-6)alkyl(C.sub.3-7)cycloalkyl, and (C.sub.1-6)alkylaryl.
Examples of suitable optional substituents for the above-mentioned
hydrocarbon groups include, heterocylyl, amino, (C.sub.1-6)alkanoylamino,
(mono, di, or tri)-(C.sub.1-6)alkylamino, hydroxy, (C.sub.1-6)alkoxy,
mercapto, (C.sub.1-6)alkylthio, heterocyclylthio, arylthio, sulphamoyl,
carbamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, carboxy and
salts and esters thereof, (C.sub.1-6)alkanoyloxy, arylcarbonyloxy,
heterocyclylcarbonyloxy and acyl groups.
Any alkyl group or moiety referred to herein may be straight or branched,
unsubstituted or substituted, and may contain, for example, up to 12
carbon atoms, suitably up to 6 carbon atoms. In particular, the alkyl
group or moiety may be an unsubstituted or substituted methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl or tert-butyl group.
Examples of suitable optional substitutents for any such alkyl group or
moiety include the above-listed substitutents for hydrocarbon groups, and
also the above-listed non-alkyl hydrocarbon groups, for example
(C.sub.2-6)alkenyl and aryl groups.
The term `aryl` as used herein includes phenyl and naphthyl, which may be
unsubstituted or substituted by up to five, preferably up to three, groups
selected from the above-listed substituents for hydrocarbon groups, and
the above-listed hydrocarbon groups, including, for example, substituents
selected from halogen, (C.sub.1-6)alkyl, phenyl, (C.sub.1-6)alkoxy,
halo(C.sub.1-6)alkyl, hydroxy, amino, nitro, carboxy,
(C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkoxycarbonyl(C.sub.1-6)alkyl,
(C.sub.1-6) alkanoyloxy, and(C.sub.1-6) alkanoyl groups.
The term `acyl` as used herein includes formyl, unsubstituted and
substituted hydrocarbon-carbonyl and hydrocarbonoxy-carbonyl groups,
including, for example, unsubstituted and substituted alkanoyl,
cycloalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, and
heterocyclylcarbonyl groups. The term `acyloxy` is used analogously.
The term `heterocyclyl` and `heterocyclic` as used herein include aromatic
and non-aromatic, single and fused, rings suitably containing up to four
hetero-atoms in each ring selected from oxygen, nitrogen and sulphur,
which rings may be unsubstituted or substituted by, for example, up to
three groups selected form halogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy,
halo(C.sub.1-6)alkyl, hydroxy, amino, carboxy, carboxy salts, carboxy
esters, (C.sub.1-6)alkoxycarbonyl,
(C.sub.1-6)alkoxycarbonyl(C.sub.1-6)alkyl, aryl, and oxo groups. Each
heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
A fused heterocyclic ring system may include carbocyclic rings and need
include only one heterocyclic ring.
The term `heteroaryl` as used herein means an aromatic heterocyclic ring or
ring system, suitably having 5 or 6 ring atoms in each ring.
In one group of compounds of the general formula I, R.sup.1 and R.sup.2
together denote an oxo group, as in naturally occurring erythromycins. In
a second group of compounds of the geeral formula I, R.sup.1 and R.sup.2
together denote an oxime group (also referred to as a hydroxyimino group,
=NOH) or a substituted oxime group (for example, an oxime ether group or
an acyl-oxime group). Such compounds may be referred to as erythromycin
oxime derivatives. In a third grop of compounds of the general formula I,
R.sup.1 and R.sup.2 together denote an imino group, and such compounds may
be referred to as erythromycin imines. In a fourth group of compounds of
the general formula I, one of R.sup.1 and R.sup.2 denotes an amino group
or a substituted amino group, and the other of R.sup.1 and R.sup.2 denotes
a hydrogen atom; such compounds may be referred to as erythromycylamines.
In a fifth group of compounds of the general formula I, one of R.sup.1 and
R.sup.2 denotes a hydrogen atom and the other of R.sup.1 and R.sup.2
together with R.sup.5 denotes a 9,11-cyclic-(optionally
substituted)-methylenedioxy group of the formula (III), as discussed in
more detail below; such compounds may be referred to as erythromycin
9,11-acetals or 9,11-ketals.
In the case of the erythromycin oxime and substituted-oxime derivatives
according to the invention, R.sup.1 and R.sup.2 may together denote a
group of the formula IV:
.dbd.N O--R.sup.11 IV
in which R.sup.11 denotes hydrogen or an unsubstituted or substituted
hydrocarbon group or an acyl group. Examples of suitable groups denoted by
R.sup.11 include unsubstituted and substituted alkyl, cycloalkyl, alkenyl,
and aryl (preferably phenyl) groups, and also unsubstituted and
substituted hydrocarbon-carbonyl and hydrocarbonoxy-carbonyl groups, for
example unsubstituted and substituted alkanoyl, cycloalkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, and aryloxycarbonyl groups; each of the said
alkyl groups and moieties suitably having up to 6 carbon atoms.
Examples of suitable substituents for the hydrocarbon group R.sup.11
include (C.sub.1-6)alkyl, heterocyclyl, amino, (C.sub.1-6)alkanoylamino,
(mono, di, or tri)-(C.sub.1-6)-alkylamino, hydroxy, (C.sub.1-6)alkoxy,
mercapto, sulphamoyl, carbamoyl, amidino, guanidino, nitro, chloro, bromo,
fluoro, carboxy, carboxy salts, carboxy esters, (C.sub.1-6)alkanoyloxy,
arylcarbonyl, and heterocyclylcarbonyl groups, and also a group of the
formula V:
--S(O).sub.n R.sup.12 V
in which n denotes 0, 1 or 2, and R.sup.12 denotes a (C.sub.1-6)alkyl,
heterocyclyl, or aryl group.
Examples of acyl groups R.sup.11 include acetyl and benzyloxycarbonyl
groups.
Examples of unsubstituted alkyl groups R.sup.11 include methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl groups. Examples
of substituted alkyl groups R.sup.11 include aralkyl (especially benzyl),
alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl,
arylalkoxyalkyl, alkoxyalkoxyalkyl (for example,
.beta.-methoxyethoxymethyl), alkylthioalkyl, alkenylthioalkyl,
alkynylthioalkyl, arylthioalkyl, aralkylthioalkyl, haloalkyl, formylalkyl,
carboxyalkyl and salts and esters thereof, thiocyanatoalkyl, cyanoalkyl,
acylalkyl, carbamoylalkyl, and aminoalkyl groups; each of the said alkyl,
alkenyl and alkynyl moieties suitably having up to 6 carbon atoms; each of
the said thio derivatives optionally being oxidised to the corresponding
sulphoxide or sulphone derivative; and the said amino moiety of the said
aminoalkyl groups suitably being of the formula VI:
##STR5##
in which each of R.sup.13 and R.sup.14, which may be identical or
different, denotes hydrogen or an unsubstituted or substituted hydrocarbon
group, advantageously an alkyl group, preferably having from 1 to 6 carbon
atoms, or R.sup.13 and R.sup.14 and the nitrogen atom to which they are
attached together denote an unsubstituted or substituted, unsaturated or
saturated heterocyclic ring, optionally containing one or more heteroatoms
additional to the said nitrogen atom, each of R.sup.13 and R.sup.14
preferably denoting a hydrogen atom.
Erythromycin oximes and substituted-oximes having 9-substituents of the
type described above have been described in, for example, GB No. 1 100
504, E. H. Massey et al, G. H. Timms et al, U.S. Pat. No. 3,681,326,
3,869,445, 4,063,014 and 4,349,545, all op. cit.
The erythromycin oxime and substituted oxime derivatives according to the
invention can exist in two geometric isomeric forms about the C.dbd.N
double bond at the 9-position, as indicated by the wavy line in formula IV
above, namely the E-form and the Z-form. The E-form is generally
preferred.
In the case of the erythromycin imine derivatives according to the
invention, R.sup.1 and R.sup.2 together denote a group of the formula VII:
.dbd.N--H VII:
Erythromycin imine has been described, for example, in G. H. Timms et al,
op. cit.
In the case of the erythromycylamine derivatives according to the
invention, one of R.sup.1 and R.sup.2 denotes hydrogen and the other of
R.sup.1 and R.sup.2 may denote a group of the formula VI above, in which
R.sup.13 and R.sup.14 are defined as above. Suitably each of R.sup.13 and
R.sup.14 denotes a hydrogen atom or an alkyl group having up to 6 carbon
atoms. Erythromycylamine and derivatives thereof have, for example, been
described in GB No. 1 100 504, E. H. Massey et al and G. H. Timms et al,
all op. cit.
The erythromycylamine derivatives according to the invention can exist in
two isomeric forms at the 9-position, namely the (9R)-form, in which
R.sup.1 denotes hydrogen and R.sup.2 denotes the optionally substituted
amino group, and the (9S)-form, in which R.sup.1 denotes the optionally
substituted amino group and R.sup.2 denotes hydrogen. The (9S)-isomer is
preferred.
The erythromycin derivatives according to the invention are characterised
by a 6-carbamate group, --OCONH.sub.2, which may optionally be
N-substituted. In particular, the carbamate group may be N-substituted by
an acyl group, for example a hydrocarbylcarbonyl group, or a
hydrocarbylsulphonyl group. Examples of N-substituted-carbamate groups
include those of the formula VIII:
--O--CO--NH--X--R.sup.15 VIII
in whic | | |
