Erythromycin derivatives, process for their preparation and their pharmaceutical use

Claim 2

A process for the preparation of a compound of the general formula I or a pharmaceutically acceptable ester or acid addition salt thereof: wherein R¹ denotes an oxime group, a substituted oxime group, or an imino group, R³ denotes a hydrogen atom or an unsubstituted or substituted alkyl group; R⁷ denotes hydrogen or methyl; one of R⁸ and R⁹ denotes hydrogen, hydroxy, alkoxy, alkanoyloxy, amino, substituted amino, or a alkoxy, alkanoyloxy, amino, substituted amino, or a group of the formula R A -SO₂-O-, in which R A denotes an organic group, and the other of R⁸ and R⁹ denotes hydrogen, or R⁸ and R⁹ together denote an oxo group, an oxime group, or a substituted oxime group; or a pharmaceutically acceptable ester or acid addition salt which comprises reacting a compound of the general formula X: wherein R 1A denotes an oxime or substituted oxime group, and R³, R⁷, R⁸ and R⁹ are as defined above, in which compound of the general formula X any reactive group (other than the 11- and 12-hydroxy groups) may optionally be protected, with a reactive carbonyl compound, to give a compound of the general formula I in which R¹ denotes an oxime or substituted oxime group; and thereafter, if necessary or desired, carrying out one or more of the following steps in any suitable order: (a) converting a substituted oxime group denoted by R¹ to another substituted oxime group or to an oxime group; (b) converting an oxime group denoted by R¹ to a substituted oxime group, or to an imino group; (c) converting any one or more of the groups denoted by R³, R⁸ and R⁹ to another such group; (d) removing any protecting group that may be present; and (e) forming a pharmaceutically acceptable ester or acid addition salt.

Claim 3

A process as claimed in claim 1, wherein R¹ denotes a substituted oxime group of the formula II: =N O-R B II in which R B denotes hydrogen or an unsubstituted or a substituted hydrocarbon group or an acyl group.

Claim 4

A process as claimed in claim 2, wherein R B denotes an unsubstituted or a substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, hydrocarbon-carbonyl or hydrocarbonoxy-carbonyl group.

Claim 5

A process as claimed in claim 3, wherein R³ denotes an unsubstituted or a substituted alkyl group.

Claim 6

A process as claimed in claim 4, wherein R³ denotes an unsubstituted or a substituted (C₁₋₆)alkyl group.

Claim 7

A process as claimed in any one of claims 1 to 5 for the preparation of a compound selected from: erythromycin A 11,12-carbonate 9-oxime; erythromycin A 11,12-carbonate 9-methoxime; 6- O -methylerythromycin A 11,12-carbonate 9-methoxime; 6- O -methylerythromycin A 11,12-carbonate 9-ethoxime; 6- O -methylerythromycin A 11,12-carbonate 9-oxime; 6- O -methylerythromycin A 11,12-carbonate 9-(2-methoxyethoxymethyl)oxime; 6- O -methylerythromycin A 11,12-carbonate 9-methoxymethyloxime; erythromycin A 11,12-carbonate 9-ethoxime; erythromycin A 11,12-carbonate 9-isopropyloxime; erythromycin A 11,12-carbonate 9-carbamoylmethyloxime; erythromycin A 11,12-carbonate 9-methoxymethyloxime; erythromycin A 11,12-carbonate 9-(2-methoxyethoxymethyl)oxime; erythromycin A 11,12-carbonate 9-(2-hydroxyethyl)­oxime; erythromycin A 11,12-carbonate-9-(2-keto-1-­pyrrolidinylmethyl)oxime; erythromycin A 11,12-carbonate-9-prop-2-enyloxime; erythromycin A 11,12-carbonate-9-n-propyloxime; erythromycin A 11,12-carbonate-9-­ethoxymethyloxime; erythromycin A 11,12-carbonate-9-(2-­dimethylaminoethyl)oxime; erythromycin A 11,12-carbonate-9-methylthio­methoxime; erythromycin A 11,12-carbonate-9-cyclopentyloxime; erythromycin A 11,12-carbonate-9-(2-methylprop-2-­enyl)-oxime; erythromycin A 11,12-carbonate-9-(2-methylpropyl)oxime; erythromycin A 11,12-carbonate-9-(2-oxopropyl)oxime; erythromycin A 11,12-carbonate-9-dimethylcarbamoyl­methoxime; erythromycin A 11,12-carbonate-9-(2-methoxyethyl)­oxime; erythromycin A 11,12-carbonate-9-methoxycarbonyl methyl-oxime; erythromycin A 11,12-carbonate-9-(2-pyridyl)­methyloxime; erythromycin A 11,12-carbonate-9-isopropyloxime; or a pharmaceutically acceptable ester or an acid addition salt of such a compound.

Claim 8

A process as claimed in any one of claims 1 to 6, wherein the reactive carbonyl compound is phosgene, oxalyl chloride, carbonyl di-imidazole, an acyl isocyanate or an aryl isocyanate.

Claim 9

A process as claimed in any one of claims 1 to 6, wherein the reactive carbonyl compound is phosgene, oxalyl chloride or an acyl isocyanate and the process is carried out at a temperature within the range of from -50 to +50°C.

Claim 10

A process as claimed in any one of claims 1 to 6, wherein the reactive carbonyl compound is carbonyl di-imidazole or an aryl isocyanate and the process is carried out at a temperature of from 0 to 150°C.

Claim 11

A process as claimed in any one of claims 1 to 9, wherein the reactive carbonyl compound is used in an excess of from 1 to 10 equivalents, based on the erythromycin compound.

Claim 12

A process for the preparation of a pharmaceutical composition, which comprises adding to or mixing with a compound of the general formula I, as defined in claim 1, a pharmaceutically acceptable carrier or excipient.

Claim 13

The use of a compound of the general formula I, as defined in claim 1, for the manufacture of a medicament.

Claim 14

A method of treating bacterial infections in animals, which comprises administering a compound of the general formula I as defined in claim 1, to a patient in need thereof.

Claim 15

A method of treating bacterial infections in animals which comprises administering a composition as defined in claim 11 to a patient in need thereof.