Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

• 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.
• R a denotes hydrogen or hydroxy
• R b denotes hydrogen or methyl.
• the basic erythromycin structure comprises:
• the erythronolide ring can exist in two forms:
• the four main naturally occurring erythromycins are as follows:
• 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.
• 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 (US 3 681 326 (A.M. Von Esch; Abbott Laboratories); US 3 869 445 and US 4 063 014 (both R. Hallas et al; Abbott Laboratories); US 4 349 545 (S. Gouin d'Ambrieres; Roussel-Uclaf); and Antimicrobial agents and chemotheraphy, 1974, 6, 479).
• the present invention provides antibacterially active 11, 12-0-methylene derivatives of erythromycin, and corresponding 9-(optionally substituted)amino, 9-imino, and 9-(optionally substituted)oxime compounds.
• the present invention provides a compound of the general formula I or a pharmaceutically acceptable ester or acid addition salt thereof:
• R 1 and R 2 denotes hydrogen and the other of R 1 and R 2 denotes an amino group or a substituted amino group, or R 1 and R 2 together denote an oxo group, an oxime group, a substituted oxime group, or an imino group;
• R 3 denotes hydrogen or a methyl group
• each of R 4 and R 5 which may be identical or different, denotes hydrogen or a hydrocarbon group
• R 6 denotes hydrogen, fluorine, or hydroxy
• R 7 denotes hydrogen or methyl
• R 8 and R 9 denotes hydrogen, hydroxy, alkoxy, alkanoyloxy, amino, substituted amino, or a group of the formula R 10 -SO 2 -O-, and the other of R 8 and R 9 denotes hydrogen, or
• R 8 and R 9 together denote an oxo group, an oxime group, or a substituted oxime group
• R 10 denotes an organic group.
• 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 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl, aryl, (C 3-7 )cycloalkyl(C 1-6 )alkyl, aryl(C 1-6 )alkyl, (C 1-6 )alkyl(C 3-7 )cycloalkyl, and (C 1-6 )alkylaryl.
• suitable optional substituents for the above-mentioned hydrocarbon groups include, heterocylyl, amino, (C 1-6 )alkanoylamino, (mono, di, or tri)-(C 1-6 )alkylamino, hydroxy, (C 1-6 )alkoxy, mercapto, (C 1-6 )alkylthio, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, carboxy and salts and esters thereof, (C 1-6 )alkanoyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy and acyl groups.
• 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.
• 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.
• 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 2-6 )alkenyl and aryl groups.
• '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 halogen, (C 1-6 )alkyl, phenyl, (C 1-6 )alkoxy, halo(C 1-6 )alkyl, hydroxy, amino, nitro, carboxy, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkoxycarbonyl(C 1-6 )alkyl, (C 1-6 )alkylcarbonyloxy, and (C 1-6 )alkylcarbonyl groups, and also the other above-listed substituents for hydrocarbon groups, and the other above-listed non-aryl hydrocarbon groups.
• R 1 and R 2 together denote an oxo group, as in naturally occurring erythormycins.
• R 1 and R 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).
• oxime group also referred to as a hydroxyimino group, -NOH
• 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.
• R 1 and R 2 together denote an imino group, and such compounds may be referred to as erythromycin imines.
• one of R 1 and R 2 denotes an amino group or a substituted amino group, and the other of R 1 and R 2 denotes a hydrogen atom; such compounds may be referred to as erythromycylamines.
• R 1 and R 2 may together denote a group of the formula II: O-R 13 II
• R 13 denotes hydrogen or an unsubstituted or substituted hydrocarbon group or an acyl group.
• suitable groups denoted by R 13 include unsubstituted and substituted alkyl, cycloalkyl, alkenyl, and aryl (preferably phenyl) groups, and also unsubstituted and substituted hydrocarbon-carbonyl and hydrocarbon-oxycarbonyl 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.
• substituents for the hydrocarbon group R 13 include (C 1-6 )alkyl, heterocyclyl, amino, (C 1-6 )alkanoylamino, (mono, di, or tri)-(C 1-6 )alkylamino, hydroxy, (C 1-6 )alkoxy, mercapto. sulphamoyl, carbamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, carboxy, carboxy salts, carboxy esters, (C 1-6 )alkanoyloxy, arylcarbonyl, and heterocyclylcarbonyl groups, and also a group of the formula
• n denotes 0, 1 or 2
• R 12 denotes a (C 1-6 )alkyl, heterocyclyl, or aryl group.
• acyl groups R 13 include acetyl and benzyloxycarbonyl groups.
• Examples of unsubstituted alkyl groups R 13 include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl groups.
• Examples of substituted alkyl groups R 13 include araikyl (especially benzyl), alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, arylalkoxyalkyl, alkoxyalkoxyalkyl (for example, ⁇ -methoxyethoxymethyl), alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, aralkylthioalkyl, haloalkyl, formylalkyl, carboxyalkyl and salts and esters thereof, thiocyanotoalkyl, cyanoalkyl, acylalkyl,
• each of R 14 and R 15 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 14 and R 15 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 14 and R 15 preferably denoting a hydrogen atom.
• Erythromycin oximes and oxime-ethers having 9-substituents of the type described above have been described in, for example, GB 1 100 504, E.H. Massey et al, G.H. Timms et al, US 3 681 326, US 3 869 445, US 4 063 014 and US 4 349 545, all op. cit..
• the E-form is generally preferred.
• Erythromycin imine has been described, for example, in G.H. Timms et al, op. cit..
• R 1 and R 2 denotes hydrogen and the other of R 1 and R 2 may denote a group of the formula III above, in which R 14 and R 15 are defined as above.
• R 14 and R 15 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 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 1 denotes hydrogen and R 2 denotes the optionally substituted amino group, and the (9S)-form, in which R 1 denotes the optionally substituted amino group and R 2 denotes hydrogen.
• the (9S)-isomer is preferred.
• the erythromycin derivatives according to the invention are characterised by an 11, 12-0-(optionally substituted)-methylene group denoted by
• R 4 and R 5 may be identical or different and each denotes a hydrogen atom or a hydrocarbon group.
• the hydrocarbon group R 4 , R 5 may suitably be an unsubstituted or substituted alkyl group, more particularly a lower alkyl group, preferably a (C 1-6 )alkyl group, for example a methyl or ethyl group.
• at least one of R 4 and R 5 denotes a hydrogen atom.
• both of R 4 and R 5 denote hydrogen atoms.
• both of R 4 and R 5 denote alkyl groups.
• the 6-position of the erythronolide ring may carry a hydroxy group or methoxy group, -OR 3 , in which R 3 denotes hydrogen or methyl.
• R 3 denotes hydrogen or methyl.
• the 6-position carries a hydroxy group, as in naturally-occuring erythromycins, in which case R 3 denotes hydrogen.
• 6-0-methyl-erythromycin derivatives have been described in EP 0 041 355 Al and EP 0 080 818 Al, both op.cit..
• the 8-position of the erythronolide ring preferably has only a methyl substitutent, as in naturally-occuring erythromycins, and therefore preferably R 6 denotes a hydrogen atom.
• R 6 denotes a hydrogen atom. 8-Hydroxy and 8-fluoro derivatives have been described (J.Antibiotics, XXVI 575-581 (1973) and XXXVI, 1439-1450 (1983)) and R 6 may denote a hydroxy group or a fluorine atom.
• the -OR 7 group in the 3''-position of the cladinose ring may be a hydroxy group or a methoxy group.
• R 7 denotes a methyl group as in erythromycin A and B.
• Various modifications of the 4''-position of the cladinose ring have previously been described and those modifications may be incorporated in the compounds according to the present invention:
• R 16 denotes a hydrocarbon group
• the organic group R 10 may suitably be an unsubstituted or substituted hydrocarbon, oxahydrocarbon, thiahydrocarbon or azahydrocarbon group, more especially an alkyl, alkenyl, unsubstituted or substituted aryl (especiallyphenyl, nitrophenyl, halophenyl or alkylphenyl), unsubstituted or substituted araikyl (especiallybenzyl, nitrobenzyl, halobenzyl or alkylbenzyl), unsubstituted or substituted aryloxyalkyl (especially phenoxyalkyl, nitrophenoxyalkyl, halophenoxyalkyl or alkylphenoxyalkyl), or substituted ethyl (especially R 17 -CH 2 -CH 2 -, wherein R 17 is defined as below) group.
• aryl especiallyphenyl, nitrophenyl, halophenyl or alkylphenoxyalkyl
• R 17
• R 10 denotes a hydrocarbon group, particularly a (C 1-6 )alkyl group, especially a methyl group.
• the present invention includes pharmaceutically acceptable esters, especially in vivo hydrolysable esters, of the compounds of the general formula I.
• the esters may be formed at any hydroxy group in the compounds of the general formula I, but usually the ester will be formed at the 2'-hydroxy group of the desosamine ring, thus giving a 2'-0-acyl derivative of the type described in US 2 862 921 (R.E. Booth et al; Upjohn Co.), US 2 993 833 (V.C. Stephens; Eli Lilly), US 3 836 519, US 3 842 069, US 3 869445, US 3 884 903, US 3 884 904 and US 4 150 220, all op. cit.
• Suitable pharmaceutically acceptable in vivo hydrolysable esters include those that break down readily in the human body to leave the parent compound or a salt thereof.
• Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include acetates, propionates, butyrates, acrylates, and ethylsuccinates.
• the present invention also includes acid addition salts, especially pharmaceutically acpeptable acid addition salts, of the compounds of the general formula I. Such acid addition salts may, in particular, be formed at the 3'-dimethylamino group of the desosamine ring.
• Suitable acid addition salts of the compounds of the invention include pharmaceutically acceptable inorganic acid addition salts, for example the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and also pharmaceutically acceptable organic acid addition salts, for example the acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphate, ⁇ -keto-glutarate, ⁇ -glycerophosphate, and glucose-1-phosphate.
• the acid addition salt is the laurylsulphate salt.
• Examples of individual compounds according to the present invention include:
• the 11,12-0-methylene-erythromycin derivatives according to the invention may be prepared by reacting erythromycin or an erythromycin 9-oxime or 9-substituted-oxime derivative having a hydroxy substituent at each of the 11- and 12-positions, in which any reactive groups (other than the 11- and
• 12-hydroxy groups may optionally be protected, with a dialkylating agent; and thereafter if necessary carrying out one or more of the following steps:
• a resulting 9-oxo compound according to the invention may, if desired, optionally be converted to a 9-oxime or 9-substituted-oxime compound according to the invention.
• a resulting 9-substituted-oxime compound according to the invention may, if desired, subsequently be converted to a 9-oxo or 9-oxime compound according to the invention.
• a resulting 9-oxime compound according to the invention may, if desired, be converted to a 9-substituted-oxime or 9-imino compound according to the invention.
• a resulting 9-imino compound may, in turn, be converted to a 9-amino compound according to the invention, which may, if desired, be further converted to a 9-substituted-amino compound according to the invention.
• a compound of the general formula I as hereinbefore defined or a pharmaceutically acceptable ester or acid addition salt thereof may be prepared by a process which comprises reacting a compound of the general formula VI:
• R 3 , R 6 , R 7 , R 8 and R 9 are defined as above with respect to general formula I,and
• R 18 denotes an oxo, oxime or substituted oxime group, in which compound of the general formula VI any reactive group (other than the 11- and 12-hydroxy groups) may optionally be protected,
• R 4 and R 5 are defined as above with respect to general formula I, or a reactive derivative of such a compound
• R 4 and R 5 are defined as above with respect to general formula I, and
• each of X and Y which may be identical or different, denotes a readily displaceable group; to give a compound of the general formula I in which R 1 and R 2 together denote an oxo, oxime or substituted oxime group;
• each of R 3 , R 6 and R 8 denotes hydrogen
• R 7 denotes methyl
• R 9 denotes hydroxy
• 9-substituted-oxime derivatives may be prepared from erythromycin A by known methods, for example by the methods described in the above-cited references relating to erythromycin 9-oximes and 9-substitutedoximes.
• Other compounds of the general formula VI may also be prepared, by methods known per se, from erythromycin A or the corresponding 9-oxime or 9-substituted-oxime derivative.
• erythromycin A or the corresponding 9-oxime or 9-substituted-oxime derivative.
• a compound in which the 4''-position is substituted other than as in naturally-occuring erythromycin A (that is to say, in which R 8 is other than hydrogen and/or R 9 is other than hydroxy) may be prepared as described in the respective references cited above.
• the conversion of the 9-oxo group of erythromycin A to a 9-oxime or 9-substituted-oxime group may be effected prior to or subsequent to modification of other positions of the erythromycin molecule.
• any reactive group of a compound of the general formula VI may optionally be protected.
• the 3'-dimethylamino group will generally be protected by an N-protecting group.
• the N-protection may be effected in known manner, for example by the method described by E.H. Flynn et al, (J . Amer . Chem. Soc , 1955, 77 , 3104-3106 ) .
• N-protecting groups examples include benzyloxycarbonyl, and substituted benzyloxycarbonyl, (for example, p-methylbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, and p-(p'-methoxyphenylazo)-benzyloxycarbonyl).
• a preferred N-protecting group is benzyloxycarbonyl.
• hydroxy groups present in the erythromycin molecule may also be advantageous to protect one or more of the hydroxy groups present in the erythromycin molecule (other than the 11- and 12- hydroxy groups) prior to carrying out the reaction.
• Any reactive substituents that may be present in the group R 8 or R 9 or in a 9-substituted-oxime group should preferably also be protected in a conventional manner.
• Method (i) of the process according to the invention is suitably carried out using a compound of the general formula VI in which R 18 denotes an oxime group or a substituted oxime group, or a compound of the general formula VI in which R 18 denotes an oxo group and in which R 3 denotes a methyl group or the 6-hydroxy group is otherwise protected.
• Suitable reactive derivatives of aldehydes or ketones of the general formula VII include, for example, acetals of the general formula IX:
• R 4 and R 5 are defined as above with respect to general formula I;
• each of R 19 and R 20 which may be identical or different, denotes a hydrocarbon group, advantageously a (C 1-6 )hydrocarbon group, preferably an alkyl group, especially a methyl or ethyl group; and
• R 21 denotes a divalent hydrocarbon group corresponding to the monovalent hydrocarbon group R 5 with the loss of a hydrogen atom on the carbon atom carrying the free valency.
• the reaction according to method (i) is suitably carried out in the presence of an acid catalyst.
• Preferred acid catalysts include pyridinium salts, for example pyridinium p-toluene-sulphonate and pyridinium chloride.
• Other suitable acid catalysts include, for example, zinc chloride, cupric sulphate, boron trifluoride etherate, and organic sulphonic acids (for example, p-toluenesulphonic acid), optionally in conjunction with, for example, tertiary organic bases (for example, pyridine, dimethylpyridines, and trimethylpyridines).
• reaction is also carried out in the presence of a drying agent, for example anhydrous calcium sulphate, magnesium sulphate, sodium sulphate, cupric sulphate, or molecular sieves.
• a drying agent for example anhydrous calcium sulphate, magnesium sulphate, sodium sulphate, cupric sulphate, or molecular sieves.
• the reaction according to method (i) may suitably be carried out in an inert solvent.
• suitable solvents include, for example, ether solvents (for example, tetrahydrofuran, dioxan, ethoxyethane, and 1,2-dimethoxyethane), halogenated solvents (for example, chloroform and methylene chloride), and aromatic solvents (for example, toluene).
• the reaction according to method (i) may suitably be effected at a cool to slightly elevated temperature, preferably at ambient temperature.
• the reaction may, for example, be effected at a temperature within the range of from -30°C to +30°C, preferably from 0°C to +30°C, especially from +10°C to + 25°C.
• Method (ii) of the process according to the invention is suitably carried out using a compound of the general formula VI in which R 18 denotes an oxo group or a substituted oxime group.
• the compound of the general formula VI optionally containing protective groups, is reacted with a compound of the general formula VIII.
• each of X and Y which may be identical to one another but are preferably different from one another, denotes a leaving group.
• Suitable leaving groups X and Y include halogen atoms (for example chlorine, bromine, and iodine), alkylsulphonyloxy groups (for example methanesulphonyloxy), and arylsulphonyloxy groups (for example p-toluenesulphonyloxy).
• halogen atoms for example chlorine, bromine, and iodine
• alkylsulphonyloxy groups for example methanesulphonyloxy
• arylsulphonyloxy groups for example p-toluenesulphonyloxy
• each of X and Y denotes a halogen atom, especially different halogen atoms. More preferably X denotes chlorine or bromine and Y denotes bromine or iodine. A compound of the general formula VIII in which X denotes chlorine and Y denotes iodine is especially preferred.
• the reaction according to method (ii) is suitably carried out under strongly basic conditions. Examples of suitable strong bases include sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, potassium t-butoxide, butyllithium, and lithium diisopropylamide.
• the reaction according to method (ii) may suitably be carried out in an inert solvent.
• suitable solvents include, for example, polar aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, hexamethylphosphoric triamide, and N-methylpyrrolidinone and mixtures of two or more such solvents) and mixtures of one or more polar aprotic solvents with one or more ether solvents (for example, tetrahydrofuran, dioxan, ethoxyethane, and 1, 2-dimethoxyethane).
• polar aprotic solvents for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, hexamethylphosphoric triamide, and N-methylpyrrolidinone and mixtures of two or more such solvents
• ether solvents for example, tetrahydrofuran, dioxan
• the reaction according to method (ii) may suitably be effected at a cool to ambient temperature preferably at a cool temperature.
• the reaction may, for example, be effected at a temperature within the range of from -30°C to +30°C, preferably from -5°C to +20°C, especially from 0°C to +15°C.
• the 9-oxo, 9-oxime or 9-substituted-oxime group may optionally be converted into another such group.
• the desired product of the general formula I contains a 9-imino group, it may be obtained by conversion from a 9-oxime group, and the resulting 9-imino group may in turn, if necessary, be converted to a 9-(optionally substituted)-amino group. All such conversions at the 9-position may be carried out in known manner, for example as described in the above-cited references.
• the oxime may be converted to the imine by reaction with titanium trichloride in known manner, and the imine may be converted to the amine by reaction with sodium borohydride in known manner.
• any of the groups R 3 , R 6 , R 8 and R 9 may be converted to any of the other such groups within the definitions given above by methods known in the art, for example by the methods disclosed in the above-cited references.
• a compound in which R 9 denotes hydrogen and R 8 denotes hydroxy can be converted to a compound in which R 8 and R 9 together denote oxo and optionally thereafter to a compound in which R 9 denotes hydroxy or acetoxy and R 8 denotes hydrogen by methods analogous to those described in US 3 884 903, op. cit..
• a compound in which R 6 denotes hydrogen can be converted to a compound in which R 6 denotes hydroxy or fluoro by methods analogous to those described in J. Antibiotics, XXVI and XXXVI, op. cit..
• any protecting groups may be removed by a conventional method. It is often appropriate to employ a hydrogenation procedure.
• the hydrogenation may suitably be carried out in the presence of a transition metal catalyst, for example palladium, which may, for example, be in the form of palladium on carbon (charcoal), palladium on barium sulphate, palladium on calcium carbonate, or palladium black.
• a transition metal catalyst for example palladium, which may, for example, be in the form of palladium on carbon (charcoal), palladium on barium sulphate, palladium on calcium carbonate, or palladium black.
• a favoured catalyst is palladium on carbon (sometimes referred to as palladium on charcoal); for example 5%, 10%, 20% or 30% palladium on carbon.
• a low, medium or high pressure of hydrogen may be used in this reaction, for example a pressure of from 1 to 6 atmospheres absolute, a pressure of 1 atmosphere absolute being convenient.
• the reaction may suitably be carried out at a non-extreme temperature, for example at a temperature within the range of from 0°C to 30°C, preferably from 12°C to 25°C. It is generally convenient to carry out the reaction at ambient temperature.
• the reaction is preferably carried out at a pH within the range of from 4.5 to 5.0, which may be maintained by the use of a suitable buffer, for example an acetate buffer at pH 4.8.
• suitable solvents for carrying out the hydrogenation include ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxan, ethyl acetate, a mixture of two or more such solvents, or such a solvent or mixture in the presence of water.
• a favoured solvent is ethanol.
• a compound of the general formula I may be converted to a pharmaceutically acceptable salt thereof or ester thereof in a conventional manner at any convenient stage in the manufacturing process, for example before or after the removal of any protecting groups and/or before or after any conversion of the 9-substituent and/or of groups R 3 , R 6 , R 8 and R 9 to other such groups.
• Isolation and purification of a compound according to the invention may be carried out using conventional methods, and may include a chromatography step.
• the product is isolated in crystalline form.
• the compounds according to the invention have antibacterial properties and are useful for the treatment of bacterial infections in animals, especially mammals, including humans, in particular humans and domesticated animals (including farm animals).
• the compounds may be used for the treatment of infections caused by a wide range of gram-positive and gram-negative organisms including, for example. Bacillus subtilis, Corynebacterium xerosis, Sarcina lutea, Staphylococcus aureus. Streptococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae. Streptococcus pneumoniae, Haemophilus sp. Neisseria sp., Chlamydia sp., and Legionella sp..
• the present invention provides a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier or excipient.
• the present invention also provides a method of treating bacterial infections in animals, especially in humans and in domesticated mammals, which comprises administering a compound or composition according to the invention to a patient in need thereof.
• the compounds and compositions according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
• compositions according to the invention may be formulated for administration by any route, for example oral, topical or parenteral.
• the compositions may, for example, be made up in the form of tablets, capsules, powders, granules, lozenges, creams, syrups, or liquid preparations, for example solutions or suspensions, which may be formulated for oral use or in sterile form for parenteral administration by injection or infusion.
• Tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients including, for example, binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; and pharmaceutically acceptable wetting agents, for example sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable vehicle before use.
• Such liquid preparations may contain conventional additives, including, for example, suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters (for example glycerine), propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring and colouring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monoole
• a compound or composition according to the invention may suitably be administered to the patient in an atrtibacterially effective amount.
• a composition according to the invention may suitably contain from 0.1% by weight, preferably from 10 to 60% by weight, of a compound according to the invention (based on the total weight of the composition), depending on the method of administration.
• the compounds according to the invention may suitably be administered to the patient at a daily dosage of from 1.5 to 50 mg/kg, suitably from 5 to 20 mg/kg, of body weight.
• a daily dosage of from 1.5 to 50 mg/kg suitably from 5 to 20 mg/kg, of body weight.
• For an adult human (of approximately 70 kg body weight) from 100 to 3000 mg, for example about 1500 mg, of a compound according to the invention may be administered daily. Higher or lower dosages may, however, be used in accordance with normal clinical practice.
• each unit dose may suitably comprises from 25 to 1000 mg, preferably from 50 to 500 mg, of a compound according to the invention.
• Example 1 The MIC data given in Example 1 is representative of the activity of the compounds of the present invention.
• 0,N-Dibenzyloxycarbonyl-des-N-methylerythromycin A (1.0 g) (prepared by the method described in E.H. Flynn et al, J. Amer. Chem. Soc, 1955, 77, 3104) in dry N,N-dimethylformamide (10 ml) was treated with chloroiodomethane (1 ml). The solution was stirred at 0°C while sodium hydride (120 mg; 50% dispersion in oil) was added in one portion. The mixture was stirred at 0°C with exclusion of moisture for 50 min, and was then allowed to warm to room temperature during 10 min.
• Table 1 gives minimum inhibitory concentration (MIC) values, in ug/ml, for the compound of Example 1b) as compared with the MIC values of erythromycin A against two representative organisms:
• Example 2(a) The product from Example 2(a) was converted into the title compound using the process described in Example 1(b). The title compound was obtained as a colourless foam (80 mg).
• 11,12-0-Methylene-erythromycin A 9-methoxime a 0,N-Dibenzyloxycarbonyl-11,12-0-methylene-des-Nmethylerythromycin A 9-methoxime 0,N-Dibenzyloxycarbonyl-des-N-methylerythromycin A 9-methoxime (prepared from erythromycin A by conventional methods) (200 mg) in dry N,N-dimethylformamide (2 ml) was treated with powdered potassium carbonate (100 mg), chloroiodomethane (0.2 ml), 15-crown-5 ether (1 drop), and sodium hydride (25 mg; 50% dispersion in oil). The mixture was stirred at room temperature with exclusion ⁇ f moisture for 30 min.
• 0,N-Dibenzyloxycarbonyl-des-N-methylerythromycin A (3.0 g) was dissolved in glacial acetic acid (30 ml) and the solution was kept for 2 hours at room temperature. The acetic acid was removed by evaporation under reduced pressure and the residue was crystallised from ether-petroleum ether (b.p. 60 - 80°C) to give the title compound as colourless prisms (2.7 g), m.p. 177 - 178°C.
• Example 4(b) The product from Example 4(b) (240 mg) in ethyl acetate (6 ml) was treated with water, (1.5 ml), and the mixture was stirred with m-chloroperbenzoic acid (55 mg) was added in small portions over 30 mins. The mixture was stirred for a further 2 hours and was then diluted with ethyl acetate (50 ml) and washed with water, saturated sodium hydrogen carbonate, and water. The solution was dried, the solvent was removed and the residue was chromatographed on silica gel using ethyl acetate-petroleum either (b.p. 60 - 80°C) to give the title compound as colourless prisms (220 mg), m.p. 210 - 212°C.
• Example 4(c) The product from Example 4(c) (170 mg) was converted into the title compound using the process described in Example Kb). The title compound was obtained as a colourless foam (140 mg).
• Example 1(a) The product from Example 1(a) (320 mg) in dry dimethylsulphoxide (3 ml) was treated with triethylamine (100 mg) and acetic anhydride (1 ml). The mixture was kept at room temperature for 18 hours, and was then diluted with ethyl acetate (20 ml), treated with saturated sodium hydrogen carbonate (10 ml), and stirred for 10 min. More ethyl acetate (50 ml) was added and the solution was washed with water (3 x). The solution was dried, the solvent was removed, and the residue was chromatographed on silica gel using ethyl acetate-petroleum ether (b.p.
• Example 6 The product from Example 5(a) (100 mg) was converted into the title compound using the process described in Example Kb). The title compound was obtained as a colourless gum (80 mg). Spectral properties of the product indicate that it exists largely as the 6,9-hemi-ketal tautomer.
• Example 6 The product from Example 5(a) (100 mg) was converted into the title compound using the process described in Example Kb). The title compound was obtained as a colourless gum (80 mg). Spectral properties of the product indicate that it exists largely as the 6,9-hemi-ketal tautomer.
• Example 6 Example 6
• the title compound can be prepared from the intermediate prepared in Example 4(b) using the fluorination process described in Tetrahedron Letters, 1983, 5527, followed by deprotection as in Example 4(d).
• Example 9(a) The product (200 mg) from Example 9(a) was converted into the title compound using the process described in Example 1(b). The title compound was obtained as a colourless foam (150 mg). c) 11,12-0-Isopropylidene-erythromycin A 9-oxime
• Example 10 The product (150 mg) from Example 9(b) was dissolved in acetone (10 ml) - water (10 ml) and the pH of the solution was adjusted to 3 using 0.1 M HCl. The solution was kept at pH 3 for 3 h. The acetone was removed under reduced pressure, and the aqueous residue was basified (pH 12) by addition of potassium carbonate and extracted with ethyl acetate (2 x 30 ml). The ethyl acetate solution was dried (Na 2 SO 4 ) and the solvent was removed to yield a colourless gum. The gum was chromatographed on silanised silica gel using 3:2 methanol - phosphate buffer (0.067 M; pH 7.0) to give the title compound as a white solid (50 mg).
• Example 10 Example 10

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