EP0190278A1

EP0190278A1 - Erythromycin derivatives

Info

Publication number: EP0190278A1
Application number: EP19850904014
Authority: EP
Inventors: Eric Hunt
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1984-08-23
Filing date: 1985-08-16
Publication date: 1986-08-13
Also published as: WO1986001513A1; GB8421429D0

Abstract

Dérivés d'érythromycine à base de 11,12-O-méthylène à action antibactérienne de formule (I) et leurs esters et sels d'addition d'acide pharmaceutiquement acceptables, où R1 ou R2 est amino éventuellement substitué, et R2 ou R1 est H, ou R1 + R2 est oxo, oxime éventuellement substitué ou imino; R3 est H ou CH3; R4 et R5 sont chacun H ou un hydrocarbure; R6 est H, F ou OH; R7 est H ou CH3; R8 ou R9 est H, OH, alkoxy, alkanoloxy, amino éventuellement substitué, ou R10-SO2-O-, et R9 ou R8 est H, ou R8 + R9 est oxo ou oxime éventuellement substitué; R10 est organique.11,12-O-methylene erythromycin derivatives with antibacterial action of formula (I) and their pharmaceutically acceptable esters and acid addition salts, where R1 or R2 is optionally substituted amino, and R2 or R1 is H, or R1 + R2 is oxo, optionally substituted oxime or imino; R3 is H or CH3; R4 and R5 are each H or a hydrocarbon; R6 is H, F or OH; R7 is H or CH3; R8 or R9 is H, OH, alkoxy, alkanoloxy, optionally substituted amino, or R10-SO2-O-, and R9 or R8 is H, or R8 + R9 is optionally substituted oxo or oxime; R10 is organic.

Description

Erythromycin derivatives

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 US 2 653 899 (R.L. Bunch et al; Eli Lilly). The structure of erythromycins can be represented as follows:

in which

R^a denotes hydrogen or hydroxy and

R^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^a = OH)

erythronolide B (in which R^a = H).

The four main naturally occurring erythromycins are as follows:

Erythromycin R^a R^b

A OH CH₃

B H CH₃

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 (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).

Certain aldehyde-erythromycylamine condensation products with a 9-N,6-O- or 9-N, 11-O-cyclic substituent have previously been disclosed (US 4 048 306 (R. Maier et al; Boehringer Ingelheim GmbH)). 4''-Deoxy-11-0-methylthiomethyl-4''-oxo-erythromycin B and its conversion to (i) 4''-deoxy-9,11-0-(optionally substituted)methylene-4''-oxo-erythromycin B 6,9-hemiacetal and the corresponding 4''-epi-hydroxy, 2', 4''-0-diacetyl-4''-epi, and 4''-0-acetyl-4''-epi derivatives, and (ii) 4''-deoxy-4''-oxo-, 4''-Oacetyl-4''-epi-, and 4''-epi-erythromycin B; as well as 4''-0-formyl-11-0-methylthiomethyl-erythromycin B and its conversion to 11-0-methylthiomethyl-erythromycin B, 9,11-0-methylene-erythromycin B 6,9-hemiacetal, 11-0-methyl-erythromycin B and 11-0-n-butylerythromycin B; and also 4''-deoxy-4'"-oxoerythromycin A are described in US 3 842 069, US 3 884 903 and US 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 11-0-acetyl and 11,12-cyclic carbonate derivatives, and also 4''-deoxy-4''-amino-erythromycin B and 4''-deoxy-4''-oxo-erythromycin A 4''-0-oxime or 4''-0-acetyloxime, are described in US 4 150 220 (F.C. Sciavolino; Pfizer).

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, 12-0-isopropylidene-erythromycin A and the corresponding 4''-epi compound have been described in US 4 382 086 (F.C. Sciavolino et al; Pfizer). 6-0-Methyl-, 6,11-di-0-methyl-, 11-0-methyl- and 11-0-ethyl-erythromycin A, and also 6-0-methyl6,4''-di-0-methyl-, and 6,11,4''-tri-0-methylerythromycin B are described in EP O 041 355 Al, EP O 080 818 Al and EP 0 080 819 Al (all Taisho Pharmaceutical).

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.

In particular, the present invention provides a compound of the general formula I or a pharmaceutically acceptable ester or acid addition salt thereof:

wherein

one of R¹ and R² denotes hydrogen and the other of R¹ and R² denotes an amino group or a substituted amino group, or R¹ and R² together denote an oxo group, an oxime group, a substituted oxime group, or an imino group;

R³ denotes hydrogen or a methyl group;

each of R⁴ and R⁵, which may be identical or different, denotes hydrogen or a hydrocarbon group;

R⁶ denotes hydrogen, fluorine, or hydroxy;

R⁷ denotes hydrogen or methyl;

one of R⁸ and R⁹ denotes hydrogen, hydroxy, alkoxy, alkanoyloxy, amino, substituted amino, or a group of the formula R¹⁰-SO₂-O-, 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; and

R¹⁰ denotes an organic 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_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.

Examples of 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.

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_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 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.

In one group of compounds of the general formula I, R¹ and R² together denote an oxo group, as in naturally occurring erythormycins. In a second group of compounds of the general formula I, R¹ and R² 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 group of compounds of the general formula I, R¹ and R² 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 R¹ and R² denotes an amino group or a substituted amino group, and the other of R¹ and R² denotes a hydrogen atom; such compounds may be referred to as erythromycylamines.

In the case of the erythromycin oxime and oxime-ether derivatives according to the invention, R¹ and R² may together denote a group of the formula II: O-R¹³ II

in which R¹³ denotes hydrogen or an unsubstituted or substituted hydrocarbon group or an acyl group. Examples of suitable groups denoted by R¹³ 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.

Examples of suitable substituents for the hydrocarbon group R¹³ 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

-S(O)_nR₁₂

in which n denotes 0, 1 or 2, and R¹² denotes a (C_1-6)alkyl, heterocyclyl, or aryl group.

Examples of acyl groups R¹³ include acetyl and benzyloxycarbonyl groups.

Examples of unsubstituted alkyl groups R¹³ include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl groups. Examples of substituted alkyl groups R¹³ include araikyl (especially benzyl), alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, arylalkoxyalkyl, alkoxyalkoxyalkyl (for example, β-methoxyethoxymethyl), alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, aralkylthioalkyl, haloalkyl, formylalkyl, carboxyalkyl and salts and esters thereof, thiocyanotoalkyl, 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 III: III

in which each of R¹⁴ and R¹⁵, 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 R¹⁴ and R¹⁵ 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 R¹⁴ and R¹⁵ 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 erythromycin oxime and substituted oxime derivatives according to the invention can exist in two geometric isomeric forms about the C=N double bond at the 9-position, as indicated by the wavy line in formula II 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, R¹ and R² together denote a group of the formula IV: =N-H IV

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 R¹ and R² denotes hydrogen and the other of R¹ and R² may denote a group of the formula III above, in which R¹⁴ and R¹⁵ are defined as above. Suitably each of R¹⁴ and R¹⁵ 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 R¹ denotes hydrogen and R² denotes the optionally substituted amino group, and the (9S)-form, in which R¹ denotes the optionally substituted amino group and R² 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

in the general formula I. R⁴ and R⁵ may be identical or different and each denotes a hydrogen atom or a hydrocarbon group. The hydrocarbon group R⁴, R⁵ 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. Suitably, at least one of R⁴ and R⁵ denotes a hydrogen atom. Advantageously, both of R⁴ and R⁵ denote hydrogen atoms. In another embodiment, both of R⁴ and R⁵ denote alkyl groups.

The 6-position of the erythronolide ring may carry a hydroxy group or methoxy group, -OR³, in which R³ denotes hydrogen or methyl. Suitably, the 6-position carries a hydroxy group, as in naturally-occuring erythromycins, in which case R³ 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 R⁶ 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 R⁶ may denote a hydroxy group or a fluorine atom.

The -OR⁷ group in the 3''-position of the cladinose ring may be a hydroxy group or a methoxy group. Preferably, R⁷ denotes a methyl group as in erythromycin A and B.

The 4''-position of the cladinose ring may suitably carry a hydroxy group as in erythromycin A and B (R⁸ = H; R⁹ = OH). 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:

(i) 4''-deoxy-4''-oxo derivatives (R⁸ + R⁹ = 0=) are described in US 3 842 069, US 3 884 903 and US 4 150 220, all op. cit.;

(ii) 4''-epi-hydroxy derivatives (R⁸ = OH; R⁹ = H) and 4''-deoxy-4''-alkanoyloxy-4''-epi derivatives (R⁸ = alkanoyloxy, especially CH₃COO-; R⁹ = H) are described in US 3 884 903, op. cit.;

(iii) 4''-0-alkyl derivatives (R⁸ or R⁹ = alkoxy, especially methoxy; the other of R⁸ and R⁹ = H) are described in EP O 080 818 Al, op. cit.;

(iv) 4''-deoxy-4''-amino derivatives (R⁸ or R⁹ = amino or substituted amino; the other of R⁸ and R⁹ = H) are described in US 4 150 220, op. cit.;

(v) 4''-deoxy-4''-oxime derivatives (R⁸ + R⁹ = oxime (=N-OH) or substituted oxime, especially acetyloxime (=N-O-CO-CH₃)) are also described in US 4 150 220, op. cit.;

(vi) 4''-0-sulρhonyl derivatives (R⁸ = H, R9 - R¹²-SO₂-O-) are described in US 3 836 519, US 3 869 445 and US 4 063 014 (all

R. Hallas et al; Abbott Laboratories); and

(vii) 4''-deoxy derivatives (R⁸ = R⁹ = H) are described in JP 58-049396 (Toyo Jozo KK). In the 4''-deoxy-4''-(substituted amino) derivatives, the substituted amino group R⁸ or R⁹ may suitably be a group of the formula

-NHCOR¹⁶ or -NHSO₂R¹⁶

in which R¹⁶ denotes a hydrocarbon group.

In the 4''-0-sulphonyl derivatives, in which R⁸ or R⁹ denotes a sulphonyloxy group of the formula

R¹⁰-SO₂-O-,

the organic group R¹⁰ 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 R¹⁷-CH₂-CH₂-, wherein R¹⁷ is defined as below) group.

Examples of groups R¹⁷ in the 4''-substituent

R¹⁷-CH₂-CH₂-SO₂-O-

include amino, substituted amino, carbamoyl, substituted carbamoyl, sulphamoyl, substituted sulphamoyl, substituted ureido, substituted thioureido, alkoxy, alkythio, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted benzyloxy, optionally substituted benzylthio, substituted suphonyl, substituted sulphinyl, substituted alkyl, substituted alkanoyl, substituted cyano, and other groups more specifically described in US 3 869 445 and US 4 063 014, op. cit.

Preferably, R¹⁰ 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.

Various acid addition salts of erythromycin are described in US 2 761 859 (C.E. Hoffhine, Jr.; Abbott Laboratories) and US 2 852 429 (J.T. Shepler; Eli Lilly).

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, α-keto-glutarate, α-glycerophosphate, and glucose-1-phosphate. Preferably the acid addition salt is the laurylsulphate salt.

Examples of individual compounds according to the present invention include:

(i) ll,12-£-methylene-erythromycin A (in general formula I, R¹ + R² = =0, R³ = R⁴ = R⁵ = R⁶ = H, R⁷ = CH₃, R⁸ = H, R⁹ = OH);

(ii) ll,12-£-methylene-erythromycin A 6-methyl ether (in general formula I, R³ = CH₃, R¹ + R² and R⁴ to R⁹ as for compound (i)); (iii) 11, 12-0-methylene-erythromycin A 9-methoxime (R¹ + R² = =N-OCH₃, R³ to R⁹ as for compound (i));

(iv) 8-hydroxy-11,12-0-methylene-erythromycin A

(R⁶ = OH, R¹ + R² and R³ to R⁵ and R⁷ to R⁹ as for compound (i));

(v) 11, 12-0-methylene-4''-deoxy-4''-oxoerythromycin A (R³- + R² and R³ to R⁷ as for compound (i), R⁸ + R⁹ = =0);

(vi) 11,12-0-methylene-4''-0-methanesulphonylerythromycin A (R¹ + R² and R³ to R⁸ as for compound (i), R⁹ = -SO₂CH₃);

(vii) 11,12-0-methylene-erythromycin A 9-(2-methoxyethoxy)methoxime (R¹ + R² = =N-OCH₂OC₂H₄OCH₃, R³ to R⁹ as for compound (i));

(viii) 11,12-0-isopropylidene-erythromycin A 9-oxime (R¹ + R² = =N-OH, R⁴ = R⁵ = CH₃, R³ and R⁶ to R⁹ as for compound (i));

(ix) 11,12-0-isoproρylidene-erythromycin A 9-amine (R¹ = -NH₂, R² = H, R³ to R⁹ as for compound (i)); and

(x) 8-fluoro-11,12-0-methylene-erythromycin A (R⁶ = F, R¹ + R² and R³ to R⁵ and R⁷to R⁹ as for compound ( i));

and also pharmaceutically acceptable esters and acid addition salts of such compounds.

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) converting a substitutent on the erythromycin structure to another such substituent in a conventional manner;

(b) removing any protecting groups; and

(c) forming a pharmaceutically acceptable ester or acid addition salt.

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.

More particularly, 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:

wherein

R³, R⁶, R⁷, R⁸ and R⁹ are defined as above with respect to general formula I,and

R¹⁸ 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,

with:

(i) a compound of the general formula VII

VII

in which R⁴ and R⁵ are defined as above with respect to general formula I, or a reactive derivative of such a compound; or

(ii) a compound of the general formula VIII

viii

in which

R⁴ and R⁵ 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 R¹ and R² together denote an oxo, 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 an oxo group denoted by R¹ and R² together to an oxime group or a substituted oxime group;

(b) converting a substituted oxime group denoted by R¹ and R² together to another substituted oxime group or an oxime group;

(c) converting an oxime group denoted by R¹ and R² together to a substituted oxime group or an imino group;

(d) converting a resulting imino group denoted by R¹ and R² together to an amino group denoted by R¹ or R²;

(e) converting a resulting amino group denoted by R¹ or R² to a substituted amino group;

( f) converting any one or more of the groups denoted by R³, R⁶, R⁸ and R⁹ to another such group;

(g) removing any protecting group that may be present; and

(h) forming a pharmaceutically acceptable ester or acid addition salt. The compound of the general formula VI in which:

each of R³, R⁶ and R⁸ denotes hydrogen,

R⁷ denotes methyl, and

R⁹ denotes hydroxy,

is erythromycin A or a 9-oxime or a 9-substituted-oxime derivative thereof. The 9-oxime and

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. For example, a compound in which the 4''-position is substituted other than as in naturally-occuring erythromycin A (that is to say, in which R⁸ is other than hydrogen and/or R⁹ is other than hydroxy) may be prepared as described in the respective references cited above.

In general, in the preparation of 9-oxime and 9-substituted-oxime compounds of the general formula VI, 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.

Prior to carrying out the reaction of a compound of the general formula VI with the compound of the general formula VII, VIII or IX, any reactive group of a compound of the general formula VI (other than the 11and 12-hydroxy groups) may optionally be protected.

In particular, 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 ) .

Examples of suitable N-protecting groups 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.

It 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. In particular, it may be advantageous to protect any hydroxy groups present at the 2'- and 4''-positions. It is convenient to employ the same group to protect the hydroxy group (s) as that employed to protect the amino moiety, especially a benzyloxycarbonyl group.

Any reactive substituents that may be present in the group R⁸ or R⁹ 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 R¹⁸ denotes an oxime group or a substituted oxime group, or a compound of the general formula VI in which R¹⁸ denotes an oxo group and in which R³ denotes a methyl group or the 6-hydroxy group is otherwise protected. In this method, the compound of the general formula VI, optionally containing protective groups, is reacted with an aldehyde (R⁴ and/or R⁵ = H) or a ketone (R⁴, R⁵ are not H) of the general formula VII or a reactive derivative thereof. Suitable reactive derivatives of aldehydes or ketones of the general formula VII include, for example, acetals of the general formula IX:

IX

hemiacetals of the general formula X:

and enol ethers of the general formula XI :

XI in which formulae IX to XI,

R⁴ and R⁵ are defined as above with respect to general formula I;

each of R¹⁹ and R²⁰, 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

R²¹ denotes a divalent hydrocarbon group corresponding to the monovalent hydrocarbon group R⁵ 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).

Advantageously, the 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.

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 R¹⁸ denotes an oxo group or a substituted oxime group. In this method, the compound of the general formula VI, optionally containing protective groups, is reacted with a compound of the general formula VIII. In 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.

Examples of 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).

Preferably, 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).

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.

After completion of the reaction according to method (i) or (ii) above, and preferably prior to removal of any protecting groups, the 9-oxo, 9-oxime or 9-substituted-oxime group may optionally be converted into another such group. If 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. For example, 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.

Also after completion of the reaction according to method (i) or (ii) above, and prior or subsequent to any conversion of the 9-substituent, any of the groups R³, R⁶, R⁸ and R⁹ 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. For example, a compound in which R⁹ denotes hydrogen and R⁸ denotes hydroxy can be converted to a compound in which R⁸ and R⁹ together denote oxo and optionally thereafter to a compound in which R⁹ denotes hydroxy or acetoxy and R⁸ denotes hydrogen by methods analogous to those described in US 3 884 903, op. cit.. Also, a compound in which R⁶ denotes hydrogen can be converted to a compound in which R⁶ denotes hydroxy or fluoro by methods analogous to those described in J. Antibiotics, XXVI and XXXVI, op. cit..

After completion of the alkylation reaction, 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 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.

In order to restore the dimethylamino group at the 3'-position, it is convenient to effect a reductive methylation, which advantageously may be carried out at the same time as the reductive removal of the protecting groups, as in the method of Flynn et: al, op. cit..

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 R³, R⁶, R⁸ and R⁹ 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.

Preferably the product is isolated in crystalline form.

The compounds according to the invention, that is to say, the compounds of the general formula I and their pharmaceutically acceptable salts and esters, 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.

The compounds and 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.

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. 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.

When the compositions according to the invention are presented in unit dosage form, each unit dose may suitably comprises from 25 to 1000 mg, preferably from 50 to 500 mg, of a compound according to the invention.

No adverse toxicological effects are indicated when the compounds according to the invention are administered within the above-mentioned dosage ranges.

The following examples illustrate the preparation of compounds according to the present invention. The MIC data given in Example 1 is representative of the activity of the compounds of the present invention.

Example 1

11,12-0-Methylene erythromycin A (formula I, R¹=R²=R³=H)

a) 0,N-Dibenzyloxycarbonyl-11,12-0-methylene-des-Nmethylerythromycin A

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. The mixture was diluted with ethyl acetate (100 ml) and was washed with dilute sodium sulphite and water (3 x). The solution was dried (sodium sulphate) and the solvent was evaporated under reduced pressure. The resulting oil was chromatographed on silica gel using ethyl acetate-petroleum ether (b.p. 60-80°C) to give the title compund (90 mg), [α]²⁴ - 56.8° (£ 1.0, CHCI₃); v_max (CHCI₃) 3500, 1735, and 1690 cm^-1.

b) 11,12-0-methylene-erythromycin A

0,N-Dibenzyloxycarbonyl-11,12-0-methylene-des-Nmethylerythromycin A (160 mg) in a mixture of ethanol (10 ml) and acetate buffer [1 ml; sodium acetate (1.0 g) and acetic acid (0.6 ml) in water (30 ml)] was shaken with 10% palladium-charcoal (50 mg) under hydrogen (1 atm.) at room temperature for 25 min. 38% aqueous formaldehyde solution (1 ml) was then added and the hydrogenation was continued for a further 1.5 hours. The catalyst was removed by filtration and was washed with ethanol. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was dissolved in water (15 ml). The solution was brought to pH 10 by adding solid potassium carbonate and was then extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with water

(10 ml) and dried (Na₂SO₄). The solvent was evaporated under reduced pressure to give the title compound (100 mg), [α]²⁴ -37.7° ( c 1.0, CHCI₃); v_max (CHCI₃) 3500 and

1730 cm^-1. Spectral properties of the product indicate that it exists as the 6,9-hemi ketal tautomer.

c) Biological data

The following 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:

d) Acid Stability

The acid stability of the compound of Example 1b) was compared with that of erythromycin A, by determining the percentage of compound remaining after 15 minutes in solution at pH 2. The results are given in Table 2.

Example 2

11,12-0-Methylene-erythromycin A 6-methyl ether a) 0,N-Dibenzyloxycarbonyl-11,12-0-methylene-des-Nmethyloxyerythromycin A 6-methyl ether

0,N-Dibenzyloxycarbonyl-des-N-methylerythromycin A 6-methyl ether (prepared according to EP 41,355) (1.516 g) and chloroiodomethane (1.52 ml) in dry N,N-dimethylformamide (11 ml) was stirred at 0°C while sodium hydride (188 mg; 50% dispersion in oil) was added in one portion. The mixture was stirred at 0°C for 50 min. and then at room temperature for 20 min.

The mixture was diluted with ethyl acetate (100 ml) and washed with dilute sodium sulphite and water (3 x). The solution was dried and the solvent was removed toyield a colourless oil. Chromatography on silica gel using ethyl acetate - petroleum ether (b.p. 60 - 80°C) gave the tile compound as a colourless gum (160 mg) .

b) 11,12-0-Methylene-erythromycin A 6-methyl ether

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).

Example 3

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 αf moisture for 30 min. The mixture was diluted with ethyl acetate (30 ml) and washed with dilute sodium sulphite solution and water (2 x). The solution was dried, the solvent was removed, and the residue was chromatographed on silica gel using ethyl acetate - petroleum ether (b.p. 60 80°C) to give the title compound as a colourless gum (70 mg).

b) 11,12-0-Methylene-erythromycin A 9-methoxime

0,N-Dibenzyloxycarbonyl-des-N-methylerythromycin A 9-methoxime (160 mg) was converted into the title compound using the process described in Example 1(b). The title compound was obtained as a colourless foam (120 mg).

Example 4

( 8S)-8_Hydroxy-11,12-0-methylene-erythromycin A a) 0-,N-Dibenzyloxycarbonyl-des-N-methyl-8,9anhydroerythromycin A 6,9-hemi-ketal

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.

b) 0,N-Dibenzyloxycarbonyl-des-N-methyl-11,12-0methylene-8,9-anhydroerythromycin A 6,9-hemi-ketal The product from Example 4(a) (500 mg) and chloroiodomethane (0.5 ml) were dissolved in dry N,N-dimethylformamide (5 ml) and to the stirred solution sodium hydride (50 mg; 50% dispersion in oil) was added in one portion. The mixture was stirred with exclusion of moisture for 30 mins. and was then worked-up and chromatographed as described in Example 1(a) to give the title compound as colourless needles (240 mg), m.p. 190 - 191°C.

c) 0,N-Dibenzyloxycarbonyl-des-N-methyl-(8S)-hydroxy11,12-0-methylene-erythromycin A

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.

d) (8s)-8-Hydroxy-11,12-0-methylene-erythromycin A

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 5

11, 12-0-Methylene-4"-deoxy-4"-oxo-erythromycin A a) 0,N-Dibenzyloxycarbonyl-11,12-0-methylene-des-Nmethyl-4"-deoxy-4"-oxo-erythromycin 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. 60 - 80°C) to give the product as a pale yellow gum, which crytallised from ether-petroleum ether (b.p. 60 - 80°C). The title compound was thus obtained as colourless needles (230 mg), m.p. 128 - 129°C.

b) 11,12-_0-Methylene-4"-deoxy-4'-koxo-erythromycin A

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

8-fluoro-11,12-0-methylene-erythromycin A

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 7

11,12-0-Methylene-4''-0-methanesulphonyl-erythromycin A

11, 12-0-Methylene-erythromycin A (200 mg) in dry pyridine (3 ml) was treated with methanesulphonyl chloride (70 mg) and the mixture was stirred at room temperature for 2 hours. The mixture was poured into dilute sodium hydrogen carbonate solution and was extracted twice with chloroform. The combined extracts were washed with water and dried (Na₂SO₄). The solvent was removed to yield the title compound as a pale yellow foam (170 mg); [ α]_D ²² = -44.2° (c. 1.0, CHCI₃).

Example 8

11,12-0-Methylene-erythromycin A 9-(2-methoxyethoxy)methoxime

a) 0,N-Dibenzyloxycarboriyl-des-N-methylerythromycin A 9-(2-methoxyethoxy)-methoxime

0,N-Dibenzyloxycarbonyl-des-N-methylerythromycin A 9-oxime (400 mg) in dry N,N-dimethylformamide (6 ml) treated with powdered potassium carbonate (320 mg) and sodium hydride (24 mg; 50% dispersion in oil) and the mixture was stirred for 5 min. 2-Methoxyethoxymethyl chloride (0.4 ml) was added and stirring was continued for a further 30 min. The mixture was diluted with ethyl acetate and washed with water (3 x). The solution was dried, the solvent was removed, and the residue was chromatographed on silica gel using ethyl acetate - hexane to give the title compound as a colourless gum (260 mg).

b) 0,N-Dibenzyloxycarbonyl-11,12-0-methylene-des-Nmethyl-erythromycin A 9-(2-methoxyethoxy)methoxime

0,N-Dibenzyloxycarbonyl-des-N-methyl erythromycin A 9-(2-methoxyethoxy)-methoxime (260 mg) in N,N-dimethylformamide (4 ml) was treated with powdered potassium carbonate (170 mg), chloroiodomethane (0.26 ml), 15-crown-5 ether (1 drop), and sodium hydride (40 mg; 50% dispersion in oil) and the mixture was stirred for 30 mins. The mixture was diluted with ethyl acetate and washed with dilute sodium sulphite solution and water (3 x). The solution was dried, the solvent was removed, and the residue was chromatogaphed on silica gel using ethyl acetate - hexane to give the title compound as a colourless gum (70 mg).

c) 11,12-0-Methylene-erythromycin A 9-( 2-methoxyethoxy)-methoxime

0, N-Dibenzyloxycarbonyl-11,12-0-methylene-des-N-methylerythromycin A 9-(2-methoxyethoxy)-methoxime (180 mg) was converted into the title compound using the process described in Example 1(b). The title compound was obtained as a colourless foam (110 mg); [α]_D ²⁰ = -24.5° (c. 1.2, CHCI₃). Example 9

11,12-0-Isopropylidene-erythromycin A 9-oxime

a) 0,N-Dibenzyloxycarbonyl-11,12-0-Isopropylidene4''-0-(1-methoxy-isopropyl)-des-N-methyl erythromycin A 9-oxime

0,N-Dibenzyloxycarbonyl-des-N-methylerythromycin A 9-oxime (600 mg) and 2-methoxypropene (0.7 ml) in ethanol-free chloroform (6 ml) was treated with pyridinium p-toluenesulphonate (60 mg) and the mixture was stirred at room temperature with exclusion of moisture for 18 h. The mixture was diluted with ethyl acetate (60 ml) and was washed with water (3 x 30 ml). The solution was dried (Na₂SO₄) and the solvent was removed under reduced pressure to give a yellow foam. Four major products were detected on t.l.c. (silica gel; 2:1 ethyl acetate - hexane), the least polar of these being the required product. Chromatography on silca gel using 1:2 to 2:1 ethyl acetate - hexane gave the title compound as a colourless gum (200 mg).

b) 11, 12-0-Isopropylidene-4''-0-(1-methoxy-isopropyl)erythromycin A 9-oxime

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

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 (Na₂SO₄) 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

(9S)-11,12,-0-isopropylidene-erythromycylamine

11, 12-0-isopropylidene-erythromycin 9-oxime (obtained as described in Example 9) can be reduced to the title compound by reduction as described by E.H. Massey et al (Tetrahedron Letters, 1970, 2, 157-160).

Claims

Claims B1700

1. A compound of the general formula I or a pharmaceutically acceptable ester or acid addition salt thereof:

wherein

one of R¹ and R² denotes hydrogen and the other of R¹ and R² denotes an amino group or a substituted amino group, or

R¹ and R² together denote an oxo group, an oxime group, a substituted oxime group, or an imino group;

R³ denotes hydrogen or a methyl group;

each of R⁴ and R⁵, which may be identical or different, denotes hydrogen or a hydrocarbon group; R⁶ denotes hydrogen, fluorine, or hydroxy;

R⁷ denotes hydrogen or methyl;

R⁸ and R⁹ together denote an oxo group, an oxime group,or a substituted oxime group; and

R¹⁰ denotes an organic group.

2. A compound as claimed in dlaim 1, wherein each of R⁴ and R⁵ denotes a hydrogen atom or an unsubstituted or substituted alkyl group.

3. A compound as claimed in claim 1, wherein each of R⁴ and R⁵ denotes a hydrogen atom.

4. A compound as claimed in claim 1, wherein each of R⁴ and R⁵ denotes an alkyl group.

5. The compounds:

11, 12-0-methylene-erythromycin A;

11, 12-0-methylene-erythromycin A 6-methyl ether;

11, 12-0-methylene-erythromycin A 9-methoxime; 8-hydroxy-11,12-0-methylene-erythromycin A;

11,12-0-methylene-4''-deoxy-4''-oxo-erythromycin A;

11,12-0-methylene-4''-0-methanesulphonylerythromycin A;

11,12-0-methylene-erythromycin A 9-(2-methoxyethoxy)methoxime; 11,12-0-isopropylidene-erythromycin A 9-oxime; 11,12-0-isopropylidene-erythromycylamine; and 8-fluoro-11,12-0-methylene-erythromycin A.

6. A process for the manufacture of a compound of the general formula I as defined in claim 1, or a pharmaceutically acceptable ester or acid addition salt thereof, which comprises reacting a compound of the general formula VI:

wherein

R³, R⁶, R⁷, R⁸ and R⁹ are defined as in claim 1, and

R¹⁸ denotes an oxo, oxime or substituted oxime group,

in which compound of the general formula VI any reactive group (other than 11- and 12-hydroxy groups) may be optionally be protected, with:

(i) a compound of the general formula VII

VII

(ii) a compound of the general formula VIII

VIII

in which

R⁴ and R⁵ 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 R¹ and R² together denote an oxo, oxime or substituted oxime group; and thereafter, if necessary or desired, carrying out one or more of the following steps in any suitable order:

(c) converting an oxime group denoted by R¹ andR² together to a substituted oxime group or an imino group;

(e) converting a resulting amino group denoted by

R¹ or R² to a substituted amino group;

(g) removing any protecting group that may be present; and

(h) forming a pharmaceutically acceptable ester or acid addition salt.

7. A pharmaceutical composition, which comprises a compound of the general formula I as defined in claim 1, or a pharamceutically acceptable ester or acid addition salt thereof, in admixture or conjunction with a pharmaceutically acceptable carrier or excipient.

8. A method of treating bacterial infections in animals, which comprises administering a compound as claimed in claim 1 or a composition as claimed in claim 7 to a patient in need thereof.