WO2004101584A1 - Macrolides substituted at the 3-position having antimicrobial activity - Google Patents

Abstract

The present invention relates to 14- or 15-membered macrolides substituted at the 3-position of formula (I) and pharmaceutically acceptable derivatives thereof, to processes for their preparation and their use in therapy or prophylaxis of systemic or topical microbial infections in a human or animal body.

Description

MACROLIDES SUBSTITUTED AT THE 3-POSITION HAVING ANTIMICROBIAL ACTIVITY

The present invention relates to novel semi-synthetic macrolides having antimicrobial activity, in particular antibacterial activity. More particularly, the invention relates to 14- and 15-membered macrolides substituted at the 3-position, to processes for their preparation, to compositions containing them and to their use in medicine.

Macrolide antibacterial agents are known to be useful in the treatment or prevention of bacterial infections. However, the emergence of macrolide-resistant bacterial strains has resulted in the need to develop new macrolide compounds.

According to the present invention, we have now found novel 14- and 15-membered macrolides substituted at the 3-position which have antimicrobial activity.

Thus, the present invention provides compounds of general formula (I)

(I)

wherein

A is a bivalent radical selected from -C(O)-, -C(O)NH-, -NHC(O)-, -N(R⁷)-CH2-, -CH2- N(R⁷)-, -CH(NR⁸R⁹)- and -C(=NR¹⁰)-;

R¹ is -OC(O)C(R^{1 1}R¹²)B(CH₂)dXR¹³;

R² is hydrogen or a hydroxyl protecting group; R³ is hydrogen, C-j^alkyl, or C^alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;

R⁴ is hydroxy, C3_6aikenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C- galkoxy optionally substituted by C^galkoxy or -O(CH2)_eNR⁷R¹⁴,

R⁵ is hydroxy, or R⁴ and R⁵ taken together with the intervening atoms form a cyclic group having the following structure:

wherein Y is a bivalent radical selected from -CH2-, -CH(CN)-, -O-, -N(R¹⁵)- and -

CH(SR¹⁵)-;

R6 is hydrogen or fluorine;

R⁷ is hydrogen or C<|_galkyl;

R⁸ and R⁹ are each independently hydrogen, C^βalkyl, -C(=NR¹⁰)NR¹⁶R¹⁷ or -

C(O)R¹⁶, or

Rδ and R⁹ together form =CH(CRl⁶R ⁷)_faryl, =CH(CR¹⁶R¹⁷)_fheterocyclyl, =CR16R17 or =C(R16)C(O)OR^_> wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R¹⁸;

R10 is -OR¹⁹, C|_₆alkyl, -(CH₂)_garyl, -(CH₂)_gheterocyclyl or -(CH₂)hO(CH₂)iOR⁷, wherein each R¹^ group is optionally substituted by up to three groups independently selected from R¹⁸;

R^{1 1} is hydrogen, hydroxy, Chalky! or C-μealkoxy;

R12 is hydrogen or C^.galkyl;

R¹3 is a heterocyclic group having the following structure:

or

R14 js hydrogen or C-μβalkyl;

R^"15 is hydrogen or C-j.4alkyl optionally substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl; R¹6 and R^"17 are each independently hydrogen or C^galkyl;

R¹⁸ is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R²³, -C(O)OR²³, -OC(O)R²³, - OC(O)OR²³, -NR²⁴C(O)R²⁵, -C(O)NR²⁴R²5 -NR²⁴R²⁵, hydroxy, Chalky!, -S(O)_kC-|_ galkyl, C^galkoxy, -(CH2)_m ^aryl ^or -(CH2)_mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from -NR¹⁶R¹⁷, halogen and -OR¹⁶, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, - C(O)R²⁶, -C(O)OR²⁶, -OC(O)OR²⁶, -NR²⁷C(O)R²⁸, -C(O)NR²⁷R²⁸ -NR²7R28_I hydroxy,

R¹⁹ is hydrogen, C-j.ρalkyl, C3_7cycloalkyI, C3_βalkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, -OR²⁹, -S(O)_nR²⁹ -NR²⁹R³⁰, -CONR²⁹R³⁰, halogen and cyano; R²⁰ is hydrogen, -C(O)OR³¹ , -C(O)NHR³¹ , -C(O)CH₂NO₂ or -C(O)CH₂SO₂R⁷; R²¹ is hydrogen, C^^alkyl optionally substituted by hydroxy or Cι_4alkoxy, C3_ 7cycloalkyl, or optionally substituted phenyl or benzyl; R²² is halogen, C-^alkyl, C<|_4thioalkyl, C<|_4alkoxy, -NH2, -NH(Cι_4alkyI) or -N(C-). 4alkyl)2;

R²³ is hydrogen, Ci.-jnalkyl, -(CH2)paryl or -(CH2)nheteroaryl;

R²⁴ and R²⁵ are each independently hydrogen, -OR¹⁶, C^galkyl, -(CH2)qaryl or - (CH2)q heterocyclyl ; R²⁶ is hydrogen, Cι_-]oalkyl, -(CH2)raryl or -(CH2)_rheteroaryl;

R²⁷ and R²⁸ are each independently hydrogen, -OR¹⁶, C-j_ρalkyl, -(CH2)_saryl or - (CH2)_sheterocyclyl;

R²⁹ and R^3(J are each independently hydrogen, C-^alkyl or C-|_4aIkoxyCι_4alkyl; R³¹ is hydrogen, C-j-galkyl optionally substituted by up to three groups independently selected from halogen, cyano, C-|_4alkoxy optionally substituted by phenyl or C-|_4alkoxy, -

C(O)C-|_₆alkyl, -C(O)OC-|.₆alkyl, -OC(0)C<|_6alkyl, -OC(O)OC-ι_₆alkyl, -

C(O)NR³⁴R³⁵, -NR³ R³⁵ and phenyl optionally substituted by nitro or -C(O)OCι,_ ρalkyl, -(CH2)_wC3-7cycloalkyl,

-(CH2) heterocyclyl,

-(CH2)_wheteroaryl,

-(CH₂)_waryl,

C3_6alkenyl, or C3_galkynyl;

R³² is hydrogen, C^alkyl, C3_7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl;

R³³ is hydrogen or R²², or R³³ and R²¹ are linked to form the bivalent radical -O(CH2)2- or -(CH₂)_t-; R³⁴ and R³⁵ are each independently hydrogen or Chalky! optionally substituted by phenyl or -C(O)OCι_6alkyl, or R³⁴ and R³5, together with the nitrogen atom to which they are bound, form a 5 or 6 membered heterocyclic group optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur;

B is phenyl or pyridyl;

X is -U¹ (CH2)_VU²-, -U¹ (CH2 or a group selected from:

and

U¹ and U² are independently a divalent radical selected from -N(R³²)-, -O-, -S(O)₂-, -

N(R³²)C(O)-, -C(O)N(R³²)- and -N[C(O)R³²]-; W is -C(R³³)- or a nitrogen atom; d is an integer from 1 to 5; e is an integer from 2 to 4; f, g, h, m, p, q, r, s and w are each independently integers from 0 to 4; i is an integer from 1 to 6; j, k, n and z are each independently integers from 0 to 2; t is 2 or 3; v is an integer from 1 to 8; and pharmaceutically acceptable derivatives thereof.

According to a further embodiment the present invention provides compounds of general formula (IA):

(IA)

wherein A is a bivalent radical selected from -C(O)-, -C(O)NH-, -NHC(O)-, -N(R⁷)-CH2-, -CH₂- N(R⁷)-, -CH(NR⁸R⁹)- and -C(=NR¹⁰)-;

R¹ is -OC(O)C(R^{1 1} R 2)B(CH₂)dXR¹³;

R² is hydrogen or a hydroxyl protecting group;

R³ is hydrogen,

or C3_galkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;

R⁴ is hydroxy, C3_ealkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C^alkoxy optionally substituted by C-μgalkoxy or -O(CH2)_eNR⁷R¹⁴,

R? is hydroxy, or

R⁴ and R⁵ taken together with the intervening atoms form a cyclic group having the following structure:

11 12

H₃C wherein Y is a bivalent radical selected from -CH2-, -CH(CN)-, -O-, -N(R¹^)- and -

CH(SR¹⁵)-;

R⁶ is hydrogen or fluorine; R⁷ is hydrogen or C^alkyl;

R⁸ and R⁹ are each independently hydrogen, Chalky!, -C(=NR¹⁰)NR ⁶R¹⁷ or -

C(O)R¹⁶ or

R⁸ and R⁹ together form =CH(CR¹⁶R¹⁷)_faryl, =CH(CR¹⁶R¹⁷)fheterocyclyl, =CR¹⁶R¹⁷ or =C(R¹⁶)C(O)OR¹⁶, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R¹⁸;

R¹⁰ is -OR¹⁹, C<_|_₆alkyl, -(CH₂)_garyl, -(CH₂)_gheterocyclyl or -(CH₂)hO(CH₂)iOR⁷, wherein each R¹⁹ group is optionally substituted by up to three groups independently selected from R¹⁸;

R^{1 1} is hydrogen, hydroxy, Chalky! or C-μρalkoxy; R¹² is hydrogen or C-| -βalkyl; R¹³ is a heterocyclic group having the following structure:

or

R¹⁴ is hydrogen or C-j .ρalkyl;

R¹⁵ is hydrogen or C-j^alkyl substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl; R¹⁶ and R¹⁷ are each independently hydrogen or C-j .ρalkyl;

R¹⁸ is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R²³, -C(O)OR²³, -OC(O)R²³, - OC(O)OR²³, -NR²⁴C(O)R²⁵, -C(O)NR²⁴R²⁵, -NR²⁴R²⁵, hydroxy, C^ρalkyl, -S(O)_kC-|_ ρalkyl, C<|_ρalkoxy, -(CH2)_maryl or -(CH2)_mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from -NR¹⁶R¹⁷, halogen and -OR¹⁶, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, - C(O)R²⁶ -C(O)OR²⁶, -OC(O)OR²⁶, -NR²⁷C(O)R²⁸, -C(O)NR²⁷R²⁸, -NR²⁷R²⁸ hydroxy, C<| .ρalkyl and C-|_ρalkoxy;

R¹⁹ is hydrogen, C-j .ρalkyl, C3_7cycloalkyl, C3_ρalkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, -OR²⁹, -S(O)_nR²⁹ -NR²⁹R³⁰, -CONR²⁹R³⁰, halogen and cyano; R²⁹ is hydrogen, -C(O)OR³¹, -C(O)NHR³¹ or -C(O)CH₂NO₂;

R²¹ is hydrogen, C-j.4alkyl optionally substituted by hydroxy or C-^alkoxy, C3_ 7cycloalkyl, or optionally substituted phenyl or benzyl; R²² is halogen, C-^alkyl, C-^thioalkyl, C-|_4alkoxy, -NH2, -NH(C-|_4alkyl) or -N(C-|. 4alkyl)₂;

R²³ is hydrogen, Ci.-jrjalkyl, -(CH2)_paryl or -(CH2)_pheteroaryl;

R²⁴ and R²⁵ are each independently hydrogen, -OR¹⁶, C<_| .ρalkyl, -(CH2)_qaryl or -

(CH2)qheterocyclyl; R²⁶ is hydrogen, C-_|_-_|oalkyl, -(CH2)_raryl or -(CH2)_rheteroaryl;

R²⁷ and R²⁸ are each independently hydrogen, -OR¹⁶, C-j. ρalkyl, -(CH2)_saryl or - (CH2)_sheterocyclyl;

R²⁹ and R³⁰ are each independently hydrogen, C-j_4alkyl or Cι_4alkoxyC<|_4alkyl; R³¹ is hydrogen or C-| .ρalkyl optionally substituted by up to three groups independently selected from halogen, C<|_4alkoxy, -OC(O)C-| .ρalkyl and -OC(O)OC-| .ρalkyl; R³² is hydrogen, C-|_4alkyl, C^cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl;

R³³ is hydrogen or R²², or R³³ and R²¹ are linked to form the bivalent radical -O(CH2)2- or -(CH₂)t-;

B is phenyl or pyridyl;

X is -U¹ (CH2)_VU²-, -U¹ (CH2)v- or a group selected from:

and

U¹ and U² are independently a divalent radical selected from -N(R³²)-, -O-, -S(O)_z-,

N(R³²)C(O)-, -C(O)N(R³²)- and -N[C(O)R³²]-; W is -C(R³³)- or a nitrogen atom; d is an integer from 1 to 5; e is an integer from 2 to 4; f, g, h, m, p, q, r and s are each independently integers from 0 to 4; i is an integer from 1 to 6; j, k, n and z are each independently integers from 0 to 2; t is 2 or 3; v is an integer from 2 to 8; and pharmaceutically acceptable derivatives thereof.

The term "pharmaceutically acceptable" as used herein means a compound which is suitable for pharmaceutical use. Salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non- pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates. The term "pharmaceutically acceptable derivative" as used herein means any pharmaceutically acceptable salt, solvate or prodrug, e.g. ester, of a compound of the invention, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof. Such derivatives are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5^th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives. Preferred pharmaceutically acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters. Particularly preferred pharmaceutically acceptable derivatives are salts, solvates and esters. Most preferred pharmaceutically acceptable derivatives are salts and esters, in particular salts.

The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. For example, an aqueous solution of an acid such as hydrochloric acid may be added to an aqueous suspension of a compound of formula (I) and the resulting mixture evaporated to dryness (lyophilised) to obtain the acid addition salt as a solid. Alternatively, a compound of formula (I) may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent. The resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.

Suitable addition salts are formed from inorganic or organic acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, alkyl or aryl sulphonates (eg methanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate) and isethionate. Representative examples include trifluoroacetate and formate salts, for example the bis or tris trifluoroacetate salts and the mono or diformate salts, in particular the bis trifluoroacetate salt and the diformate salt.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.

Compounds of the invention may have both a basic and an acidic centre may therefore be in the form of zwitterions.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compound of the invention are within the scope of the invention. The salts of the compound of formula (I) may form solvates (e.g. hydrates) and the invention also includes all such solvates.

The term "prodrug" as used herein means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., "Bioreversible Carriers in Drug Design", American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which are incorporated herein by reference.

Prodrugs are any covalently bonded carriers that release a compound of structure (\) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. Esters may be active in their own right and/or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.

References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable derivatives. With regard to stereoisomers, the compounds of structure (I) have more than one asymmetric carbon atom. In the general formula (I) as drawn, the solid wedge shaped bond indicates that the bond is above the plane of the paper. The broken bond indicates that the bond is below the plane of the paper.

It will be appreciated that the substituents on the macrolide may also have one or more asymmetric carbon atoms. Thus, the compounds of structure (I) may occur as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

Where a compound of the invention contains an alkenyl group, cis (Z) and trans (E) isomerism may also occur. The present invention includes the individual stereoisomers of the compound of the invention and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.

Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. A stereoisomeric mixture of the agent may also be prepared from a corresponding optically pure intermediate or by resolution, such as H.P.L.C, of the corresponding mixture using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding mixture with a suitable optically active acid or base, as appropriate.

The compounds of structure (I) may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.

Compounds wherein R² represents a hydroxyl protecting group are in general intermediates for the preparation of other compounds of formula (I).

When the group OR² is a protected hydroxyl group this is conveniently an ether or an acyloxy group. Examples of particularly suitable ether groups include those in which R² is a trialkylsilyl (i.e. trimethylsilyl). When the group OR² represents an acyloxy group, then examples of suitable groups R² include acetyl or benzoyl.

R⁶ is hydrogen or fluorine. However, it will be appreciated that when A is -C(O)NH- or - CH2-N(R⁷)-, R⁶ is hydrogen.

When R ³ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 5, 6, 7 or 8 position to the X group as above defined. In one embodiment, the heterocyclic is linked in the 6 or 7 position. In another embodiment, the heterocyclic is linked in the 5 or 8 position. When present, the R²² group or groups may be attached at any position on the ring. In one embodiment, an R²² group is attached at the 6, 7 or 8 position.

When R¹³ is a heterocyclic group having the following structure:

wherein W is -C(R³³)- where R³³ is R²² or R³³ and R² are linked to form the bivalent radical -O(CH2)2- or -(CH2)t-, said heterocyclic is linked in the (i), (ii) or (iii) position to the X group as above defined. In one embodiment, the heterocyclic is linked in the (i) position. In another embodiment, the heterocyclic is linked in the (ii) or (iii) position.

When R¹³ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 5, 6 or 7 position to the X group as defined above. In one embodiment, the heterocyclic is linked in the 6 or 7 position. In another embodiment, the heterocyclic is linked in the 5 position.

When R¹³ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 6, 7, 8 or 9 position to the X group as above defined. In one embodiment, the heterocyclic is linked in the 7 or 8 position. In another embodiment, the heterocyclic is linked in the 6 or 9 position.

When R¹³ is a heterocyclic group having the following structure:

wherein W is -C(R³³)- where R³³ is R²² or R³³ and R²¹ are linked to form the bivalent radical -O(CH2)2^_ or -(CH2)f> said heterocyclic is linked in the (i), (ii) or (iii) position to the X group as above defined. In one embodiment, the heterocyclic is linked in the (i) position. In another embodiment, the heterocyclic is linked in the (ii) or (iii) position.

When R¹³ is a heterocyclic group having the following structure:

said heterocyclic is linked in the 2, 3 or 4 position to the X group as above defined. In one embodiment, the heterocyclic is linked in the 2 or 3 position. In another embodiment, the heterocyclic is linked in the 4 position.

The term "alkyl" as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, Cι_ιnal yl means a straight or branched alkyl containing at least 1, and at most 10, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl, hexyl, heptyl, octyl, nonyl and decyl. A C-^alkyl group is preferred, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.

The term "C3_7cycloalkyl" group as used herein refers to a non-aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "alkoxy" as used herein refers to a straight or branched chain alkoxy group containing the specified number of carbon atoms. For example, C-j.ρalkoxy means a straight or branched alkoxy containing at least 1, and at most 6, carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop- 2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy. A C<|_4alkoxy group is preferred, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2-methylprop-2-oxy.

The term "alkenyl" as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one double bond. For example, the term "C2-ρalkenyl" means a straight or branched alkenyl containing at least 2, and at most 6, carbon atoms and containing at least one double bond. Similarly, the term "C3_ρalkenyl" means a straight or branched alkenyl containing at least 3, and at most 6, carbon atoms and containing at least one double bond. Examples of "alkenyl" as used herein include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl and 1,1-dimethylbut-2-enyl. It will be appreciated that in groups of the form -O-C2-ρalkenyl, the double bond is preferably not adjacent to the oxygen.

The term "alkynyl" as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one triple bond. For example, the term "C3_ρalkenyl" means a straight or branched alkynyl containing at least 3, and at most 6, carbon atoms containing at least one triple bond. Examples of "alkynyl" as used herein include, but are not limited to, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 3-methyl-1-butynyl.

The term "aryl" as used herein refers to an aromatic carbocyclic moiety such as phenyl, biphenyl or naphthyl.

The term "heteroaryl" as used herein, unless otherwise defined, refers to an aromatic heterocycle of 5 to 10 members, having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono and bicyclic ring systems. Examples of heteroaryl rings include, but are not limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, 1 ,3-benzodioxazolyl, indolyl, benzothiazolyl, furylpyridine, oxazolopyridyl and benzothiophenyl.

The term "5 or 6 membered heteroaryl" as used herein as a group or a part of a group refers to a monocyclic 5 or 6 membered aromatic heterocycle containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl and triazinyl.

The term "9 to 10 membered fused bicyclic heteroaryl" as used herein as a group or a part of a group refers to quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, 1,3-benzodioxazolyl, indolyl, benzothiazolyl, furylpyridine, oxazolopyridyl or benzothiophenyl.

The term "heterocyclyl" as used herein, unless otherwise defined, refers to a monocyclic or bicyclic three- to ten-membered saturated or non-aromatic, unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur. Preferably, the heterocyclyl ring has five or six ring atoms. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl and thiomorpholino.

The term "5 or 6 membered heterocyclic group" as used herein as a group or part of a group refers to a monocyclic 5 or 6 membered saturated hydrocarbon ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Examples of such heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl and thiomorpholino.

The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

The terms "optionally substituted phenyl", "optionally substituted phenyl or benzyl", "optionally substituted 5 or 6 membered heteroaryl", "optionally substituted 9 to 10 membered fused bicyclic heteroaryl" or "optionally substituted 5 or 6 membered heterocyclic group" as used herein refer to a group which is substituted by 1 to 3 groups selected from halogen, C^alkyl, C-j^alkoxy, hydroxy, nitro, cyano, amino, C- . 4alkylamino or diC-^alkylamino, phenyl and 5 or 6 membered heteroaryl. In one embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, -N(R )-CH₂-, -CH₂-N(R⁷)- or - C(=NR¹⁰)-. A representative example of A is -C(O)-.

A representative example of R² is hydrogen.

In one embodiment, R³ is hydrogen or C_π_4alkyl. A representative example of R³ is C-|_ 4alkyl, in particular methyl.

A representative example of R⁴ and R^ is hydroxy.

A representative example of R⁶ is hydrogen.

A representative example of R^{1 1} is hydrogen.

A representative example of R¹² is hydrogen.

Representative examples of R¹³ include heterocyclic groups having the following structure:

wherein the heterocyclic is linked in the 5, 6, 7 or 8 position to the X group as above defined, and heterocyclic groups having the following structure:

wherein W is -C(R³³)- and R³³ and R²¹ are linked to form the bivalent radical -(CH2)f, and the heterocylic is linked in the (i), (ii) or (iii) position, in particular the (ii) position, to the X group as above defined.

In one embodiment, R¹⁵ is hydrogen or C-^alkyl substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl. In one embodiment, R²⁰ is hydrogen, -C(O)OR³¹, -C(O)NHR³¹ or -C(O)CH₂NO₂. In a further embodiment, R²⁰ is -C(O)OR³¹ , -C(O)NHR³¹ or -C(O)CH NO₂. A representative example of R²⁰ is -C(O)OR³¹, wherein R³¹ is hydrogen or C-j^alkyl, for example hydrogen or methyl. In particular, R³¹ is hydrogen.

Representative examples of R²¹ include C-^alkyl, in particular ethyl, and C3_7cycloaIkyl, in particular cyclopropyl.

A representative example of R²² is halogen, in particular chlorine or fluorine.

In one embodiment, R³¹ is hydrogen or C^ .ρalkyl optionally substituted by up to three groups independently selected from halogen, C<|_4alkoxy, -OC(O)C-j .ρalkyl and - OC(O)OC-j .ρalkyl. A representative example of R³¹ is hydrogen or C^alkyl, for example hydrogen or methyl. In particular, R³¹ is hydrogen.

In one embodiment, R³² is hydrogen or C-j^alkyl. A representative example of R³² is hydrogen.

A representative example of R³³ is hydrogen or R²², or R³³ and R²¹ are linked to form the bivalent radical -(CH₂)t--

In one embodiment, B is a phenyl or pyridyl ring wherein the group -(CH2)₍jXR¹³ is meta or para to the point of attachment of the -OC(O)C(R^{1 1}R¹²)- group. A representative example of B is phenyl, in particular phenyl wherein the group -(CH2)dXR^ is meta or para to the point of attachment of the -OC(O)C(R¹ R ²)- group.

In one embodiment, X is -U¹(CH2)vU -, -U¹(CH₂)_V- or a group selected from:

/ \

N N

\ / and

Representative examples of X include -U¹ (CH₂)_VU²- and -U¹ (CH₂)_V-.

Representative examples of U¹ and U² include the divalent radicals -N(R³²)-, -O- and S(O) . In particular, when X is -U¹(CH2)_VU²-, U¹ is -N(R³²)- and U² is selected from the divalent radicals -N(R³²)-, -O- and -S(O) . Alternatively, when X is -U (CH2)_v-_> U¹ is - N(R³²)-.

A representative example of d is 1 to 3, for example 1.

A representative example of t is 3.

In one embodiment, v is an integer from 2 to 8. Representative examples of v include 2, 3 and 4.

A representative example of z is 0.

Representative examples of j include 0 and 1. In particular, j is 0.

It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove. It is also to be understood that the present invention encompasses compounds of formula (I) in which a particular group or parameter, for example R⁷, R¹⁶, R¹⁷ R ⁸ R²² R²³, R²⁴ R²5 R²⁶, R²⁷ R²⁸ R²⁹ R30_J R32 R34_J R35_ _{k> mj nj p>} q_{? fj s} and z may occur more than once. In such compounds it will be appreciated that each group or parameter is independently selected from the values listed.

Particularly preferred compounds of the invention are:

3-O-Des(cladinosyl)-3-O-(3-{[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-7-ylsulfanyl)- ethylamino]-methyl}-phenyl)-acetyl-6-O-methyl erythromycin A;

3-O-Des(cladinosyl)-3-O-(3-{[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-8-yloxy)- ethylamino]-methyl}-phenyl)-acetyl-6-O-methyl erythromycin A; 3-O-Des(cladinosyl)-3-O-(4-{[2-(3-carboxy-1 -ethyl-4-oxo-1 ,4-dihydro-quinolin-8-yloxy)- ethylamino]-methyl}-phenyl)-acetyl-6-O-methyl erythromycin A; and pharmaceutically acceptable derivatives thereof.

Compounds according to the invention also exhibit a broad spectrum of antimicrobial activity, in particular antibacterial activity, against a wide range of clinical pathogenic microorganisms. Using a standard microtiter broth serial dilution test, compounds of the invention have been found to exhibit useful levels of activity against a wide range of pathogenic microorganisims. In particular, the compounds of the invention may be active against strains of Staphylococcus aureus, Streptopococcus pneumoniae, Moraxella catarrhalis, Streptococcus pyogenes, Haemophilus influenzae, Enterococcus faecalis, Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. The compounds of the invention may also be active against resistant strains, for example erythromycin resistant strains. In particular, the compounds of the invention may be active against erythromycin resistant strains of Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus.

The compounds of the invention may therefore be used for treating a variety of diseases caused by pathogenic microorganisms, in particular bacteria, in human beings and animals. It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.

Thus, according to another aspect of the present invention we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in therapy.

According to a further aspect of the invention we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the therapy or prophylaxis of systemic or topical microbial infections in a human or animal subject.

According to a further aspect of the invention we provide the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for use in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body.

According to a yet further aspect of the invention we provide a method of treatment of the human or non-human animal body to combat microbial infections comprising administration to a body in need of such treatment of an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation eg when the agent is in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

Accordingly, in one aspect, the present invention provides a pharmaceutical composition or formulation comprising at least one compound of the invention or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable excipient, diluent and/or carrier. The excipient, diluent and/or carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In another aspect, the invention provides a pharmaceutical composition comprising, as active ingredient, at least one compound of the invention or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable excipient, diluent and/or carrier for use in therapy, and in particular, in the treatment of human or animal subjects suffering from a condition susceptible to amelioration by an antimicrobial compound.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the present invention and a pharmaceutically acceptable excipient, diluent and/or carrier (including combinations thereof).

There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing at least one compound of the invention or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable excipient, diluent and/or carrier.

The compounds of the invention may be formulated for administration in any convenient way for use in human or veterinary medicine and the invention therefore includes within its scope pharmaceutical compositions comprising a compound of the invention adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable excipients, diluents and/or carriers. Acceptable excipients, diluents and carriers for therapetic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical excipient, diluent and/or carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as - or in addition to - the excipient, diluent and/or carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).

Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

For some embodiments, the agents of the present invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non- inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e. g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148. The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example see International Patent Application No. WO 02/00196 (SmithKline Beecham).

The routes for administration (delivery) include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.

There may be different composition/formulation requirements depending on the different delivery systems. By way of example, the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be delivered by both routes.

Where the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. It is to be understood that not all of the compounds need be administered by the same routed Likewise, if the composition comprises more than one active component, then those components may be administered by different routes.

The compositions of the invention include those in a form especially formulated for parenteral, oral, buccal, rectal, topical, implant, ophthalmic, nasal or genito-urinary use. For some applications, the agents of the present invention are delivered systemically (such as orally, buccally, sublingually), more preferably orally. Hence, preferably the agent is in a form that is suitable for oral delivery.

If the compound of the present invention is administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the agent; and/or by using infusion techniques.

For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

The compounds according to the invention may be formulated for use in human or veterinary medicine by injection (e.g. by intravenous bolus injection or infusion or via intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose form, in ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an added preservative; The compositions for injection may be in the form of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, solubilising and/or dispersing agents. Alternatively the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The compounds of the invention can be administered (e. g. orally or topically) in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

The compounds of the invention may also be presented for human or veterinary use in a form suitable for oral or buccal administration, for example in the form of solutions, gels, syrups, mouth washes or suspensions, or a dry powder for constitution with water or other suitable vehicle before use, optionally with flavouring and colouring agents. Solid compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powder, pastes, granules, bullets or premix preparations may also be used. Solid and liquid compositions for oral use may be prepared according to methods well known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.

The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropyicellulose (HPC), sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The compounds of the invention may also be administered orally in veterinary medicine in the form of a liquid drench such as a solution, suspension or dispersion of the active ingredient together with a pharmaceutically acceptable carrier or excipient.

The compounds of the invention may also, for example, be formulated as suppositories e.g. containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g. containing conventional pessary bases.

The compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g. eye ear or nose drops) or pour- ons.

For application topically to the skin, the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds may also be dermally or transdermally administered, for example, by use of a skin patch.

For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

As indicated, the compound of the present invention can be administered intranasaliy or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1,1 ,2-tetrafluoroethane (HFA 134AT"") or 1 ,1,1 ,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e. g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e. g. sorbitan trioleate.

Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

For topical administration by inhalation the compounds according to the invention may be delivered for use in human or veterinary medicine via a nebuliser.

The compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.

When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. The compounds of the present invention may for example be used for topical administration with other active ingredients such as corticosteroids or antifungals as appropriate.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the invention or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

The compositions may contain from 0.01-99% of the active material. For topical administration, for example, the composition will generally contain from 0.01-10%, more preferably 0.01-1% of the active material.

Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

For oral and parenteral administration to humans, the daily dosage level of the agent may be in single or divided doses.

For systemic administration the daily dose as employed for adult human treatment it will range from 2-100mg/kg body weight, preferably 5-60mg/kg body weight, which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and the condition of the patient. When the composition comprises dosage units, each unit will preferably contain 200mg to 1g of active ingredient. The duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.

Compounds of general formula (I) and salts thereof may be prepared by the general methods outlined hereinafter, said methods constituting a further aspect of the invention. In the following description, the groups R¹ to R³⁵, A, B, X, Y, U¹, U², W, d, e, f, g, h, i, j, k, m, n, p, q, r, s, t, v, w and z have the meaning defined for the compounds of formula (I) unless otherwise stated.

The groups X^aR^13a, U^2aR ^3a and R^13a are XR¹³, U²R¹³ and R ³ as defined for formula (I) or groups convertible to XR¹³, U²R¹³ and R¹³. Conversion of a group X^aR^13a U^2aR^13a or R^13a to a XR¹³, U²R¹³ or R¹³ group typically arises if a protecting group is needed during the reactions described below. A comprehensive discussion of the ways in which such groups may be protected and methods for cleaving the resulting protected derivatives is given by for example T.W. Greene and P.G.M Wuts in Protective Groups in Organic Synthesis 2^nd ed., John Wiley & Son, Inc 1991 and by P.J. Kocienski in Protecting Groups, Georg Thieme Verlag 1994 which are incorporated herein by reference. Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl and acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz, and 9-fluorenylmethoxycarbonyl (Fmoc)), aliphatic urethane protecting groups (e.g. t-butyloxycarbonyl (Boc), isopropyloxycarbonyl and cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, trityl and chlorotrityl). Examples of suitable oxygen protecting groups may include for example alkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate. Hydroxy groups may be protected by reaction of for example acetic anhydride, benzoic anhydride or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, N,N- dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like.

Compounds of formula (I) wherein d is 1 may be prepared by reaction of a compound of formula (II) wherein R² is a hydroxy protecting group with a suitable amine derivative of formula (IIIA) or (NIB), followed where necessary by subsequent removal of the hydroxyl protecting group R² and conversion of the U^2aR^13a or R^13a group to U²R¹³ or R¹³.

(ID

HN(R³²)(CH₂)_vU^2aR^13a HN(R³²)(CH₂)_vR^13a (IIIA) ("IB)

The reductive amination reaction is preferably carried out in a solvent such as methanol and DMF. A suitable reducing agent is, for example, sodium cyanoborohydride.

In another embodiment of the invention, compounds of formula (I) wherein d is an integer from 1 to 5 and U¹ is a group selected from -N(R³²)- and -S-, may be prepared by reaction of a compound of formula (IV),

(IV)

wherein d is an integer from 1 to 5 and L is a suitable leaving group, with X^aR^13a (V) in which U¹ is a group selected from -N(R³²)- and -S-. The reaction is preferably carried out in a solvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuran or dimethoxyethane), acetonitrile or ethyl acetate and the like, dimethylsulfoxide, N,N-dimethylformamide or 1-methyl-pyrrolidone and in the presence of a base, followed, if desired, by removal of the hydroxyl protecting group R² and conversion of the X^aR^13a group to XR¹³. Examples of the bases which may be used include organic bases such as diisopropylethylamine, triethylamine and 1,8- diazabicyclo[5.4.0]undec-7-ene, and inorganic bases such as potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride and the like. Suitable leaving groups for this reaction include halide (e.g. chloride, bromide or iodide) or a sulfonyloxy group (e.g. tosyloxy or methanesulfonyloxy).

In a further embodiment of the invention, compounds of formula (I) wherein d is an integer from 1 to 5 and U¹ is -N(R³²)-, may be prepared by reverse reductive amination between an amine compound of formula (VI) and an aldehyde compound of formula (VII)

HC(O)(CH₂)_v.-ιU^2aR^13a

(VI) (VII)

Compounds of formula (II) may be prepared by reaction of a 3-hydroxy compound of formula (VIII) with a carboxylic acid of formula (IX).

HOC(O)C(R¹ R¹²)BCHO

(VIII) (IX)

The reaction is preferably carried out in the presence of a carbodiimide such as 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide. Compounds of formula (I) may be converted into other compounds of formula (I). Thus compounds of formula (I) wherein U¹ or U² is -S(O)_z- and z is 1 or 2 may be prepared by oxidation of the corresponding compound of formula (I) wherein z is 0. The oxidation is preferably carried out using a peracid, e.g. peroxybenzoic acid, followed by treatment with a phosphine, such as triphenylphosphine. The reaction is suitably carried out in an organic solvent such as methylene chloride. Compounds of formula (I) wherein U¹ or U² is - N(R³²)- and R³² is C<|_4alkyl can be prepared from compounds wherein R³² is hydrogen by reductive alkylation.

In order that the invention may be more fully understood the following examples are given by way of illustration only.

The following abbreviations are used in the text: BOC for t-butoxycarbonyl, DMF for N,N- dimethylformamide, DMSO for dimethyl sulfoxide, EtOH for ethanol, MeOH for methanol and THF for tetrahydrofuran.

Examples

Intermediate 1 : 6-r(2-Aminoethyl)amino1-7-chloro-1 -cyclopropyl-4-oxo-1 ,4-di vdro- quinoline-3-carboxylic acid

7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (56.3 g) and ethylenediamine (36 g) were dissolved in N.N-dimethylacetamide (650 mL) at 100°C and stirred for 8.5 h at 115°C. Water (700 mL) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5°C and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, cold EtOH, and dried at 110°C under reduced pressure for 1 h. The crude product was treated with HCI (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40°C and a first precipitation happened. The precipitate was filtered, washed with water and dried at 110°C for 1 h. The title compound (6.4 g) was obtained as the hydrochloride salt. The hydrochloride salt was then converted to the free base using standard conditions; ESMS m/z 320 [M-H]~.

Intermediate 2: 7-(2-Aminoethylsulfanyl)-1 -ethyl-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid trifluroacetate salt

a) Benzyl-2-(4-bromo-2-fluorobenzoyl)acetate.

To mono benzyl malonate (9.7 g, 50 mmol) in THF (50 mL) was added magnesium ethoxide (2.85 g, 25 mmol). The mixture was sonicated until a uniform yellow suspension was formed. The solvent was removed by evaporation under reduced pressure and to the residue added a solution of 1-(4~bromo-2-fluorobenzoyl)imidazole prepared by treating 4- bromo-2-fluorobenzoic acid (10.95 g, 50 mmol) in THF (50 mL) with carbonyl diimidazole (8.1 g, 50 mmol) at 20°C for 1 h and 50°C for 1 h. After stirring at 20°C for 20 h, the brown mixture was diluted with ethyl acetate and washed with water, 2M HCI and brine. The organic layer was dried and the solvent was removed under reduced pressure. To the residue was added dichloromethane/petrol (100 mL, 1:1), the mixture filtered, and the soluble material purified by chromatography (silica gel) eluting with 0 - 10% ethyl acetate/ hexane to give the title product (9.85 g, 56%); ESMS m/z 351 , 353 [M+H]⁺ (100%).

b) Benzyl 7-bromo-1 -ethyl-4-oxo-1 ,4-dihydro-quino!ine-3-carboxylate. To a solution of Intermediate 2a (9.82 g, 28 mmol) in THF (50 mL) was added dimethyl formamide dimethyl acetal (3.9 mL, 29 mmol). After 16 h at 20°C the solvent was removed by evaporation under reduced pressure, the residue was taken up in THF (20 mL), and cooled in an ice bath. Ethylamine in THF (2M, 14 mL) was added and the mixture stirred at 0°C. After 45 min the mixture was evaporated to dryness and the residue taken up in DMF (40 mL). Potassium carbonate (5.28 g, 38 mmol) was added and the mixture stirred and heated to 100°C under argon. After 45 min the mixture was cooled and diluted with ice water to precipitate a yellow solid. The solid was dried and refluxed with ethyl acetate (100 mL) then the mixture filtered. This was repeated with further portions of ethyl acetate (100, 50 mL) and the combined filtrates diluted with hexane to give the title product. Further material was obtained by chromatography of the mother liquors and the ethyl acetate insoluble material on silica gel eluting with 0-20% ethyl acetate in dichloromethane gave a total of the title product (2.65g, 24%); H NMR δ (CDCI₃/MeOD) 1.54 (3H, t), 4.35 (2H, q), 5.36 (2H, s), 7.3-7.5 (5H, m), 7.63 (1H, dd), 7.9 (1H, d), 8.33 (1H,d), 8.70 (1 H, s).

c) Benzyl 7-(2- tert-Butoxycarbonyiaminoethylsulfanyl)-1-ethyl-4-oxo-1,4-dihydro- quinoline-3-carboxylate.

A solution of Intermediate 2b (0.386g, 1 mmol) and Λ/-Boc-cysteinamine (0.354 g, 2 mmol) in DMSO (3 mL) was treated with potassium carbonate (0.278 g, 2 mmol) and stirred at 60°C under argon for 3 h. The cooled mixture was diluted with ethyl acetate and washed with water. The crude product was purified by chromatography on silica gel eluting with 0 - 20% ethyl acetate in dichloromethane. The product containing fractions were precipitated from dichloromethane solution with hexane to give the title product (0.346 g, 72%); H NMR δ (CDCI₃) 1.45 (9H, s), 1.52 (3H, t), 3.18 (2H, t), 3.39 (2H, m), 4.35 (2H, q), 4.95 (1H, bt), 5.4 (2H, s), 7.2-7.4 (4H, m), 7.52 (3H, m), 8.42 (1H,d), 8.47 (1H, s).

d) 7-(2-Aminoethylsulfanyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid trifluoroacetate salt.

Intermediate 2c (0.2 g, 0.415 mmol) was dissolved in THF, and aqueous sodium hydroxide solution (2M, 0.25 mL) added. The reaction was heated to 65°C under argon. After 3 h further sodium hydroxide solution (2M, 0.25 mL) was added, and after a further 30 min methanol (1 drop) was added. After a total reaction time of 4.5 h the reaction was cooled to 20°C. The organic solvents were removed and a small piece of solid carbon dioxide added. The aqueous mixture was evaporated to dryness under reduced pressure and triturated with ethanol. The insoluble material (0.12 g) was treated with anisole (0.5 mL) and trifluoroacetic acid (2 mL) for 1 h. Toluene (10 mL) was added and the solution evaporated to low volume. Diethyl ether (10 mL) was added to give a precipitate of the title compound (0.12g) which was used without further purification; ESMS m/z 293 [M+H]⁺ (100%).

Intermediate 3: 9-(2-Amino-ethoxy)-1 -oxo-6 -dihvdro-1 H.5H-Oyrϊdo\3.2A - f/lquinoline-2-carboxylic acid hydrochloride

a) 9-(2-Dibenzylamino-ethoxy)-1 -oxo-6,7-dihydro-1 H,5W-pyrido[3,2,1 -/y]quinoline-2- carboxylic acid 2-dibenzylamino-ethyl ester. 9-Hydroxy-1 -oxo-6,7-dihydro-1 H,5r -pyrido[3,2, 1-/)]quinoline-2-carboxylic acid

(GB1417129) (0.905 g, 3.69 mmol) was suspended in dry DMF (50 mL). To this was added potassium carbonate (3.06 g, 22 mmol) and dibenzyl-(2-chloroethyl)amine hydrochloride (2.37 g, 8 mmol). The mixture was heated at 60°C for 16 h, then more potassium carbonate (0.55 g) and dibenzyl-(2-chloroethyl)amine hydrochloride (1.18 g, 4 mmol) were added. After a further 25 h at 75°C the mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated under reduced pressure. The crude product (4.0 g) was purified by chromatography on silica gel (100 g), eluting with 0 - 4% methanol in dichloromethane, to give the title compound (2.25 g, 89%); ESMS m/z 692 [M+H]⁺ (100%).

b) 9-(2-Dibenzylamino-ethoxy)-1 -oxo-6,7-dihydro-1 H,5H-pyrido[3,2,1 -//Jquinoline-2- carboxylic acid sodium salt.

Intermediate 3a (2.22 g, 3.21 mmol) was dissolved in methanol (30 mL) and 1,4-dioxane (20 mL), and treated with aqueous sodium hydroxide (0.4N, 8.03 mL, 3.21 mmol). The mixture was stirred for 88 h at 20°C. Solid carbon dioxide was then added and the mixture evaporated to dryness under reduced pressure. The residue was triturated with diethyl ether to give the title compound as a white powder (1.6 g, 100%); ESMS m/z 469 [M+H]⁺ for free acid (100%).

c) 9-(2-Amino-ethoxy)-1 -oxo-6,7-dihydro-1 H,5H-pyrido[3,2,1 -ij]quinoline-2- carboxylic acid hydrochloride.

Intermediate 3b (0.8 g, 1.63 mmol) was dissolved in 1,4-dioxane (100 mL), water (15 mL) and hydrochloric acid (2N, 1.6 mL, 3.2 mmol). This solution was hydrogenated over 20% palladium (II) hydroxide on carbon (0.4 g) at 50 psi for 42 h. The mixture was diluted with water and filtered through kieselguhr, washing well with water. The filtrate was then evaporated to dryness under reduced pressure to give the title compound as an off-white solid (0.54 g, 87%) (containing one equivalent of sodium chloride); ESMS m/z 289 [M+H]⁺ for free acid (100%).

Intermediate 4: 6-(2-Amino-ethoxy)-1 -ethyl-4-oxo-1 ,4-dihvdro-quinoline-3- carboxylic acid hydrochloride

a) 6-(2-Dibenzylamino-ethoxy)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 2-dibenzylamino-ethyl ester.

1-Ethyl-6-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (GB 1433774) (1.4 g, 6 mmol) was dissolved in dry DMF (80 mL). To this was added potassium carbonate (5 g, 36 mmol) and dibenzyl-(2-chloroethyl)amine hydrochloride (4.37 g, 14.8 mmol). The mixture was heated at 65°C with stirring for 72 h, then allowed to cool overnight. The mixture was evaporated to a small volume, diluted with water and extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried and evaporated under reduced pressure to give a dark viscous oil (4.9 g). This residue was purified by chromatography on silica gel (100 g), eluting with 0.2 - 3.8% methanol in dichloromethane, to give the title compound as a brown solid (2.46 g, 60%); ESMS m/z 680 [M+H]⁺ (100%).

b) 6-(2-Dibenzylamino-ethoxy)-1 -ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid sodium salt.

Intermediate 4a (2.44 g, 3.59 mmol) was dissolved in methanol (25 mL) and 1,4-dioxane (25 mL), then aqueous sodium hydroxide (0.4N, 8.75 mL, 3.5 mmol) was added. Stirred for 40 h then a little more sodium hydroxide was added and stirring continued for a further 72 h. Excess solid carbon dioxide was then added and the mixture evaporated to dryness under reduced pressure. Trituration with diethyl ether gave the title compound as a pale brown powder (1.382 g, 84%); ESMS m/z 457 [M+H]⁺for the free acid (100%).

c) 6-(2-Amino-ethoxy)-1 -ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid. Intermediate 4b (1.38 g, 2.89 mmol) was dissolved in 1,4-dioxane (80 mL), water (40 mL) and hydrochloric acid (2N, 2.9 mL, 5.8 mmol). This solution was hydrogenated over 20% palladium (II) hydroxide on carbon (0.6 g) at 50 psi for 18 h. The mixture was filtered through kieselguhr, washing well with water. The filtrate was then evaporated to dryness under reduced pressure to give the title compound as a pale yellow solid (1 g, 94%) (containing one equivalent of sodium chloride); ESMS m/z 277 [M+H]⁺ for free acid (100%).

Intermediate 5: 6-(2-Aminoethylsulfanyl)-1-ethyl-4-oxo-1 ,4-dihydro-quinolone-3- carboxylic acid trifluoroacetate salt

a) 6-Bromo-1-ethyl-4-oxo-1,4-dihydro-quinolin-3-carboxylic acid ethyl ester.

A mixture of potassium carbonate (2.95 g, 21.2 mmol) and 6-bromoquinolone-3-carboxylic acid in dimethylformamide (25 mL) was heated to 40°C under argon for 10 minutes and iodoethane (3.4 mL, 42.4 mmol) was added. After 14 h the mixture was cooled and the DMF evaporated. The residue was treated with water (40 mL), cooled to 5°C and filtered under vacuum. The resultant cream-coloured solid was dried under vacuum to yield the title compound; ¹ H NMR δ [(CD₃)₂SO] 1.41 (3H, t, J = 7.1 Hz), 1.54 (3H, J = 7.2 Hz), 4.24 (2H, q, J = 7.2 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.34 (1H, d, J = 9 Hz), 7.76 (1 H, dd, J = 2.4 & 9 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.49 (1H, s).

b) 6-(2-f-Butoxycarbonylaminoethylsulfanyl)-1 -ethyl-4-oxo-1 ,4-dihydro-quinolone-3- car boxy lie acid ethyl ester.

A mixture of Λ/-Boc-cysteinamine (0.35 g, 2 mmol), Intermediate 5a (0.32 g, 1 mmol) and potassium carbonate (0.28 g, 2 mmol) was heated in DMSO (10 mL) for 16 h at 90°C. After chromatography over silica gel eluting with dichloromethane containing an increasing concentration of methanol/ammonium hydroxide the title compound was obtained as a white solid; ESMS m/z 421 [M+H]⁺ (100%). c) 6-(2-f-Butoxycarbonylaminoethylsulfanyl)-1 -ethyl-4-oxo-1 ,4-dihydro-quinolone-3- carboxylic acid sodium salt.

To a solution of Intermediate 5b (0.11 g, 0.27 mmol) in THF (2 mL) was added 2M sodium hydroxide (0.13 mL, 0.27 mmol). After stirring for 16 h at room temperature the mixture was saturated with carbon dioxide and the solvent evaporated. The residue was treated with methanol (10 mL), filtered and the solvent evaporated to yield the title compound as a pale yellow solid; ESMS m/z 393 [M+H]⁺ (25%).

d) 6-(2-Aminoethylsulfanyl)-1 -ethyl -4-oxo-1 ,4-dihydro-quinolone-3-carboxylic acid trifluoroacetate salt.

To Intermediate 5c (0.068 g, 0.17 mmol) was added trifluoroacetic acid (1 mL). After 1 h the solvent was evaporated to yield a green gum; ¹H NMR δ [(CD3)₂SO] 1.54 (3H, t, J = 7.2 Hz), 3.20 (2H, q, J = 6.8 Hz), 3.38 (2H, t, J = 6.8 Hz), 4.56 (2H, q, J = 7.2 Hz), 7.98- 7.90 (2H, m), 8.40 (1H, d, J = 2.0 Hz), 8.94 (1H, s).

Intermediate 6: 6-(3-Aminopropyl)-1 -ethyl-4-oxo-1.4-dihydro-quinoline-3-carboxylic acid trifluoroacetate salt

a) 1-Ethyl-6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester. A mixture of 1 ,4-dihydro-6-iodo-4-oxo-quinoline-3-carboxylic acid (J. Ellis et al, Aust. J. Chem., 1973, 26, 907) (3.15 g, 10 mmol), potassium carbonate (6.9 g, 50 mmol) and iodoethane (15.6 g, 100 mmol) in dry DMF was heated at 70°C with vigorous stirring. After 16 h the mixture was cooled and diluted with ethyl acetate. The resultant mixture was washed with water and the organic phase separated, dried and evaporated to yield the title compound as pale yellow solid, ¹H NMR δ (CDCI3) 1.41 (3H, t, J = 7.1 Hz), 1.54 (3H, t, J = 7.3 Hz), 4.23 (2H, q, J = 7.2 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.20 (1H, d, J = 8.9 Hz), 7.95 (1H, dd, J = 2.1 & 8.9 Hz), 8.48 (1H, s), 8.86 (1H, d, J = 2.1 Hz).

b) 6-(3-f-Butoxycarbonylamino-prop-1 -ynyl)-1 -ethyl-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid ethyl ester.

Intermediate 6a (0.371g, 1 mmol), copper (I) iodide (26 mg, 0.13 mmol) and triethylamine (6.16 mL, 44 mmol) were suspended in dry acetonitrile (22 mL). The light green suspension was heated to 50°C whilst argon was bubbled through. After 20 min, dichlorobis(triphenylphosphine)palladium (II) (0.026g, 0.0379 mmol) and f-butoxycarbonylpropargylamine (0.264 g, 1.7 mmol) were added and the brown suspension was heated under reflux. After 2h the reaction mixture was cooled, filtered and concentrated. The residue was taken up in dichloromethane and washed with water. The organic phase was dried and concentrated to provide a brown oil which was purified by chromatography on silica gel eluting with 0-2.5% (9:1 MeOH/20 M ammonia) in dichloromethane to yield the title compound as a yellow solid; ESMS m/z 399 (M+H⁺). c) 6-(3-f-Butoxycarbonylaminopropyl)-1 -ethyl-4-oxo-1 ,4-dihydro-quinoline-3- carboxylic acid ethyl ester.

Intermediate 6b (0.366. mg, 0.77 mmol) in dichloromethane (10 mL) was hydrogenated over 10% palladium on charcoal (50 mg) for 16 h. The resultant mixture was filtered and the solvent evaporated to give the title compound as a yellow oil; ESMS m/z 403 [M+H]⁺.

d) 6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester.

Using a similar procedure to that described in Intermediate 5d, Intermediate 6c (355 mg, 0.88 mmol) gave the title compound as a yellow oil; ESMS m/z 303 [M+H]⁺.

e) 6-(3-Aminopropyl)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium salt.

Using a similar procedure to that described in Intermediate 5c, Intermediate 6d (250 mg, 0.83 mmol) gave the title compound as a yellow solid; ESMS m/z 275 [M+H]⁺.

f) 6-(3-Aminopropyl)-1 -ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid trifluoroacetate salt.

Intermediate 6e (0.06 g, 0.2 mmol) was subjected to reverse phase HPLC purification to give the title compound as white solid; ¹ H NMR δ [(CD₃)₂SO] 1.54 (3H, t, J = 7.2 Hz), 2.0- 2.1 (2H, m), 2.9-3.0 (4H, m), 4.58 (2H, q, J = 7.2 Hz), 7.85,(1 H, dd, J = 2.2 & 8.8 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.36 (1H, d, J = 1.8 Hz), 8.97 (1H, s).

Intermediate 7: 5-(2-AminoethylsulfanvD-1 -ethyl-8-f luoro-4-oxo-1 ,4-dihvdro- quinolone-3-carboxylic acid sodium salt

a) 5,8-Difluoro-1-ethyl-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid ethyl ester.

Using a similar procedure described for the preparation of Intermediate 5a, 5,8-difluoro-4- oxo-1 ,4-dihydro-quinolone-3-carboxylic acid (1.00 g, 4.0 mmol) was treated with iodoethane and potassium carbonate to give the title compound; ESMS m/z 282 [M+H]⁺ (100%).

b) 5-(2-tert-Butoxycarbonylaminoethylsulfanyl)-1 -ethyl-8-f luoro-4-oxo-1 ,4-dihydro- quinolone-3-carboxylic acid ethyl ester. Using a method similar to that described for the preparation of Intermediate 2c, Intermediate 7a (0.281 g, 1 mmol) gave, after purification by reverse phase HPLC, the title compound as a white solid; ESMS m/z 439 [M+H]⁺ (40%), 339 [MH-Boc]⁺ (100%).

c) 5-(2-Aminoethylsulfanyl)-1 -ethyl-8-f luoro-4-oxo-1 ,4-dihydro-quinolone-3- carboxylic acid ethyl ester.

Using a method similar to that described for the preparation of Intermediate 5d, Intermediate 7b (0.23 g, 0.53 mmol) was deprotected with trifluoroacetic acid (2.5 mL). Chromatography over silica gel eluting with dichloromethane containing an increasing concentration of methanol/ammonium hydroxide gave the title compound; ESMS m/z 339 [M+H]⁺ (100%).

d) 5-(2-Aminoethylsulfanyl)-1-ethyl-8-fluoro-4-oxo-1,4-dihydro-quinolone-3- carboxylic acid sodium salt.

Using a method similar to that described for the preparation of Intermediate 5c, Intermediate 7c (0.15 g, 0.43 mmol) was converted to the title compound; ESMS m/z 311 [M+H]⁺ (100%).

Intermediate 8: 8-(2-Aminoethoxy)-1 -ethyl -4-oxo-1 ,4-dihvdro-quinoline-3-carboxylic acid hydrochloride

a) 8-Benzyloxy-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester. To a mixture of 8-benzyloxy-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (M. Pesson et al, Comptes Rendes des Seances des I'Academie des Science Series C, 1970, 270, 1189; 1.50 g, 5.08 mmol) and potassium carbonate (2.00 g, 15.0 mmol) in DMF at 40°C was treated with iodoethane (2.00 mL, 25 mmol). After 16 h the mixture was cooled and the DMF evaporated and the residue treated with water (25 mL), cooling to 5°C resulted in the formation of a cream-coloured solid. Filtration and drying under vacuum gave the title product as a powder; ESMS m/z 352 [M+H]⁺ (100%).

b) 8-Hydroxy-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester.

A solution of Intermediate 8a (1.60 g, 4.56 mmol) in methanol (20 mL) was hydrogenated over 10% palladium-on-charcoal (0.20 g), at 1 atmosphere and room temperature. After 14 h the mixture was filtered and the solvent evaporated to yield the title compound as a bright yellow solid; H NMR δ [(CD₃)₂SO] 1.28 (3H, t, J = 7.1 Hz), 1.36 (3H, t, J = 6.9 Hz), 4.22 (2H, q, J = 7.1 Hz), 4.68 (2H, q, J = 6.9 Hz), 7.20-7.30 (2H, m), 7.75 (1H, d x d, J = 1.9 & 7.7 Hz), 8.49 (1H, s), 10.6-10.8 (1H, brd s).

c) 8-(2-Dibenzylaminoethoxy)-1 -ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester.

To a mixture of Intermediate 8b (1.00 g, 3.83 mmol) and potassium carbonate (0.60 g, 4.32 mmol) in DMF (10 mL) was added dibenzyl-(2-chloroethyl)amine hydrochloride (1.13 g, 3.83 mmol). After heating at 70°C for 14 h the mixture was cooled and the DMF evaporated, the residue was partitioned between diethyl ether (40 mL) and water (25 mL). The organic layer was separated, dried and evaporated to yield the title compound as a brown gum; ESMS m/z 485 [M+H]⁺ (100%).

d) 8-(2-Dibenzylam^'moethoxy)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride salt. To a solution of Intermediate 8c in THF (10 mL) was added 2M aqueous sodium hydroxide solution. After stirring at room temperature for 14 h and at 80°C for 0.5 h. The mixture was then cooled and treated with excess solid carbon dioxide. The solvent was evaporated and the residue partitioned between dichloromethane and water. The organic layer was separated, dried and evaporated to yield a light yellow foam, the product was re-dissolved in dichloromethane and treated with 1 M hydrogen chloride in diethyl ether. Filtration and evaporation of the solvent yielded the title compound as a yellow solid; ¹ H NMR δ [(CD₃)₂SO] 1.14 (3H, t, J = 6.8 Hz), 2.91 (2H, t, J = 5.6 Hz), 3.66 (4H, s), 4.33 (2H, t, J = 6.0 Hz), 4.73 (2H, q, J = 7.2 Hz), 7.20-7.52 (12H, m), 7.96 (1H, d x d, J = 2.0 & 7.2 Hz), 8.86 (1 H, s), 15.25 (1 H, brd s).

e) 8-(2-Aminoethoxy)-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride.

A mixture of Intermediate 8d (1.4 g, 3.07 mmol) and 10% palladium-on-charcoal (0.50 g) suspended in methanol (70 mL) was hydrogenated at atmospheric pressure and room temperature. After 48 h the mixture was filtered and the solvent evaporated. The resultant crude product was crystallised from methanol to yield the title compound as a light brown solid; ¹H NMR δ [(CD₃)₂SO + D₂O] 1.41 (3H, t, J = 7.2 Hz), 3.36-3.38 (2H, m), 4.64-4.74 (2H, m), 4.83-4.85 (2H, m), 7.62-7.64 (2H, m), 8.06 (1H, d x d, 4 & 5.6 Hz), 8.92 (1H, s).

Intermediate 9: 7-(2-Aminoethylsulfanyl)-1 -ethyl-4-oxo-l ,4-dihydro-quinolone-3- carboxylic acid methyl ester

A suspension of the sodium salt of Intermediate 2 (0.46 g, 0.15 mmol) in 4M hydrogen chloride in methanol (15 mL) was heated at 50°C. After 16 h the mixture was cooled and the solvent evaporated to yield the title compound; ESMS m/z 307 [M+H]⁺ (30%).

Intermediate 10: 7-(4-Aminobutylamino)-1 -ethyl-6-f luoro-4-oxo-1 ,4-dihvdro- quinoline-3-carboxylic acid

a) 7-Bromo-1 -ethyl-6-f luoro-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid.

A solution of 7-bromo-1-ethyl-6-fluoro-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester (EP184384, 1986; 1.56 g, 4.55 mmol) in dioxane (25 mL) was treated with 2M sodium hydroxide solution (4.6 mL, 9.2 mmol). After stirring at room temperature for 48 h the mixture was acidified with 2M hydrochloric acid and the precipitated white solid filtered and dried to yield the title compound; ¹ H NMR (d6-DMSO) 1.4 (3H, t), 4.63 (2H, q), 8.14 (1H, d), 8.54 (1H, d), 9.06 (1H, s), and 14.8 (1H, s).

b) 7-Bromo-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid benzyl ester.

Using a procedure similar to that described for the synthesis of Intermediate 5a but with benzyl bromide in place of ethyl iodide, Intermediate 10a (1.43 g, 4.55 mmol) was esterified to yield the title compound as white solid after chromatography over silica gel eluting with diethyl ether/dichloromethane; ESMS m/z 405 [M+H]⁺ (100%).

c) 7-Benzyloxycarbonylamino-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3- carboxylic acid benzyl ester.

Benzyl carbamate (0.31 g, 2.0 mmol), caesium carbonate (0.83 g, 2.55 mmol), palladium acetate (0.015 g, 0.068 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.039 g, 0.068 mmol) were rigorously pre-dried in vacuo. These reagents were then added to a solution of Intermediate 10b (0.69 g, 1.7 mmol) in dry dioxane (10 mL) under argon. The resultant solution was degassed and sonicated for 5 mins. After heating at 75°C for 48 h the mixture was cooled and diluted with ethyl acetate. The solution was washed with water, dried and evaporated to give the crude product. Chromatography over silica gel eluting with diethyl ether in dichloromethane gave the title compound; ESMS m/z 475 [M+H]⁺ (100%).

d) [Benzyloxycarbonyl-(4-bromobutyl)-amino]-1 -ethyl-6-f luoro-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid benzyl ester.

A mixture of Intermediate 10c (0.31 g, 0.65 mmol) and potassium carbonate (0.14 g, 1 mmol) in dry DMF was treated with 1 ,4-dibromobutane (0.032 mL, 2.62 mmol) and heated at 55°C for 3 h and at 50°C for 14 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water, the organic layer was separated, dried an evaporated to yield a yellow oil. Chromatography over silica gel eluting with dichloromethane/diethyl ether (0 to 4%) gave the title compound; ESMS m/z 610 [M+H]⁺ (100%).

e) [Benzyloxycarbonyl-(4-azidobutyl)-amino]-1 -ethyI-6-f luoro-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid benzyl ester.

To a solution of Intermediate 10d (0.31 g, 0.5 mmol) in DMF (5 mL) was added sodium azide (0.036 g, 0.55 mmol) and the mixture warmed at 45°C. After 3.5 h most of the DMF was evaporated and the residue diluted with ethyl acetate. The resultant solution was washed with water, dried and evaporated to yield a colourless gum; ESMS m/z 572 [M+H]⁺ (100%).

f) 7-(4-Aminobutylamino)-1 -ethyl-6-fluoro-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid.

A mixture of Intermediate 10e (0.091 g, 0.17 mmol) and 10% palladium-on-charcoal in ethanol was hydrogenated at 1 atmosphere and room temperature. After 22 h the mixture was filtered and the solvent evaporated to yield the title compound; ESMS m/z 322 [M+H]⁺ (100%).

Intermediate 11 : 2'-0-Acetyl-3-0-des(cladinosyl)-3-0-(3-formylphenyl)acetyl-6-0- methyl erythromycin A To a solution of 2'-O-acetyi-3-O-des(cladinosyl)-6-O-methyl erythromycin (T. Tanikawa et al, J. Med. Chem. 2001, 14, 4027; 1.9 g, 3 mmol) and 4-dimethylaminopyridine (0.37 g, 3 mmol) in dichloromethane (30 mL) at 5°C was added 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (1.15 g, 6 mmol), and 3-formylphenylacetic acid (US patent 3,860,639, 1975; 0.49 g, 3 mmol). The resultant orange solution was stirred at room temperature, after 16 h the mixture was washed sequentially with aqueous sodium bicarbonate solution and water. The organic layer was separated, dried and evaporated to yield the crude product. Chromatography over silica gel eluting with dichloromethane containing an increasing concentration of methanol (0 to 1%) gave the title compound as a white solid; ESMS m/z 778 [M+H]⁺ (100%).

Intermediate 12: 2'-0-Acetyl-3-0-des(cladinosyl)-3-0-(4-formylphenyl)acetyl-6-Q- methyl erythromycin A

A similar procedure to Intermediate 11 but using 4-formylphenylacetic acid (WO 97/24331; 1.9 g, 3 mmol), gave the title compound; ESMS m/z 778 [M+H]⁺ (100%).

Examples 1 to 14 General Procedure

a) Reductive Amination. To a solution of Intermediate 11 or 12 (0.093 g, 0.12 mmol) in methanol (2.5 mL) and DMF (2.5 mL) was added the amine component (0.12 mmol), sodium acetate (9.8 mg, 0.12 mmol), and acetic acid (0.3 mL). After stirring for 0.25 h at room temperature the mixture was treated with sodium cyanoborohydride (0.015g, 0.24 mmol). After a further 16 h the mixture was evaporated and the residue chromatographed over silica gel eluting with dichloromethane containing an increasing concentration of methanol/ammonium hydroxide (0 to 1%) to yield 2'-O-acetyl protected compound.

b) 2'-0-Deacetylation. The 2'-O-acetyl protected products from General Procedure 1a were dissolved in methanol (5 mL) and heated at 50°C. After 7 h the methanol was evaporated.

Examples 1-14 were prepared by the General Procedure described above and purified by chromatography on silica or by reverse phase HPLC. In the following table, the term "2.TFA" means bis trifluoroacetate and the term "2.HCO₂H" means diformate.

Biological Data

Using a standard broth dilution method in microtitre, compounds were tested for antibacterial activity. The compounds in the above examples gave minimum inhibitory concentrations (MICs) less than 1 microgram per millilitre against erythromycin-sensitive and erythromycin-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes.

In addition, the MIC (μg/mL) of test compounds against various organisms was determined including:

S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565, E. faecalis ATCC 29212, H. influenzae ATCC 49247, M. catarrhalis ATCC 23246.

Examples 2, 3, 5, 9, 12 and 13 have an MIC <1 g/mL against S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565 and E. faecalis ATCC 29212. Examples 3, 5 and 13 have an MIC <2 //g/mL against H. influenzae ATCC 49247 and M. catarrhalis ATCC 23246.

Examples 3, 5, 8 and 13 have an MIC <1 //g/mL against erythromycin resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

A compound of formula (I)

(I)

wherein

A is a bivalent radical selected from -C(O)-, -C(O)NH-, -NHC(O)-, -N(R⁷)-CH₂-, -CH₂- N(R⁷)-, -CH(NR⁸R⁹)- and -C(=NR¹ °)-;

R1 is -OC(O)C(R¹ R ²)B(CH₂)dXR¹³; R² is hydrogen or a hydroxyl protecting group;

R³ is hydrogen, C-j_4alkyl, or C3_ρalkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl; R4 is hydroxy, C3_ρalkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or Cι_ρalkoxy optionally substituted by C-|.ρalkoxy or -O(CH2)_e R⁷R¹ , R⁶ is hydroxy, or

R⁴ and R^ taken together with the intervening atoms form a cyclic group having the following structure:

wherein Y is a bivalent radical selected from -CH2-, -CH(CN)-, -O-, -N(R¹^)- and - CH(SR¹⁵)-;

R⁶ is hydrogen or fluorine; R⁷ is hydrogen or C-j .ρalkyl; R⁸ and R⁹ are each independently hydrogen, C-j .ρalkyl, -C(=NR¹⁰)NR¹⁶R¹⁷ or - C(O)R¹⁶ or

R⁸ and R⁹ together form =CH(CR ⁶R¹⁷)_faryl, =CH(CR¹⁶R¹⁷)_f heterocyclyl, =CR¹⁶R¹⁷ or =C(R¹⁶)C(O)OR¹⁶, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R¹ ; R™ is -OR¹⁹, C-|_ ρalkyl, -(CH₂)_garyl, -(CH₂)_gheterocyclyl or -(CH₂)_hO(CH₂)jOR⁷, wherein each R¹⁰ group is optionally substituted by up to three groups independently selected from R¹⁸;

R¹¹ is hydrogen, hydroxy, C-j .ρalkyl or C-|_ρalkoxy;

R¹ is hydrogen or C-j .ρalkyl;

R¹³ is a heterocyclic group having the following structure:

or

R ⁴ is hydrogen or C-j .ρalkyl;

R¹5 is hydrogen or C-j^alkyl optionally substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl; R¹⁶ and R¹⁷ are each independently hydrogen or C-|. ρalkyl;

R¹⁸ is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R²³ -C(O)OR²³, -OC(O)R²³, - OC(O)OR²³, -NR²⁴C(O)R²⁵, -C(O)NR²⁴R²⁵, -NR²⁴R²⁵, hydroxy, C) .ρalkyl, -S(O)_kC-ι_ ρalkyl, C<|_ρalkoxy, -(CH₂)m^aryl ^or -(CH2)_mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from -NR R¹⁷, halogen and -OR¹⁶, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, - C(O)R²⁶, -C(O)OR²⁶ -OC(O)OR²⁶, -NR ⁷C(O)R²⁸ -C(O)NR² R²⁸ -NR²⁷R²⁸, hydroxy, C-j .ρalkyl and C-j.ρalkoxy;

R¹⁹ is hydrogen, C-| .ρalkyl, C3_7cycloalkyl, C3_ρalkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, -OR²⁹, -S(O)_nR²⁹, -NR²⁹R³⁰, -CONR²⁹R³⁰, halogen and cyano; R²⁰ is hydrogen, -C(O)OR³¹ , -C(O)NHR³¹ , -C(O)CH₂NO₂ or -C(O)CH₂SO₂R⁷; R²¹ is hydrogen, C-^alkyl optionally substituted by hydroxy or C^alkoxy, C3_ 7cycloalkyl, or optionally substituted phenyl or benzyl; R²² is halogen, C-^alkyl, Ci^thioalkyl, C-^alkoxy, -NH₂, -NH(C<|_4alkyl) or -N(C-|.

4alkyl)2;

R²³ is hydrogen,

-(CH2)_paryl or -(CH2)_pheteroaryl;

R²⁴ and R²⁵ are each independently hydrogen, -OR¹⁶, C-| .ρalkyl, -(CH2)qaryl or - (CH₂)qheterocyclyl;

R²⁶ is hydrogen, C-j.-ioalkyl, -(CH₂)_raryl or -(CH₂)_rheteroaryl;

R²⁷ and R²⁸ are each independently hydrogen, -OR¹⁶, C-j .ρalkyl, -(CH₂)_saryl or -

(CH₂)_sheterocyclyl;

R²⁹ and R³^ are each independently hydrogen, C-^alkyl or Cι_4alkoxyCι_4alkyl; R³¹ is hydrogen,

C-_j. ρalkyl optionally substituted by up to three groups independently selected from halogen, cyano, C^alkoxy optionally substituted by phenyl or C^alkoxy, - C(O)Cι, .ρalkyl, -C(O)OC-) .ρalkyl, -OC(O)C-ι_₆alkyi, -OC(O)OC<| .ρalkyl, - C(O)NR³ R³⁵, -NR³ R³⁵ and phenyl optionally substituted by nitro or -C(O)OC-|_ ρalkyl,

-(CH₂)_wC3_ cycloalkyl, -(CH₂)_wheterocyclyl,

-(CH2)w^neteroaryl. -(CH₂)_waryl, C3_ρalkenyl, or

C₃.₆alkynyl;

R³² is hydrogen, C-^alkyl, C3_7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl;

R³³ is hydrogen or R²² or R³³ and R²¹ are linked to form the bivalent radical -O(CH₂)₂- or -(CH₂)t-;

R³⁴ and R³⁵ are each independently hydrogen or C-| .ρalkyl optionally substituted by phenyl or -C(O)OC<| .ρalkyl, or

R³⁴ and R³^, together with the nitrogen atom to which they are bound, form a 5 or 6 membered heterocyclic group optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur;

B is phenyl or pyridyl;

X is -U¹(CH2)_VU²-, -U (CH₂)v- or a group selected from:

/ \

— N N —

\ /

and

U¹ and U² are independently a divalent radical selected from -N(R³²)-, -O-, -S(O)_z-, N(R³²)C(O)-, -C(O)N(R³²)- and -N[C(O)R³²]-; W is -C(R³³)- or a nitrogen atom; d is an integer from 1 to 5; e is an integer from 2 to 4; f, g, h, m, p, q, r, s and w are each independently integers from 0 to 4; i is an integer from 1 to 6; j, k, n and z are each independently integers from 0 to 2; t is 2 or 3; v is an integer from 1 to 8; or a pharmaceutically acceptable derivative thereof.

A compound according to claim 1 wherein A is -C(O)-.

3. A compound according to claim 1 or claim 2 wherein X is -U¹(CH )_VU²- or U (CH₂)v-.

A compound according to any one of the preceding claims wherein d is 1.

5. A compound according to any one of the preceding claims wherein R¹³ is a heterocyclic group of the following formula:

wherein the heterocyclic is linked in the 5, 6, 7 or 8 position and j, R²⁰, R²¹ and R²² are as defined in claim 1 , or a heterocyclic group of the following formula:

wherein the heterocylic is linked in the (i), (ii) or (iii) position, W is -C(R³³)- and R³³ and R^2"! are linked to form the bivalent radical -(CH₂)t- as defined in claim 1, and j, R²⁰, R²¹ and R²² are as defined in claim 1.

6. A compound according to claim 1 as defined in any one of Examples 1 to 14, or a pharmaceutically acceptable derivative thereof.

7. A compound selected from: 3-O-Des(cladinosyl)-3-O-(3-{[2-(3-carboxy-1 -ethyl-4-oxo-1 ,4-dihydro-quinolin-7-ylsulfanyl)- ethylamino]-methyl}-phenyl)-acetyl-6-O-methyl erythromycin A; 3-O-Des(cladinosyl)-3-O-(3-{[2-(3-carboxy-1-ethyl-4-oxo-1 ,4-dihydro-quinolin-8-yloxy)- ethylamino]-methyl}-phenyl)-acetyl-6-O-methyl erythromycin A; and 3-O-Des(cladinosyl)-3-O-(4-{[2-(3-carboxy-1-ethyl-4-oxo-1 ,4-dihydro-quinolin-8-yloxy)- ethylamino]-methyl}-phenyl)-acetyl-6-O-methyl erythromycin A; or a pharmaceutically acceptable derivative thereof.

8. A process for the preparation of a compound as claimed in claim 1 which comprises:

a) reacting a compound of formula (II) with an amine derivative of formula (IIIA) or (IIIB)

(II)

HN(R³²)(CH₂)_vU² R^13a HN(R³²)(CH₂)_vR^13a (IIIA) (IIIB) wherein U^2aR^13a and R^13a are U²R¹³ or R¹³ as defined in claim 1 or groups convertible to U²R ³ or R¹³;

b) reacting a compound of formula (IV)

(IV) with a compound of formula X^aR^13a (V), wherein R^"l^3a is R¹³ as defined in claim 1 or a group convertible to R¹³ and X^a is -U¹ (CH₂)_V- or -U¹ (CH )_VU²-, or a group convertible to -U¹(CH₂)v- or -U¹(CH )_VU²-, in which U¹ is a group selected from -N(R³²)- and -S-, and L is suitable leaving group, to produce a compound of formula (I) wherein U is a group selected from -N(R³²)- and -S-; or

c) reverse reductive amination between an amine compound of formula (VI) and an aldehyde compound of formula (VII)

(VI) (VII)

wherein U^2aR^13a is U²R¹³ as defined in claim 1 or a group convertible to U²R¹³, and thereafter, if required, subjecting the resulting compound to one or more of the following operations: i) removal of the protecting group R², ii) conversion of X^aR^13a to XR¹³ iii) conversion of U^2aR ^3a to U²R¹³, iv) conversion of R^13a to R¹³, and v) conversion of the resultant compound of formula (I) into a pharmaceutically acceptable derivative thereof.

9. A compound as claimed in any one of claims 1 to 7 for use in therapy.

10. The use of a compound as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body.

11. The use of a compound as claimed in any one of claims 1 to 7 for use in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body.

12. A method for the treatment of the human or non-human animal body to combat microbial infection comprising administration to a body in need of such treatment of an effective amount of a compound as claimed in any one of claims 1 to 7.

13. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1 to 7 in association with a pharmaceutically acceptable excipient, diluent and/or carrier.

14. A compound of formula (IA)

(IA)

wherein A is a bivalent radical selected from -C(O)-, -C(O)NH-, -NHC(O)-, -N(R7)-CH₂-, -CH₂-

N(R⁷)-, -CH(NR⁸R⁹)- and -C(=NR¹⁰)-;

R is -OC(O)C(R ¹ R¹²)B(CH₂)dXR¹³;

R² is hydrogen or a hydroxyl protecting group;

R³ is hydrogen, C^alkyl, or C3_ρalkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;

R⁴ is hydroxy, C3_ρalkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C-]_ρalkoxy optionally substituted by C-|_ρalkoxy or -O(CH2)_eNR⁷R¹4,

R⁵ is hydroxy, or

R⁴ and R⁵ taken together with the intervening atoms form a cyclic group having the following structure:

wherein Y is a bivalent radical selected from -CH₂-, -CH(CN)-, -O-, -N(R¹⁵)- and -

CH(SR¹5)-;

R⁶ is hydrogen or fluorine;

R⁷ is hydrogen or C-j. ρalkyl;

R⁸ and R⁹ are each independently hydrogen, C<|_ρalkyl, -C(=NR¹⁰)NR¹⁶R¹⁷ or -

C(O)R¹⁶, or

R⁸ and R⁹ together form =CH(CR¹⁶R¹⁷)faryl, =CH(CR¹⁶R¹⁷)fheterocyclyl, =CR¹⁶R¹⁷ or =C(R¹ )C(O)OR¹⁶, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R¹⁸;

R¹⁰ is -OR¹⁹, C-i .ρalkyl, -(CH₂)_garyl, -(CH₂)_gheterocyclyl or -(CH₂)_hO(CH₂)jOR⁷, wherein each R¹^ group is optionally substituted by up to three groups independently selected from R¹⁸;

R¹¹ is hydrogen, hydroxy, C-j_ρalkyl or C-|_ρalkoxy;

R¹² is hydrogen or C-j .ρalkyl;

R¹³ is a heterocyclic group having the following structure:

or

R¹⁴ is hydrogen or C-_| .ρalkyl;

R15 is hydrogen or C-j_4alkyl substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to

10 membered fused bicyclic heteroaryl;

R¹⁶ and R¹⁷ are each independently hydrogen or C-| .ρalkyl;

R¹⁸ is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R²³, -C(O)OR²³, -OC(O)R²³, -

OC(O)OR²³ -NR²⁴C(O)R²⁵, -C(O)NR² R²⁵, -NR²⁴R²⁵, hydroxy, C-i, .ρalkyl, -S(O)_kC-|_ ρalkyl, C-_j_ρalkoxy, -(CH2)_maryl or -(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from -NR¹⁶R¹⁷, halogen and -OR¹⁶, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -

C(O)R²⁶, -C(O)OR²⁶, -OC(O)OR²⁶ -NR²⁷C(O)R²⁸, -C(O)NR²⁷R²⁸, -NR²⁷R²⁸, hydroxy, C-j .ρalkyl and C-ι_ρalkoxy;

R¹⁹ is hydrogen, C-j .ρalkyl, C3_7cycloalkyl, C3_ρalkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, -OR²⁹, -S(O)_nR²⁹, -NR²⁹R³⁰, -CONR²⁹R³⁰, halogen and cyano;

R²⁰ is hydrogen, -C(O)OR³¹, -C(O)NHR³¹ or -C(O)CH₂NO₂;

R²¹ is hydrogen,

optionally substituted by hydroxy or

C3_

7cycloalkyl, or optionally substituted phenyl or benzyl;

R²² is halogen, C-^alkyl, C-^thioalkyl, C<|_4alkoxy, -NH₂, -NH(Cι_4alkyl) or -N(Cι_ ₄a!kyl)₂;

R²³ is hydrogen, C-j.-if_jalkyl, -(CH2)_paryl or -(CH )_pheteroaryl;

R²⁴ and R²⁵ are each independently hydrogen, -OR¹⁶, C-j .ρalkyl, -(CH₂)qaryl or -

(CH₂)qheterocyclyl;

R²⁶ is hydrogen, C-j.-joalkyl, -(CH₂)_raryl or -(CH₂)_rheteroaryl; R²⁷ and R²⁸ are each independently hydrogen, -OR¹⁶, C-| .ρalkyl, -(CH₂)_saryl or -

(CH₂)_sheterocyclyl;

R²⁹ and R³^ are each independently hydrogen, C<|_4alkyl or C<|_4alkoxyCι_4alkyl;

R³¹ is hydrogen or C^ .ρalkyl optionally substituted by up to three groups independently selected from halogen, C-i ^alkoxy, -OC(O)C-j .ρalkyl and -OC(O)OC-| .ρalkyl; R³² is hydrogen, C-ι_4alkyl, C3_7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl; R³³ is hydrogen or R²², or R³³ and R²¹ are linked to form the bivalent radical -O(CH₂) - or -(CH₂)_t-;

B is phenyl or pyridyl;

X is -U¹ (CH₂)_VU²-, -U (CH₂)v- or a group selected from:

/ \

N N

\ / and

U¹ and U² are independently a divalent radical selected from -N(R³²)-, -O-, -S(O)₂-,

N(R³²)C(O)-, -C(O)N(R³²)- and -N[C(O)R³²]-;

W is -C(R³³)- or a nitrogen atom; d is an integer from 1 to 5; e is an integer from 2 to 4; f, g, h, m, p, q, r and s are each independently integers from 0 to 4; i is an integer from 1 to 6; j, k, n and z are each independently integers from 0 to 2; t is 2 or 3; v is an integer from 2 to 8; or a pharmaceutically acceptable derivative thereof.