Indian Patents. 231395:NOVEL 14 AND 15 MEMBERED-RING COMPOUNDS

Title of Invention	NOVEL 14 AND 15 MEMBERED-RING COMPOUNDS
Abstract	The present invention relates to 14- or 15-membered macrolides substituted at the 4" 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.

Full Text	NOVEL 14 AMD 15 MEMBERED-RING COMPOUNDS The present Invention relates to novel semt-synthetic macrolides having antimicrobial activity, in particular antibacterial activity. More particularly, the invention relates to 14- and 15-membered macrolldes substituted at the 4" 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-reslstant bacterial strains has" resulted in the need to develop new macrolide compounds. For example, EP 0 895 999 describes derivatives modified at the 4" position of the macrolide ring having antibacterial activity. According to the present invention, we have now found novel 14- and 15-membered macrolldes substituted at the 4" position which also have antimicrobial activity. Thus, the present invention provides compounds of general formula (I) wherein A is a bivalent radical selected from -C(O)-, -C(0)NH-, -NHC(0)-, -N(R7)-CH2-, -CH2- N(R7)-, -CH(NR8R9)- and -C(=NR10)-; R1is-0(CH2)dXR11; R2 is hydrogen or a hydroxyl protecting group; R3 is hydrogen, C1-4alkyl, or C3alkenyl optionally substituted by 9 to 10 membered fused blcyclic heteroaryl; R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or -o(CH2)eNR7R12, 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)-, -0-, -N(R13)- and - CH(SR13)-; R6 is hydrogen or fluorine; R7 is hydrogen or C1-6alkyl; R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or - C(O)R14, or R8 and R9 together form CH (CR14R15)faryl, =CH(CR14Rl5)fheterocyclyl, =CR14R15 or =C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16; R10 is -OR17, C1-6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)iOR7, wherein each R10 group is optionally substituted by up to three groups independently selected from R16; R11 Is a heterocyclic group having the following structure: R12 is hydrogen or C1-6halkyl; R13 IS hydrogen or C1-4alkyl 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; R14 and R15 are each independently hydrogen or C1-6alkyl; R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(0)R21, .C(0)OR21, -OC(0)R21, - OC(O)OR21. -NR22C(O)R23, -C9(O)NR22R23, -NR22R23 hydroxy, C1-6alkyl, -S(O)kC1_ 6alkyl. C1-6alkoxy, -(CH2)maryl or -(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from -NR14R15 halogen and -OR14, and the aryl and heteroaryl groups are optionally substituted by up to five groups Independently selected from halogen, cyano, nifro, trifluoromethyl, azido, - C(O)R24 -C(O)OR24, -OC(O)OR24, -NR25C(O)R26, -C(O)NR25R26 -NR25R26, hydroxy, C1-6alkyL and C1-6alkoxy; R17 is hydrogen, C1-6alkyL, C3-7cycloalkyl, C3-6alkenyl 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, -OR27 -S(O)nR27, -NR27R28 -CONR27R28 halogen and cyano; R18 is hydrogen, -C(O)OR29 -C(O)NHR29 -C(O)CH2NO2 or-C(O)CH2S02R7; R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3- 7cycloalkyl, or optionally substituted phenyl or benzyl; R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1- 4alkyl)2; R21 is hydrogen, C1-10alkyl, -(CH2)parylor-(CH2)pheteroaryl; R22 and R23 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or - (CH2)qheterocyclyl; R24 is hydrogen, C1-10nalkyl, -(CH2)raryl or-(CH2)rheteroaryl; R25 and R26 are each Independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or - (CH2)sheterocyclyl; R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl; R29 IS hydrogen, C1-6alkyl optionally substituted by up to three groups independently selected from halogen, cyano, C1-4alkoxy optionally substituted by phenyl or C1-4alkoxy, - C(O)C1-6alkyl, -C(O)OC1-6alkyl. -OC(O)C1-6alkyl, -OC(O)OC1-6alkyl, - C(O)NR32R33, -NR32R33 and phenyl optionally substituted by nltro or -C(O)OC1- 6alkyl. -(CH2)wC3-7cycloalkyl, -(CH2)wheferocyclyl, -(CH2)wheteroaryl, -(CH2)waryl, C3-6alkenyl, or C3-6alkynyl; R30 IS hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl; R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical -0(CH2)2- or-(CH2)t-; R32 and R33 are each independently hydrogen or C1-6alkyl optionally substituted by phenyl or-C(O)OC1-6alkyl, or R32 and R33, 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 suifur; X is -U(CH2)yB-, -U(CH2)v- or a group selected from: U and B are independently a divalent radical selected from -N(R30)-, -0-, -S(O)z-, - N(R30)C(O)-, -C(O)N(R30)- and -N[C(O)R3°]-; W is -C(R31)- or a nitrogen atom; d is an integer from 2 to 6; 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 another embodiment the present invention provides compounds of general formula (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)-; R1is-O(CH2)dXR11; R2 is hydrogen or a hydroxyl protecting group; R3 is hydrogen, C1-4alkyl. or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicydic heteroaryl; R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused blcyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6lkoxy or -O(CH2)eNR7R12, 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(R13)- and - CH(SR13).; R6 is hydrogen or fluorine; R7 is hydrogen or C1-6alkyl; R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or - C(O)R14, or R8 and R9 together form CH(CRl4Rl5)faryl, =CH(CR14R15)fheterocyclyl, =CR14R15 or C(Rl4)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16; R10 is -OR17 C1_6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)\|OR7 wherein each R10 group is optionally substituted by up to three groups independently selected from R16; R11 is a heterocyclic group having the following structure: R12 is hydrogen or C1-6alkyl; R13 is hydrogen or C1-4alkyl substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclc heteroaryl; R14 and R15 are each independently hydrogen or C1-6alkyl; R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R21, -C(O)0R21 -OC(O)R21, - OC(O)OR21, -NR22C(O)R23, -C(O)NR22R23, -NR22R23, hydroxy, C3-6alkyl, S(O)KC1- 6alkyl, C1-6alkoxy, -(CH2)aryl or -(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups Independently selected from -NR14R15, halogen and -OR14, and the aryi and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, - C(O)R24 -C(O)OR24 -OC(O)OR24, -NR25C(O)R26, -C(O)NR25R26 -NR25R26 hydroxy, C1-6alkyl and.C1-6alkoxy; R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyi, 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, -OR27, -S(O)nR27, -NR27R28, -CONR27R28, haiogen and cyano; R18 iS hydrogen, -C(O)OR29, -C(O)NHR29 or -C(O)CH2N02; R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3. 7cycloalkyl, or optionally substituted phenyl or benzyl; R20 is halogen, C1-4alkyl, C1-4thioalkvl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1- 4alkyl)2; R21 is hydrogen, C1-10alkyl, -(CH2)paryl or-(CH2)pheteroaryl; R22 and R23 are each Independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or - (CH2)qheterocyclyl; R24 is hydrogen, C1-10alkyl. -(CH2)raryl or -(CH2)rheteroaryl; R25 and R26 are each Independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or - (CH2)sheterocyclyl; R27 and R28 are each Independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl; R29 is hydrogen or C1-6alkyl optionally substituted by up to three groups Independently selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and -OC(O)OC1-6alkyl; R30 is hydrogen, C1-4alkyl, C3-10cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl; R31 Is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical -O(CH2)2- or-(CH2)t-; X is -U(CH2)vB-, -U(CH2)v- or a group selected from: U and B are Independently a divalent radical selected from -N(R30)-, -0-, -S(O)Z-, - N(R30)C(O)-, -C(O)N(R30)- and -N[C(O)R30]-; W is -C(R31)- or a nitrogen atom; d is an Integer from 2 to 6; 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 is2or3; 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 counterforts 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 pharmaceutJcally acceptable salts and solvates. Compounds of the Invention may have both a basic and an acidic centre may therefore be inihe 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., "Bioreverslble 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 covalentty 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 sulfhydryi groups. Thus, representative examples of prodrugs Include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryi 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 The term "pharmaceutlcally acceptable derivative" as used herein means any pharmaceutlcally 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, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives. Preferred pharmaceutlcally acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters. Particularly preferred pharmaceutlcally acceptable derivatives are salts, solvates and esters. Most preferred pharmaceutlcally 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 pharmaceutlcally acceptable salt. For a review on suitable salts see Berge et al., J. Pharm. Scl., 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 (lyophlllsed) 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 dllsopropyl 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, hydrobromlde, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, trlfluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trlfluoroacetate, saccharate, benzoate, alkyl or aryl sulphonates (eg methanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate) and isethlonate. Representative examples include trlfluoroacetate and formate salts, for example the bis or tris trlfluoroacetate salts and the mono or dlformate salts. Pharmaceutlcally 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-glucamlne. 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 substltuents on the macrollde may also have one or more asymmetric carbon atoms. Thus, the compounds of structure (I) may occur as individual enantiomers or dlastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Where a compound of the invention contains an alkenyl group, cls (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 chlral support or by fractional crystallisation of the dlastereoisomeric salts formed by reaction of the corresponding mixture with a suitable optically active acid or base, as appropriate. The compounds of structure (1) 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. trimethylsllyl). 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 R11is a heterocyclic group having the following structure: sald 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 R20 group or groups may be attached at any position on the ring. In one embodiment, an R20 group is attached at the 6 or 7 position. When R11 is a heterocyclic group having the following structure: wherein W is -C(R31)- where R31 is R20 or R31 and R19 are linked to form the bivalent radical -0(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 R11 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. The R20 group or groups may be attached at any position on the ring. In one embodiment, an R20 group is attached at the 6 position. When R11 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 R11 is a heterocyclic group having the following structure: wherein W is -C(R31)- where R31 is R20 or R31 and R19 are linked to form the bivalent radical -0(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 R11is 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, C1-10alkyl 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, isopropvl. t-butvl. hexvl. heDtyl, octyl, nonyl and decyl. A C1-4alkyl group is preferred, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl. The term "C3-7cycloalkyl" Qroup 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, C1-6alkoxy 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 C1-4alkoxy 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 "C2-6alkenyl" 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 "C3-6alkenyl" 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-enyi. It will be appreciated that in groups of the form -0-C2-6alkenyl, 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 'C3-6alkenyl' 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, triazolyi, oxadiazolyl, tetrazolyl, thiadiazolyl, pyridyi, pyridazlnyl, pyrazinyl, pyrimldlnyl, trlazlnyl, quinolinyt, isoquinollnyl, 1,2,3,4-tetrahydrolsoquinolinyl, benzofuranyl, benzimldazolyl, benzothienyl, benzoxazolyl, 1,3-benzodioxazolyl, indolyl, benzothlazolyl, furylpyrldine, oxazolopyrfdyl and benzothlophenyl. 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, thlophenyl, pyrrolyl, pyrazolyl, imldazolyl, oxazolyl, isoxazolyl, thlazolyl, Isothlazolyl, triazolyi, oxadiazolyl, tetrazolyl, pyridyl, pyridazlnyl, pyrazinyl, pyrimldlnyl 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 quinolinyt, lsoquinolinyl, 1,2,3,4-tetrahydrolsoquinolinyl, benzofuranyl, benzimldazolyl, benzothienyl, benzoxazoiyl, 1,3-benzodloxazolyl, indolyl, benzothlazolyl, furylpyrldine, oxazolopyridyl or benzothlophenyl. The term "heterocyclyT as used herein, unless otherwise defined, refers to a monocyclic or blcyclic 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, tetrahydrothlophenyl, Imldazoildlnyl, pyrazolldinyl, piperidyl, piperazinyl, morphollno, tetrahydropyranyl and thlomorphollno. 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, tetrahydrothlophenyl, Imldazoildlnyl, pyrazolldinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl and thlomorphollno. 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 substltuted 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, C1-4alkyl, C1-4alkoxy, hydroxy, nitro, cyano, amino, C1- 4alkylamlno or diC1-4alkylamino, phenyl and 5 or 6 membered heteroaryl. In one embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, -N(R7)CH2-, -CH2N(R7)- or - CH(NR8R9)-. In another embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, -CH2-N(R7)-,- CH(NR8R9)- or -C(=NR10)-. In a further embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, - CH2-NR7- or -CH(NR8R9)-. Representative examples of A include -C(O)- and -N(R7). CH2-. In particular, A is-C(O)-. A representative example of R2 is hydrogen. Representative examples of R3 Include hydrogen and C1-4alkyl, for example hydrogen and methyl. In particular, R3 is methyl. In one embodiment, R4 and R5 are hydroxy. Alternatively, 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 -O- and -N(R13)-. A representative example of R6 is hydrogen. A representative example of R7 is C1-6alkyl, for example Chalkyl, in particular methyl. In one embodiment, R1 1 Includes heterocyclic groups having the following structures: wherein the heterocyclic is linked in the 8 or 7 position to the defined; heterocyclic groups having the following structure: wherein W is -C(R31)- and R31 and R19 are linked to form the bivalent radical -(CH2)t-, and the heterocyllc Is linked in the (ii) or (iii), position to the X group as above defined; and heterocyclic groups having the following structure: the heterocyclic is linked in the 7 or 8 position to the X group as above defined. Representative examples of R11 Include heterocyclic groups having the following structures: wherein the heterocyclic is linked in the 6 or 7 position to the X group as above defined, and heterocyclic groups having the following structure: wherein W is -C(R31)- and R31 and R19 are linked to form the bivalent radical -(CH2)t-, and the heterocylic is linked in the (ii) or (iii), position to the X group as above defined. A further representative example of R11 is a heterocyclic group having the following structure: said heterocyclic is linked in the 7 or 8 position to the X group as above defined. In one embodiment, R13 is hydrogen or C1-4alkyl substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused blcyciic heteroaryl. Representative examples of R13 include hydrogen and C1-4alkyl, for example hydrogen and methyl. In one embodiment, R18 iS hydrogen, -C(O)OR29, -C(O)NHR29 or -C(O)CH2NO2. In a further embodiment, R18 is -C(O)OR29, -C(O)NHR29 or -C(O)CH2NO2. A representative example of R18 is -C(O)OR29, wherein R29 is hydrogen. Representative examples of R19 include C1-4alkyl, in particular ethyl, and C3-7cycioalkyl, in particular cyclopropyl. In one embodiment, R20 is halogen or C1-4alkyl. Representative examples of R20 include halogen, in particular chlorine or fluorine. Further representative examples of R20 Include C1-4alkyl, In particular methyl. In one embodiment, R29 is hydrogen or C1-6alkyl optionally substituted by up to three groups independently selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and OC(O)OC1-6alkyl. A representative example of R29 is hydrogen. Representative examples of R30 include hydrogen and C1-4alkyl, in particular hydrogen and methyl. A representative example of R31 is hydrogen, or R31 and R19 are linked to form the divatent radical -CH2)t- In one embodiment, X is -U(CH2)vB-. -U(CH2)V- or a group selected from: In another embodiment, X is -U(CH2)VB-, -U(CH2)V- or a group selected from: Representative examples of X are -U(CH2)VB- and -U(CH2)v- Further representative examples of X are In one embodiment, U and B are independently a divalent radical selected from -N(R30)-, -0-, -S(O)z- and -C(O)N(R30)-. Representative examples of U and B Include the dlvalenf radicals -N(R30)-, -O- and -S(O)z-. A further representative example of U and B is - C(O)N(R30)-. in one embodiment, when X is -U(CH2)VB-, U is selected from the divalent radicals - N(R30) and -C(O)N(R30)- and B is selected from the divalent radicals -N(R30)-, -O- and -S(O)z-. In particular, U is -N(R30)- and B is selected from the divalent radicals -N(R30)-, -0- and -S(O)Z-. For example, U is -N(R30)- and B is selected from the divalent radicals - N(R30)-and-S(O)Z-. In one embodiment, when X is -U(CH2)v-, U is selected from the divalent radicals - N(R30)- and-O-. For example, U is-N(R30)-. Representative examples of Y include the bivalent radicals -0- and -N(R13)-. Representative examples of d include 2 and 3. A representative example of t Is 3. In one embodiment, v Is an Integer of from 2 to 8. A representative example of v is 2 to 4, in particular 2 or 3. A representative example of z is 0. Representative examples of j include 0 and 1. 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 Rl4, R15, R16, R20, R21, R22 R23 R24, R25 R26 R27 R28, R30, R32, R33, k, m, n, p, q, r, 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: 4"-O(2{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]- methylamino}-ethyl)-6-0-methyl-etythromycin A 11,12-carbonate; 4"-0-(3{[2-(3-^arboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-qulnolin-7-ylamlno)ethyl]- methylamlno}-propyi)-6-0-methyl-erythromycIn A 11,12-carbonate; 4"-0-{3-[2-(2-carboxy-1 -oxo-6,7-dihydro-1 H,5W-pyrido[3,2,1 -lquinoline-9-yloxy)- ethylamlno]-propyl}-6-0-methyl-erythromycin A11,12-carbonate; 4"-0-(3-{[3-(3-arboxy-1-ethyl-4-xo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino} propyl)-6-0-methyl-erythromycln A 11,12-carbonate; 4"-0-(3-{I2-(3-carboxy-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridirn-7- ylamlno)ethyl]-methylamIno}-propyl)-6-0-methyl-erythromycIn A 11,12-carbonate; and pharmaceutically acceptable derivatives thereof. Further particularly preferred compounds of the invention are: 4"-0-{2-[2-(3-carboxy-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridfn-7- ylamlno)ethyl]-methylamino}-ethyl }-6-O-methyl-erythromycin A; 4"-0-{3-[[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamlno]- propyl}-6-0-methyl-11-desoxy-11-(R)amino-erythromycin A 11,12-carbamate; 4"-0-{3-[[2-(3-carboxy-1-ethvl-4-oxo-1,4dihydro-quinolin-6-ylsulfanyl)-ethyl]- methylamlno]-propyl}-6-0-methyl-11-desoxy-11-(R)-amino-erythromycin A 11,12- carbamate; 4"-0-{3-[2-(3-rarboxy-7-chloro-1-cyciopropyl-4-oxc>-1,4-dihydro-quinolin-6-ylamlno}- ethylcarbamoyl]-propyl}-azithromycin; 4"-{2-[2-(3-raitoxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydr6-quinolin-7-ylamlno)- ethylamino]-ethyl}-azithromycln 11,12-cyclic carbonate; 4"-0-{242-(3-rarboxy-7-chIoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yfamino)- ethylamlno]-ethyl}-azithromycin; 4"-Q-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)- ethylamlno]-ethyl}-azithromycin; 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 mlcroorganisims. 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 01 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 (l) 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 therapetlc 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), solubillsing 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-cyclodextrln 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 solublliser. 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 blle. 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 route. 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 genlto-urinary use. For some applications, the agents of the present Invention are delivered systemlcally (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, intraarterlally, Intraperitoneally, intrathecally, intraventricularly, intraurethraily, intrasternalfy, 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 olly or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, solubilislng and/or dispersing agents. Alternatively the active Ingredient may be In sterile powder form for reconstitutlon 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 pharmaceuticatly acceptable carriers and exciplents which may be in solid or liquid form. The tablets may contain exciplents such as mlcrocrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, dlsintegrants 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), hydroxypropylcellulose (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 exclplents 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 exdplent. 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, poiysorbate 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 micronlsed 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 benzylalkonlum chloride. Alternatively, they may be formulated in an ointment such as petrolatum. As Indicated, the compound of the present invention can be administered intranasally 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 nebullser with the use of a suitable propellant, e. g. dichlorodifluoromethane, trichlorofluoromethane, dlchlorotetrafluoroethane, 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 nebullser. 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 R33, A, B, X, Y, U, 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 R11a, BaR11a and XaR11a are R11, BR11 and XR11 as defined for formula (I) or groups convertible to R11, BR11 and XR11. Conversion of such groups 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 2nd ed., John Wiley & Son, Inc 1991 and by P.J. Koclenskl 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, trifiuoroacetyl and acetyl), aromatic urethane type protecting groups (e.g. benzyioxycarbonyl (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 trimethylsllyl or tert- butyldimethylsllyl; 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 trialkylsllyl chloride in an aprotlc solvent. Examples of aprotic solvents are dichioromethane, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like. Compounds of formula (I) wherein U is -N(R30)- may be prepared by reaction of a 4" aldehyde compound of formula (II) wherein A, R2, R3, R4 and R5 may be suitably protected, for example by cyclic protection between the 9 and 12 positions when A is - C(O)- and d is an integer from 1 to 5, with a suitable protected derivative of the amine (Illa) or (lllb), followed where necessary by subsequent removal of the hydroxyl protecting group R2 and conversion of the BaR11a or R11a group to BR11 orR11. 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. Compounds of formula (II) where d' is 1 or 2 may be prepared from suitably protected compounds of formula (IV) by hydroboration with 9-BBN, or other suitable boranes, followed by treatment with peroxide and then oxidation (d' = 2), or by osmlum tetroxide/peridoate cleavage (d' = 1). Compounds of formula (IV) can be formed by palladium-catalysed allylation of suitably protected 4" hydroxy compounds. In another embodiment of the invention, compounds of formula (I) wherein U is a group selected from -N(R30)- and -S-, may be prepared by reaction of compounds of formula (V) wherein d is an integer from 2 to 6 and L is a suitable leaving group, with XaR11a (VI) in which U is a group selected from -N(R30)- 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, dimethyisulfoxide, N.N-dimethylformamlde 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 XaR11a group to XR11. Examples of the bases which may be used include organic bases such as diisopropylethylamine, triethylamine and 1,8- dlazabicyclo[5.4.0]undec-7-ene (DBU), 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 hallde (e.g. chloride, bromide or iodide) or a sulfonyloxy group (e.g. tosyloxy or methanesulfonyloxy). Compounds of formula (I) may be converted into other compounds of formula (I). Thus compounds of formula (I) wherein U or B 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 U or B is -N(R30)- and R30 is C1-4alkyl can be prepared from compounds wherein R30 is hydrogen by reductive alkylatlon. with a suitable compound of formula XaR11a, in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium. In another embodiment of the Invention, compounds of formula (I) wherein U is -0-, may be prepared by reaction of compounds of formula (VII) In a further embodiment of the invention, compounds of formula (i) wherein U is - C(O)N(R30)-, may be prepared by reaction of compounds of formula (VIII) with a suitable amine compound. Compounds of formula (II) wherein A is -C(O)NH- or -NHC(O)-, R4 or R5 are hydroxy, R3 Is hydrogen and R6 is hydrogen are known compounds or they may be prepared by analogous methods to those known in the art. Thus they can be prepared according to the procedures described in EP 507595 and EP 503932. Compounds of formula (II), wherein A is -C(O)NH- or -NHC(O)-, R4 or R5 are hydroxy and R3 is C1-4alkyl or C3-6alkenyl optionally substituted by 9 to 10 membered fused blcyclic heteroaryl and R6 is hydrogen are known compounds or they may be prepared by analogous methods to those known in the art. Thus they can be prepared according to the procedures described in WO 9951616 and WO 0063223. Compounds of formula (II), wherein A is -C(O)NH-, R4 and R5 taken together with the intervening atoms form a cyclic group having the following structure: R3 is C1-4alkyl, or C3-6ealkenyl optionally substituted by 9 to 10 membered fused blcyclic heteroaryl and R6 is hydrogen are known compounds or they may be prepared by analogous methods to those known in the art Thus they can be prepared according to the procedures described in US 6262030. Compounds of formula (II), wherein A is -C(O)-, -C(O)NH-, -NHC(O)-, -N(R7)-CH2-, -CH2- N(R7)- or-CH(NR8R9)-. R4 or R5 are 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 -O- and -N(R13)- and R3 IS C1-4alkyl, or C3. 6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl are known compounds or they may be prepared by analogous methods to those known In the art Thus they can be prepared according to the procedures described in EP 307177, EP 248279, WO 0078773, WO 9742204. Compounds of formula (II), wherein A is -C(O)NH-, -NHC(O)-, -N(CH3)-CH2- or -CH2- N(CH3)-, R4 or R5 are hydroxy or R4 and R5 taken together with the intervening atoms form a cycllc group having the following structure: and R6 is hydrogen are known compounds or they may be prepared by analogous methods to those known in the art Thus they can be prepared according to the procedures described In EP 508699 and J.Chem. Res.Synop (1988 pages 152-153), US 6262030. Compounds of formula (II), wherein A is -C(=NR10)-, R4 or R5 are hydroxy or R4 and R5 taken together with the Intervening atoms form a cyclic group having the following structure: and R6 is hydrogen, are known compounds or they may be prepared by analogous methods to those known in the art Thus they can be prepared according to the procedures described in EP 284203. Compounds of formula (II), wherein A is -C(O), R4 and R5 taken together with the Intervening atoms form a cyclic group having the following structure: R6 is hydrogen and R3 is C1-4alkyl may be prepared by decarboxylation of a compound of formula (IX), wherein R34 is amino protecting group followed, if required, by removal of the protecting group R2 or R34. The decarboxylation may be carried out in the presence of a lithium salt such as lithium chloride, preferably in an organic solvent such as dlmethylsulfoxide. Compounds of formula (II), wherein A is -C(O)-, R4 and R5 taken together with the intervening atoms form a cyclic group having the following structure: and R3 is C1-4 alkyl may be prepared according to the procedures described in WO 02/50091 and WO 02/50092. 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 Ac for acetyl, AC2O for acetic anhydride, 9-BBN for 9-borablcyclo[3.3.1]nonane, BINAP for 2,2,-bls(dlphenyiphosphlno)-1,1'- binaphthyl, BOC for t-butoxycarbonyl, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene, DCM for dlchloromethane, D1PEA for N.N-dllsopropylethvlamine. DMF for N,N- dimethylformamide, DMSO for dimethyl sulfoxide, Et2O for diethyl ether, EtOAc for ethyl acetate, EtOH for ethanol, HBTU for2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronlum hexafluorophosphate, HOAc for acetic acid, LDA for lithium diisopropylamlde, MeCN for acetonitrile, MeOH for methanol and THF for tetrahydrofuran. 2-O-Acetyl-azithromycrn11,12-carbonate may be prepared by the procedure described by S. Djokic et al. in J. Chem. Res. (S) 1988,152. Nomenclature In the Examples, compounds of formula (I) in which R11 is a tricyclic heterocyclic group are referred to using the numbering system below: Intermediate 1; 6[(2-Amlnoethvl)amino]-7chlro-1cyclopropyl-4-oxo-1.4-dlhydro qulnollne-3-carboxyllc acid 7-Chloro-1-cyclopropyl-1,4-dihydro-oxo-quinollne-3-carboxyllc acid (56.3 g) and ethylenedlamlne (36 g) were dissolved in N.N-dimethytacetamide (650 mL) at 100°C and stirred for 8.5 h at 115oC. 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 110oC 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 35-40oC 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]-. Intermedlat 2:6-(2-Amlno-ethoxy)-1-ethyi-4-oxo-1,4dlhydro qulnollne-3- carboxyllc acid hydrochloride a) 6-(2-Dibenzamlno-thoxy)-1-ethyl-4-oxo-1,4-dlhydro-qulnollne-3-carboxyiic acid 2-dibenzytamlno-ethyl aster. 1Ethyl-6-hydroxy-4-oxo-1,4-dihydro-qulnollne-3-carboxyllc acid (GB 1433774) (1.4 g. 6 mmol) was dissotved In dry DMF (80 mL). To this was added potassium carbonate (5 g, 36 mmol) and dlbenzyl-(2-chloroethyl)amlne 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 IM+H]+ (100%). b) 6-(2-Dlbenzylamlno-ethoxy)-1-ethyl-4-oxo-1,4-dlhydro-qulnoIlne-3-carboxyllc acid sodium salt. Intermediate 2a (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-quinoiine-3-carboxylic acid. Intermediate 2b (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(ll) hydroxide on carbon (0.6 g) at 50 psl for 18 h. The mixture was filtered through kleselguhr, 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 3: 6-(2-Aminoethvlsulfanyn-1 -ethyl-oxo-1,4-dlhvdro-quinollne-3- carboxyiic acid trlfluoroacetate salt a) 6-Bromo-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxyiic acid ethyi ester. A mixture of potassium carbonate (2.95 g, 21.2 mmol) and 6-bromoquinolone-3-carboxylic acid (2.84g, 10.6 mmol) in dimethylformamlde (25 mL) was heated to 40°C under argon for 10 minutes and lodoethane (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 5oC and filtered under vacuum. The resultant cream-coloured solid was dried under vacuum to yield the title compound; 1H NMR 5 [(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 (1H, dd, J = 2.4 & 9 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.49 (1H, s). b) 6-(2-t-Butoxycarbonylamlnoethylsulfany1)-1 -ethyl-4-oxo-1,4-dlhydro-qulnollne-3- carboxyllc acid ethyl ester. A mixture of N-Bocsteinamine (0.35 g. 2 mmol), Intermediate 3a (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-chromatograpny over slilca gal editing with diotoromethane containing an increasing concentration of methanol/emmonium hydroxide the title compound was obtained as a white solid; ESMS m/z 421 [M+H]+ (100%). c)6-(2-t-Butoxycarbonytamlnoethyisulfanyl)-1-ethyl-4-oxo-1,4-dlhydro-quinoilne-3- carboxyiic add sodium salt To a solution of Intermediate 3b (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-Aminethyisulfanyl)-1-ethyl-4-oxo-1,4-dihydro-quinollne-3carboxiic acid trtfluoroacetate salt To Intermediate 3c (0.068 g, 0.17 mmol) was added trifluoroacetic acid (1 mL). After 1 h the solvent was evaporated to yleid 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). Intermedlated 4: 6-(3-Amlnopropyl)-1-ethyl-4-oxo-1,4-dlhydro-3-quinoilne-3-carboxilc acid trlfluoroacetate salt a) 1-Ethyl-6-odo-4-oxo-1,4-dihydro-quinollne-3-carboxylic acJd ethyl ester. A mixture of 1,4-dihydro-6-iodo-4-oxo quinollne-3-carboxyilc acid (J. Eills et a/, 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 8 (CDCl3) 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-t-Butoxycarbonylamino-prop-1-ynyl)-1-ethyl-4-oxo-1,4-dihydro-quinline-3- carboxylic acid ethyl ecter. Intermediate 4a (0.371g, 1 mmol), copper (I) iodide (26 mg, 0.13 mmol) and triethyiamine (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 mfn. dicniorobte(triphenylphosphine)paliadium (II) (0.026g, 0.0379 mmol) and t-butoxycanbonyipropargytarnine (0.264 g, 1.7 mmol) were added and the brown suspension was heated under reflux. After 2 h 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-t-Butoxycarbonylamlnopropyl)-1-ethyl-4-oxo-1,4-dlhydro-quinollne-3- carboxylic acid ethyl ester. Intermediate 4b (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-dlhydro-qulnoilne-3-carboxylic acid ethyl ester. Using a similar procedure to that described in intermediate 3d, Intermediate 4c (355 mg, 0.88 mmol) gave the title compound as a yellow oil; ESMS m/z 303 [M+H]+. e) 6-(3-Aminopropyl)-1-9thyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium salt. Using a similar procedure to that described in intermediate 3c, intermediate 4d (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-quinoIine-3-carboxylic acid trifluoroacetate salt. Intermediate 4e (0.06 g, 0.2 mmol) was subjected to reverse phase HPLC purification to give the title compound as white solid; 1H NMR 5 [(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,(1H, 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 5: 9-(2-Amino-ethoxy)-1-oxo-8.7'dihvdro-1H,5H-pyridor[3.2.1- ll]qulnoline-2-carboxylic acid hydrochloride a) 9-(2-Dlbenzylamino-ethoxy)-1-oxo-6,7-dlhydro-1W,5W-pyrldo[3,2,1-ij]quinoline-2- carboxylic acid 2-dibenzylamino-sthyl ester. 9-Hydroxy-1-oxo-6,7-dihydro-1H,5H-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-chioroethyl)amine hydrochloride (2.37 g, 8 mmol). The mixture was heated at 60°C for f6 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+HJ+ (100%). b) 9-(2-DlbenzyIamlno-ethoxy)-1-oxo-6,7-dihydro-1 //,5//-pyrido[3,2,1-ij]quinoline-2- carboxyllc acid sodium salt. Intermediate 5a (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]qulnollne-2- carboxyllc acid hydrochloride. Intermediate 5b (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 6: 7-(2-AmIno-ethvlamlno)-1 -ethvl-6-fluoro-4-oxo-1,4-dlhvdro- [1.8]naphthyridine-3-carboxylic acid trifluoroacetate a) 7-(2-tert-Butoxycarbonylamino-ethylamino)-1-ethyi-6-fluoro-4-oxo-1,4-dihydro- [1,8]naphthyrldine-3-carboxylic acid ethyl ester. 7-Chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (2.20 g, 7.37 mmol) in THF (20 mL) and MeCN (20 mL) was treated with triethylamine (3.07 mL, 22.0 mmol), followed by (2-amino-ethyI)-carbarnic acid terf-butyl ester (1.41 g, 8.80 mmol) and the mixture heated to 70°C. After 26 h (2-amino-ethyl)- carbamic acid fert-butyl ester (300 mg, 1.87 mmol) was added. After a further 15 h the heating was stopped and the solvent removed In vacuo. The residue was taken up in ethyl acetate, washed with water, dried filtered, and concentrated In vacuo to give a residue which was purified by chromatography (silica gel, 30-100% ethyl acetate in petroleum ether (b.p. 40-60°C)) to give the title compound (2.89 g); ESMS m/z 423 IM+H]+. b) 7-(2-fert-Butoxycarbonylamino-ethylamino)-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro- [1,8]naphthyridlne-3-carboxylic acid. To Intermediate 6a (2.89 g, 6.84 mmol) in THF (30 mL) was added 2 N aqueous sodium hydroxide (3.4 mL, 6.8 mmol), and the mixture stirred at room temperature. After 24 h 2 N aqueous sodium hydroxide (0.6 mL, 1.2 mmol) was added and stirring continued for a further 24 h. The solvent was then removed in vacuo, and the residue taken up in water (10 mL). Solid carbon dioxide-was added, and the resulting precipitate filtered off and dried in vacuo to give the title compound (2.65 g); ESMS m/z 395 [M+Hf. c) 7-(2-Amino-ethylamino)-1 -ethyl-6-fluoro-4-oxo-1,4-dlhydro-[1,8]naphthyridine-3- carboxyllc acid trlfluoroacetate. Intermediate 6b (2.65 g, 6.72 mmol) was suspended in dichloromethane (30 mL), trtfluoroacetlc acid (15 mL) added, and the solution stirred for 35 min. The mixture was concentrated in vacuo, and again from toluene, and again from hexane to give the title compound as a tan powder (2.92 g); ESMS m/z 295 [M+Hf. Intermediate 7: 2'O-Acetvl-6-0-metyl-11-desoxv-11-fR)-methyiamino- erythromycin A 11.12-carbamate 6rO-Methyl-11 desoxy-11-(R)-methylamino-erythromycin A 11,12-carbamate (W. R. Baker ef al., J. Org. Chem:, 1988, 53(10), 2340-5) (0.87 g) was dissolved in DCM (20 mL) and acetone (3 mL). Solid NaHC03 (0.6 g) and AczO (0.6 mL) were added and the reaction mixture was stirred for 1 h, then DCM (50 mL) and water (50 mL) were added. The organic phase was separated, washed with brine (20 mL), dried over K2C03, filtered and concentrated under reduced pressure, affording the title compound (0.875 g); ESMS m/z 829 [MH]+. Intermediate 8; 6-((Z)-34ert-Butoxvcarbonyloxvprop-1-enyl)-1.4-dihydro-1-ethyl-4. oxo-quinoline-3-carboxylic acid ethyl ester a) 1,4-Dlhydro-1-ethyl-6-lodo-4-oxo-qulnoline-3-carboxyIic acid ethyl ester. A mixture of 1,4-dlhydro-6-lodo-4-oxo-qulnoline-3-carboxylic acid (J. Ellis, E. Gellert, J. Robson, AusL 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), 8.88 (1H. d, J = 2.1 Hz). b) 6-(3-Hydroxyprop-1-ynyl)-1,4-dihydro-1-ethyl-4-oxo-qulnoline-3-carboxylic acid ethyl ester. Intermediate 8a (3.71 g, 10 mmol), copper (I) iodide (0.209 g, 1.1 mmol) were suspended in dry acetonitrile (100 mL) and triethylamine (49 mL). The light green suspension was heated to 50°C whilst argon was bubbled through. After 20 mln, dichlorobis(triphenylphosphine)palladlum (II) (0.21 g, 0.3 mmol) and propargyl alcohol (0.92 mL,. 17 mmol) were added and the brown suspension was heated under argon at 50°C for 3.5 h. The crude product was purified by chromatography on silica gel elutlng with a gradient of dichloromethane in hexane followed by a gradient of methanol in dichloromethane. Product containing fractions were evaporated to dryness and the residue dissolved in chloroform and filtered. The filtrate was evaporated to drynes to yield the title compound as a beige solid, (1.62 g, 54%); ESMS m/z 300 [M+H]+. c) 6-((Z)-3-Hydroxyprop-1-enyl)-1,4-dihydro-1-ethyl-4-oxo-quinoIine-3-carboxylic acid ethyl ester. Intermediate 8a (0.39 g, 1.3 mmol) in ethanol (10 mL) and 1,4-dioxan (5 mL) was hydrogenated at 20°C and 1 atm over Lindlar catalyst (0.05g). After 5 h, dichloromethane (10 mL) was added, and the hydrogenation continued for 18 h. The catalyst was filtered off and washed well with ethanol / dichloromethane. The combined filtrates were evaporated to dryness and the residue taken up in ethanol (4 mL) and dichloromethane (12 mL), and re hydrogenated at 20°C and 1 atm over Lindiar catalyst (0.2 g) for 3 h. The catalyst was filtered off and washed well with ethanol / dichloromethane. The combined filtrates were evaporated to dryness to give the title product as a white solid, (0.394g) ESMS m/z 302 [M+H]+. d) 6-((Z)-3-tert-Butoxycarbonyloxyprop-1-enyl)-1,4-dlhydro-1-ethyl-4-oxo-quinoline- 3-carboxylic acid ethyl ester. Intermedlate 8a (0.393 g, 1.3 mmol) in dichloromethane (10 mL) was treated with di-tert- butyl dicarbonate (0.327 g, 1.5 mmol) and N-methylimidazole (0.01 g). After 4 d at 20 °C the crude product was purified by chromatography on silica gel elutlng with a gradient of ethyl acetate in hexane to give the title product, (0.40g, 77%). 1H NMR δ (CDCI3) 1.42 (3H, t,J = 7.1 Hz), 1.49 (9H, s), 1.51 (3H, t, J = 7.2 Hz), 4.26 (2H, q, J = 7.2 Hz), 4.41 (2H, q, J = 7.1 Hz), 4.89 (2H, dd, J = 6.4,2.0 Hz), 5.93 (1H, dt, J = 11.8,6.4 Hz), 6.73 (1H, bd, J= 11.8 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.58 (1H, dd, J= 8.8, 2.2 Hz), 8.35 (1H, d, J= 2.2 HZ), 8.49 (1H, s). Intermediate 9:6-(3-Aminopropyl)-ethvl-5-methvl-4-oxo-1.4-dihvdro-3- qulnolinecarboxvlic acid trifluoroacetate a) Diethyl {[4-iodo-3-methyiphenyl)amino]methylidene}propanedioate. 4-lodo-3-methylanlline (5.75 g) was suspended in diethyl ethoxymethylenemalonate (5.5 mL). The mixture was heated at 130°C for 2.5 h. After cooling to ~90C, hexane was added and the mixture stirred while cooling to room temperature. The product crystallised out, and was filtered off, washing well with more hexane. The solid was dried in vacuo to yield the title compound as a pale grey powder (7.947 g);1H NMR δ (CDCI3) 1.33 (3H, t), 1.38 (3H, t), 2.43 (3H, s), 4.25 (2H, q), 4.3 (2H, q), 6.69 (1H, dd), 7.01 (1H, d), 7.75 (1H, d), 8.46 (1H, d). and 10.95 (1H, brd). b) Ethyl 6-iodo-5-methyl-4-oxo-1,4-dlhydro-3-quinolinecarboxylate. Intermediate 9a (8.73 g) was suspended in Dowtherm (30 mL) then heated at 250oC for 1 h. The mixture cooled, petroleum ether added, and the solid filtered off, washing well with more petroleum ether. The solid was dried in vacuo to give the title compound and the 7- methyl isomer as a pale grey powder (7.8 g). c) Ethyl 1-ethyl-6-iodo-5-methyl-4-oxo-1,4-dlhydro-3-quinolinecarboxylate. Intermediate 9b (3.57 g) was suspended in DMF (25 mL), potassium carbonate (1.66 g) and lodoethane (3.2 mL) added, and the mixture heated at 55°C - 60°C for 89 h. More lodoethane (2x2 mL) being added after 64 and 69 h. The mixture was evaporated, diluted with water and extracted with ethyl acetate (x 7). The combined organic extracts were washed with aqueous sodium thiosulphate solution then brine, dried and evaporated. The residue was purified by chromatography on silica gel (100 g), eluting with 40 -100% ethyl acetate in petroleum ether followed by 5% methanol in dichloromethane, to give the title compound as a pale brown solid (0.492 g); ESMS m/z 386 [M+H]+. d) Ethyl 6-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amlno)-1-propyn-1-yl]-1-ethyl-5- methyl-4-oxo-1,4-dihydro-3-qulnolinecarboxylate. Using a similar procedure to that described in intermediate 4b, intermediate 9c (0.485 g) and t-butoxycarbonylpropargylamine (0.332 g) gave the title compound as a yellow solid (0.62 g); ESMS m/z 413 [M+H]+. e) Ethyl 6-[3-{[(1,1dimethyiethyl)oxy]carbonyl}amino)propyi]-1-ethyl-5-methyl-4. oxo-1,4-dihydro-3-quinoilnecarboxylate. Intermediate 9d (0.52 g) in DCM (30 mL) was treated with 10% Pd/C (0.4 g). The mixture filtered then hydrogenated over 10% Pd/C (0.4 g) for 1 h. The resultant mixture was filtered and the solvent evaporated to give the title compound as a yellow foam (0.58 g); ESMS m/z 417 [M+H]+ f)6-[3-({I(1,1-Dimethylethyl)oxylcarbonyl}amino)propyf]-1-ethyi-5-methyl-4-oxo-1,4- dlhydro-3-qulnolinecarboxylic acid. Using a similar procedure to that described in intermediate 6b, intermediate 9e (0.524 g) was reacted to give the title compound as a cream powder (0.457 g); ESMS m/z 389 [M+H]+. g) 6-(3-Amlnopropyr)-1-ethyl-5-methyl-4-oxo-1,4-dlhydro-3>quinolinecarboxylic acid trlfluoroacetate. Using a similar procedure to that described in intermediate 6c, intermediate 9f (0.453 g) was reacted to give the title compound as a pale brown powder (0.505 g); ESMS m/z 289 [M+H]+. Intermediate 10:7-(2-Amino-ethyiamino)-1-ethyl-4-oxo-4-H-quinoline-3-carboxylic acid a) 4-Chloro-2-propyipyridine To a solution of LDA (0.13 motes) in THF/hexanes (40 mL/40 mL) at -60°C under argon was added a solution of 4-chloro-2-plcoline (15 g) in THF (250 mL) over 20 min. After a further 30 mln at -60°C iodoethane (10.4 mL) In THF (60 mL) was added over 20 min, the reaction stirred at -60°C for 1.5 h and then allowed to warm to -30°C. The mixture was poured into brine and extracted with dichloromethane. After drying (MgS04) and purification by chromatography elutlng with dichloromethane in petroleum ether (70-100%) followed by dichloromethane containing methanol (0 to 5%) the title compound was obtained as a brown oil (12.35 g). 1H NMR δ (CDCI3) 0.97 (3H, t), 1.75 (2H. m), 2.75 (2H, t), 7.12 (1H, m), 7.16 (1H, d), 8.42 (1H, d). b) [2-(4-Chloro-pyrIdln-2-yl)-1-ethoxy-butyri-malonic acid diethyl ester. To a solution of LDA (87.5 mmoles) in THF/hexanes (40 mL/40 mL) at-60°C under argon was added a solution of Example 10a (12.31g) in dry THF (150 mL) over 20 min. After a further 30 mln at -80°C diethyl ethoxymethylene malonate (18.81 g) in THF (40 mL)) was added over 20 min, the reaction stirred at -60°C for 1.5 h and then allowed to warm to -30°C. The mixture was poured into brine and extracted with ethyl acetate. After drying (MgSO4) and purification by chromatography eluting with dichloromethane in petroleum ether (70-100%) followed by dichloromethane containing methanol (0 to 5%) gave the title compound as an oil (27.38 g). ESMS m/z 372 [M+H]. c) 7-Chloro-1-ethyl-4-oxo-4-H-quinolizine-3-carboxylic acid ethyl ester. A solution of intermediate 10b (27.38 g) and DBU (10 drops) in xylene was heated at reflux. After 16 h the mixture was cooled and purifled by chromatography eluting with dichloromethane containing methanol (0 to 10%). The resultant yellow/brown solid was triturated with diethyl ether and filtered to yield the title compound as a yellow solid. ESMS m/z 280 (M+H). d) 7-(2-t-Butoxycarbonylamlnoethylamino)-1 -ethyl-4-oxo-4-H-qulnolbine-3- carboxylic acid ethyl ester. A solution of intermediate 10c (0.63 g), mono Boc ethylene diamine (0.45 g) and triethylamlne (0.9 mL) in pyridine (15 mL) was heated at 60 °C for 16 h. After evaporation the crude product was purified by chromatography eluting with dichloromethane containing methanol (0 to 5%) to give the title product as a yellow solid (0.37g. ESMS m/z 404 (M+H). e) 7-{2-t-Butoxycarbonylaminoethylamino)-1 -ethyl-4-oxo-4-H-quInolizine-3- carboxylic acid. Using a similar procedure to that described for the preparation of Intermediate 6b, intermediate 10d (0.334 g) gave the title compound as yellow solid ESMS m/z 376(M+H). f) 7-(2-AmInoethylamino)-1-ethyl-4-oxo-4-H-qulnolizine-3-carboxylic acid. Using a similar procedure to that described for the preparation of intermediate 6c Intermediate 10e ( 0.172 g) gave the title compound as yellow solid. ESMS m/z 276 (M+H). Intermediate 11: 6-(3-Amlnopropyl)-1-ethyl-4-oxo-1.4-dlhvdro-1.8-naphthvridine-3- carboxylic acid trifluoroacetate salt a)EthyI 2-[(2-chloro-5-iodo-3-pyrldinyl)carbonyl]-3-(ethylamino)-2-propenoate. 5-lodo-2-hydroxypyridine-3-carboxylic acid (T. R. Elworthy et a/., J.Med.Chem., 40, 17, 1997,2674-2687) (7.95 g) was suspended in thionyl chloride (40 mL). DMF (4 drops) was added and the mixture refluxed for 4 h. The resultant solution was evaporated to dryness. This acid chloride was then dissolved in 1,4-dioxane (40 mL) and added dropwise to a solution of ethyl 3-(ethylamino)-2-propenoate (5.15 g) and triethyiamine (10.5 mL) in 1,4- dioxane at 0°C. After 1 h the cooling bath was removed, and the reaction stirred at room temperature for 16 h. The mixture was then evaporated, saturated sodium hydrogen carbonate solution added, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated to give a dark oil. This was purified by chromatography on silica gel, eluting with 33 - 45% diethyl ether in petroleum ether, to give the title compound (5.35 g); ESMS m/z 409 [M+H]+. b) Ethyl 1 -ethyl-6-lodo-4-oxo-1,4-dlhydro-1,8-naphthyridlne-3-carboxylate. Intermediate 11a (4.92 g) was dissolved in DMF (50 mL), potassium carbonate.(1.662 g) added, and the mixture heated at 50°C for 16 h and 60oC for 2 h. After evaporation the mixture was diluted with water and extracted with DCM. The combined organic extracts were dried and evaporated to give an oil. This was purified by chromatography on silica gel, eluting with 0 - 20% diethyl ether in DCM, to give the title compound as a pale yellow solid (4.33 g); ESMS m/z 373 [M+H]+. c) Ethyl 6-[3-(t-butoxycarbonylamino)-1 -propyn-1 -yl]-1 -ethyl-4-oxo-1,4-dihydro-1,8- naphthyrldine-3-carboxylate. A mixture of Intermediate 11b (2.176 g), copper (I) Iodide (115 mg, 0.6 mmol) and triethylamine (27.9 mL, 200 mmol) were suspended in dry acetonitrile (40 mL). The light green suspension was heated to 43°C whilst argon was bubbled through. After 30 min, dlchlorobis(triphenylphosphine)palladium (II) (0.127g, 0.018 mmol) and N-t- butoxycarbonylpropargylamine (1.542 g) were added and the mixture was heated at 43°C for 25 min. 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 dark solid which was purified by chromatography on silica gel eluting with 0-25% (methanol/diethyl ether [1:24]) in dichloromethane to yield the title compound-as a pale yellow solid (1.8 g); ESMS m/z 400 [M+H]+. d) Ethyl 6-[3-(t-butoxycarbonylamino)-1-propyl]-1-ethyl-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylate. intermediate 11c (0.91 g)) in dichloromethane (50 mL) was treated with 10% palladium on carbon (60 mg) and hydrogenated at room temperature and atmospheric pressure for 75 mln. The reaction mixture was filtered and concentrated, and the residue purified by chromatography on silica gel eluting with 0-4% methanol in dichloromethane to give the title compound as an off-white solid (0.83 g); ESMS m/z 404 [M+H]+. e) 6-[3-(t-Butoxycarbonylamino)-1 -propyl]-1 -ethyl-4-oxo-1,4-dlhydro-1,8- naphthyridine-3-carboxylic acid. intermediate 11 d (0.825 g) was dissolved in THF (15 mL), 0.2 N sodium hydroxide (15 mL) added, and the reaction stirred for 16 h at room temperature. The mixture was evaporated to a small volume then solid carbon dioxide added. The precipitate which formed was filtered off, washed well with water, and dried in vacuo over phosphorous pentoxide to give the title compound as an off-white powder (0.709 g); ESMS m/z 376 [M+H]+. f) 6-(3-Aminopropyl)-1 -ethyl-4-oxo-1,4-dlhydro-1,8-naphthyridine-3-carboxylic acid trifluoroacetate salt. intermediate 11e (0.72 g) was dissolved in DCM (12 mL), trifluoroacetic acid (4 mL) was added and the reaction stirred under argon at room temperature for 0.75 h. The solution was evaporated to dryness, and the residue triturated with diethyl ether to give, after drying, the title compound as an off-white powder (0.859 g). NMR data: 1H NMR (DMSO-d6) 1.43 (3H,t), 1.95 (2H, m), 2.84 (2H, m), 2.92 (2H, t), 4.68 (2H, q), 7.78 (3H, br s), 8.63 (1H, d), 8.95 (1H, d), 9.24 (1H, s) and 14.8 (1H, br s). Intermediate 12: 9-(3-Amino-propyl)-1-oxo-6.7-dlhvdro-1H,5H-pyrido [3.2.-ij] qulnoline-2-carboxyllc acid trifluoroacetate salt a) Diethyl 2-((3,4-dlhydro-2H-qulnolin-1-yl)methylene)malonate. A mixture of tetrahydroquinoline (13.32g, 100mmol) and diethyl ethoxymethylenemalonate (21.62g, 100mmol) is heated to 130°C using a Dean-Stark apparatus. After 1 hour the reaction mixture was concentrated to give the title compound as a brown oil. ESMS m/z 304 (MH+). b) Ethyl 1-oxo-6,7-dlhydro-1H,5W-pyrldo [3,2,1-ij] qulnoline-2-carboxylate. Diethyl 2-((3,4-dihydro-2H-qulnolin-1-yl)methylene)malonate (2.5g, 8.24mmol) was dissolved in polyphosphoric acid and the viscous mixture stirred for 4hours at 110°C. The reaction mixture was cooled down before adding ice. The resuiting precipitate was filtered off, washed with water then dried In a dessicator in the presence of phosphorous pentoxide. togive the title compound as a beige solid. ESMS m/z 258 (MH+). 1H NMF (DMSO-d6) δ 8.55(s, 1H), 8.05 (dd, 1H), 7.54 (dd, 1H). 7.38 (dd, 1H), 4.27 (q, 2H), 4.Z (q, 2H), 3.00 (t, 2H), 2.10 (tt, 2H), 1.28 (t, 3H). c) Ethyl 9-romo-1-oxo-6,7-dlhydro-1H,5H-pyrkido [3,2,1-ij] qulnoline-2-carboxylate. Ethyl 1-oxo-6,7-dihydro-1H,5W-pyrido [3,2,1-ij] quinoiine-2-carboxyiate (290mg, 1.13mmol) was dissoived in acetic acid (3mL) and bromine (197mg, 1.23mmol) was added dropwise. The reaction was followed by LC/MS, additional bromine (2 X 197mg) was added. After 24 hours water was added and the precipitate was filtered off, washed with diethyl ether then dried in a dessicator in the presence of phosphorous pentoxide to provide an orange solid which was purifled by chromatography on silica gel eluting with 0- 1.5% (9:1 MeOH/20 M NH3) in dlchloromethane to yield the title compound as a white solid. ESMS m/z 336/338 (MH+). 1H NMR (CDCI3) δ 8.34(d, 1H), 8.31 (s, 1H), 7.48 (d, 1H), 4.37 (q, 2H), 4.17 (t, 2H), 3.03 (t, 2H), 2.23 (tt, 2H), 1.40 (t, 3H). d) Ethyl 9-(3-tert-butoxycarbonylamino-prop-1-oxo-6,7-dlhydro-1H,5H-Pyrido [3,2,1-ij] qulnoline-2-carboxylate. A yellow suspension of palladium acetate (73mg, 0.32 mmol) and triphenylphosphine (191mg, 0.72mmol) in dry tetrahydrofuran (6ml) under argon was cooled to 0°C. A solution of n-butyllithium (2.5M in hexanes, 284uL) was added dropwise and after 15 minutes the dark green suspension is warmed to room temperature for 15 minutes. This suspension is then cannulated under argon into a white suspension of ethyl 9-bromo-1- oxo-6,7-dlhydro-1H,5W-pyrido [3,2,1-ij] quinoline-2-carboxylate (337mg, 1mmol), copper Iodide (84mg, 0.44mmol) and t-butoxycarbonylpropargylamine (198mg, 1.28 mmol) in diethylamine (6mL). The brown suspension is warmed to 45°C for 2 hours then filtered off and preabsorbed on silica gel. Chromatography on silica gel elutlng with 0-5% (9:1 MeOH/20 M NH3) in dlchloromethane provided the title compound as a brown oil. ESMS m/z 411 (MH+). 1H NMR (CDCI3) δ 8.23(s, 1H), 8.12 (d, 1H). 7.29 (d, 1H). 5.1 (m, 1H), 4.35 (q, 2H), 4.15 (m, 2x2H), 2.97 (t, 2H), 2.19 (tt, 2H), 1.49 (s, 9H), 1.38 (t, 3H). e) Ethyl 9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7dlhydro-1/y,5H-pyrido [3,2,1-ij] qulnollne-2-carboxytate. Ethyl 9-(3-fert-butoxycarbonylamin--prop-1-ynyl)-1-oxo-6,7-dlhydro- 1H,5H-pyri [3,2,1-ij] qulnoline-2-carboxylate (318 mg, 0.77 mmol) was dissolved In dlchloromethane (50 mL), treated with 10% palladiun on carbon (200 mg) and hydrogenated at room temperature and atmospheric pressure overnight The reaction mixture was filtered and concentrated to provide a brown oil which was purified by chromatography on silica gel elutlng with 0- 1% (9:1 MeOH/20 M NH3) in dlchloromethane to yield the title compound as a brown oil. ESMS m/z 415 (MH+). 1H NMR (CDCI3) δ 8.34 (s, 1H), 8.11 (bs, 1H), 7.25 (bs, 1H), 4.60 (m, 1H), 4.37 (q, 2H), 4.17 (t, 2H), 3.13 (q, 2H), 3.02 (t, 2H). 2.71 (t,2H). 2.20 (tt, 2H). 1.85 (tt, 2H), 1.44 (s, 9H), 1.40 (t, 3H). f) 9-(3-tert-butoxycarbonylamino-propyl)-1 -oxo-6,7-dihydro-1 H,5H-pyrido [3,2,1 -ij] qulnoline-2-carboxylic acid sodium salt. Ethyl 9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrldo [3,2,1-ij] qulnollne-2-carboxylate (240 mg, 0.59 mmol) was dissolved in tetrahydrofuran (3 mL) and treated with 2N aqueous sodium hydroxide (0.32 mL). The solution was heated to 50°C overnight then treated with excess solid carbon dioxide. Evaporation of the solvent gave the title compound as a beige solid. ESMS m/z 387 (MH+). NMR (DMSO-d6) δ 8.83 (s, 1H), 8.11 (bs, 1H), 7.99 (s, 1H), 7.57 (s, 1H), 6.89 (bt, 1H), 4.41 (bt 2H), 3.04'(t, 2H), 2.94 (q, 2H), 2.71 (t,2H), 2.13 (m, 2H), 1.74 (m, 2H), 1.37 (s, 9H). g) 9-(3-Amlno-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido [3,2,1-ij] quinoline-2- carboxylic acid trifluoroacetate salt 9-(3-terf-Butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido [3,2,1-ij] quinoline-2-carboxylic acid sodium salt (224 mg, 0.58 mmol) was dissolved in trifluoroacetic acid (3 mL). After 0.5 h at room temperature the reaction mixture was concentrated to provide the title compound as a beige solid. ESMS m/z 287 (MH+). NMR (MeOD-d4) δ 8.83 (s, 1H), 8.15 (d, 1H), 7.62 (d, 1H), 4.43 (t, 2H), 3.14 (t, 2H), 2.98 (t, 2H), 2.89 (t,2H), 2.66 (tt, 2H), 2.05 (tt, 2H). Intermediate 13:4"-0-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1.4-dihvdro-quinoiin-6- yisulfanyl)-ethylamino]-propyl}-6-0-methyl-11 -desoxy-11 -(R)-amino-erythromycin A 11.12-carbamate formate The title compound was prepared from intermediate 3 by the procedure described below (see Table following Example 26). Intermediate 14: 4"-O-AIlyl-2'-O-acetvlazithromvcin-11.12-cvclic carbonate To a solution of 2'-0-acetyl azithromycin-11,12-carbonate (0.408 g, 0.5 mmoL) in dry THF (4 mL) under an atmosphere of nitrogen, was added tetraklstriphenylphosphine palladium (0.057 g, 0.05 mmol) and allyl t-butyl carbonate (0.30 g, 1.9 mmoL). The resulting mixture was stirred under reflux. After 18 h of reflux TLC indicated 50% conversion of the desired product. The solvent was evaporated and the crude product dissolved in 4 mL of methanol. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel eluting with 90:9:0.5; dichloromethane/MeOH/aq. NH3 to yield 0.24 g (56%) of a pale yellow crystals. MS (m/z) 815 (MH). Intermediate 15: 4"-(2-Oxo-ethoxy)-azithromvcin 11.12-cvclic carbonate To a solution of intermediate 14 (0.20g, 0.23 mmoL) in THF (1ml) and water (1ml), was added osmium tetraoxide (2.0 mL of a 2.5% solution in THF). After stirring for 5 minutes, sodium periodate (0.213 g, 1 mmoL) was added in one portion. The mixture was vigorously stirred for 12h at 25°C before being quenched with saturated aqueous Na2S03 (10mL). The resulting solution was stirred at 25°C for 2 h and then partitioned between EtOAc (22 mL) and water (5.0 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (2x10 mL). The combined organic extracts were dried (K2CO3) and the solvents were removed under reduced pressure. Flash column chromatography (silica gel, 90:9:0.5; dichloromethane/MeOH/aq. NH3) provided the corresponding aldehyde as a bright yellow solid (ca. 160 mg; 81% yield). MS (m/z) 817 (MH+). Intermediate 16: 4"-(3-Carboxv-propoxy)-azithromvcin a) 4"-(3-Methoxycarbonyl-aliyloxy)-azithromycin 11,12-cycllc carbonate. A mixture of Intermediate 15 (587.6 mg, 0.719 mmoL) and methoxycarbonylmethylene triphenyl phosphorane (360 mg, 1.08 mmoL, 1.5 mol equiv.) in benzene (7.2 mL) was heated at reflux for 18 h. After cooling to 25°C the solvent was removed under reduced pressure. Flash column chromatography (silica gel, 90:9:0.5 Ch2CI2:MeOH: aq. NH3) furnished unsaturated methyl ester 313,8 mg, 50%) as a mixture of Z and E isomers in 1:1 ratio according LC/MS analysis. MS (m/z) 873 (MH+). b) 4"-(3-Methoxycarbonyl-propoxy)-azithromycin 11,12-cyclic carbonate. The mixture of intermediate 16a from above (200 mg, 0.23 mmoL) was dissolved in MeOH (5 mL), treated with Pd/C (50 mg, 10 wt% Pd) and catalytically hydrogenated in Parr apparatus for 5 h. After filtration through a Celite pad, the filtrate was concentrated in vacuo and the residue purified by column chromatography (eluting with 90:9:0.5; dichloromethane/MeOH/aq. NH3) to give 125 mg (62%) of pure ester as a colourless crystalline solid. MS (m/z) 875 (MH+). c) 4"-(3-Carboxy-propoxy)-azithromycin. To a solution of intermediate 16b (875 mg, 1.0 mmoL) in 1:1 THF-water (10.0 mL) at room temperature, was added LIOH (192 mg, 4.57 mmoL), and the resulting reaction mixture was stirred at the same temperature for 12h. The solvent was removed under reduced pressure, and the solid was azeotroped with benzene (5 mL x 5) and finally dried under vacuum. The acid salt was dissolved in water and the resulting solution was made acidic by dropwise addition of 2M aqueous HCI. The precipitate was filtered of to give 787 mg (90%) of pure title compound. MS (m/z) 835 (MH+). Intermediate 17: 1 -Ethyl-4-oxo-6-plperazin-1 -yl-1.4-dihvdro-quinoline-3-carboxylic acid a) 6-(4-tert-Butoxycarbonyl-plperezin-1-yl)-1-ethyl-4-oxo-1,4-dihydro-qulnoline-3- carboxylic acid ethyl ester. An oven-dried Pyrex flask was charged with sodium tert-butoxide (134.5 mg, 1.4 mmoL), Pd2(dba)3 (2.3-9.2 mg, 0.0025-0.01 mmoL) and BINAP (47-18.7 mg, 0.0075-0.03 mmoL). The Pyrex tube was fitted with a septum, and the air atmosphere was replaced with argon, dry THF (2-9 mL), 6-iodo-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (371.2 mg, 1.0 mmoL), and N-Boc-piperazine (223.5 mg, 1.2 mmoL) were added by syringe. The reaction was heated to 80°C with stirring until the starting material was consumed as judged by LC-MS analysis. The reaction mixture was cooled to room temperature, diluted with ether (15 mL), filtered, and concentrated. The crude reaction mixture was then purifled further by flash chromatography on silica gel to give 356.5 mg (83%) of the title compound as a pale yelow solid. MS (m/z) 430 (MH+). b) 1-Ethyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester. A solution of intermediate 17a (429.5 mg, 1.0 mmoL) in 10 mL of CH2CI2 and trifluoroacetic acid (1:1) was stirred at 0°C for 5 hours. The volatile materials were evaporated under reduced pressure, and the residue was triturated with diethylether and filtered. The resulting product (354.7 mg, 80%) was used without further purification in the next step. MS (m/z) 330 (MH+). c) 1-Ethyl-4-oxo-6-plperazln-1-yl-1,4-dihydro-quinoline-3-carboxylic acid. intermediate 17b was dissolved in a mixture of THF, water and 5 eq of NaOH and stirred at 80 °C until TLC showed a complete conversion to the title compound. MS (m/z) 302 (MH+). Example 1: 4"-O-(2-{(2-(3-Carboxy-1 -cyclopropyl-6-fluoro-4-oxo-1 t4-dihydro- qulnolin-7-vlamino)-ethyl]-methylamlno}-ethyn-6-0-methyl-erythromycin A 11.12- carbonate bis trifluor oacetate a)2'-Ol3'-N-bis(Benzyloxycarbonyl)-3'-N-desmethyl-6-O-methyl-erythromycin A. To a stirred mixture of 6-O-methyl-erythromycin A (20 g, 26.8 mmol) and sodium hydrogen carbonate (30 g) cooled in an ice bath was added portionwise benzyl chloroformate (60 mL). After 10 min the ice bath was removed and the mixture was stirred for 15 min. The reaction was then heated at 60-70°C for 1 h. After cooling, the reaction mixture was loaded onto a silica gel column (150 g) and eluted with a gradient of 10-50% ethyl acetate in hexane. Evaporation of the product containing fractions gave the title product as a white solid foam (20.22 g); ESMS m/z 1024 [M+Na]+, 1060 [M+NH4+acetonitrile]+. b) 4"-0-Allyloxycarbonyl-2'-0,3,-N-bis(benzyioxycarbonyl)-3,-N-desmethyl-6-0- methyl-erythromycin A 11,12-carbonate. Example 1a (13 g, 12.97 mmol) in dichloromethane (50 mL) at 0°C under argon was added pyridine (11.5 mL) and a solution of phosgene in toluene (20%, 30 mL). After 30 min the mixture was allowed to warm to 20°C. After 2.5 h the reaction was recooled to 0°C and allyl alcohol (5 mL) was added dropwise. After stirring at 0°C for 15 min and 20°C for 30 min the mixture was poured onto ice. Extraction with diethyl ether and washing with water, 5% aq citric acid, and saturated aq sodium hydrogen carbonate gave a crude product solution which was dried, evaporated and purified by chromatography (silica gel, 20-50% ethyl acetate in hexane) to give the title product as a white solid foam (12.5 g); ESMS m/z 1129 [M+NH4]+, 1134 [M+Na]+, 1170 [M+NH4+acetonitrile]+. c) 40'-O-Allyl-2'-O,3'-A/-bls(benzyloxycarbonyI)-3'-N-desmethyl-6-O-methyl- erythromycin A 11,12-carbonate. Example 1b (7.9 g, 7.1 mmol) in tetrahydrofuran (50 mL) was treated with tetrakis(triphenylphosphine) palladium (0.16 g). The reaction was heated to reflux for 30 min after which time methyl allyl carbonate (1.7 mL) was added. After a further 1.75 h reflux, the reaction was cooled and evaporated to dryness. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate in dichloromethane) to give the title product as a white solid foam (3.93 g); ESMS m/z 1085 [M+NH4]+, 1090 [M+Na]+, 1126 [M+NH4+acetonitrile]+. d) 2'-O, 3'-N-bis(Benzyloxycarbonyl)-4"-O-{2-[2-(3-Carboxy-1 -cyclopropyl-6-fluoro-4- oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-6-0-methyl-3'-N-desmethyl- erythromycln A 11,12-carbonate. To Example 1c (0.256 g, 0.25 mmol) in tetrahydrofuran (1 mL) and water (1 mL) under argon was added osmium tetroxlde (4% in water, 0.015 mL). After 5 min sodium periodate (0.213 g, 1 mmol) was added. After 2.5 h the mixture was diluted with diethyl ether and water. The organic phase was washed with saturated aq. sodium thiosulphate, dried, and evaporated to dryness to give the crude aldehyde as a white solid foam (0.255 g). This material (0.094 g) in methanol (1.5 mL) and dimethylformamide (1.5 mL/was treated with acetic acid (0.15 mL), 7-(2-amlnoethylamino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- qulnoline-3-carboxylic acid (Yoshida et al, J. Pharm. Soc. Japan, 1990, 110, 258) (0.031 g, 0.1 mmol) and sodium cyanoborohydride (0.013 g, 0.2 mmol). After 3 h the reaction was evaporated to dryness, and the residue purified by chromatography (silica gel, 0-10% 2 M methanolic ammonia in dichioromethane) to give the title product as a white solid foam (0.066g); ESMS m/z 1359 [M+H]+. e) 4"-O-(2-{[2-{3-Carboxy-1 -cyciopropyl-6-fiuoro-4-oxo-1,4-dihydro-quinolin-7- ylamlno)-ethyl]-methylamino}-ethyl)-6-0-methyl-erythromycin A 11,12-carbonate blstrifluoroacetate. Example 1d (0.066 g) in ethanol (20 mL) and dioxan (10 mL) was hydrogenated at 50 psi over paliadium hydroxide (20% on carbon, 0.080 g) for 72 h. The catalyst was removed by filtration, washed well with dioxan and ethanol, and the combined filtrates evaporated to dryness. The residue was taken up in ethanol (20 mL) and dioxan (10 mL), and 28% aq formaldehyde (2 mL), 0.7min pH 4.5 acetate buffer (2 mL) and palladium hydroxide (20% on carbon, 0.080 g) added. The mixture was hydrogenated at 50 psi for a further 5 days, then the catalyst was removed by filtration, washed well with dioxan and ethanol, and the combined filtrates evaporated to dryness. The residue was purified by chromatography (silica gel, 5-10% methanol in dichloromethane then 10-20% 2 M methanolic ammonia in dichloromethane). Later fractions contained impure title product. Early eluted fractions contained 3'-/V-benzyloxycarbonyl-4'-0-(2-{[2-(3-carbbxy-1-cyclopropyl-6-fluoro-4-oxo- 1,4-dihydro-quinolin-7-ylamino)-ethy]-methylamino}-ethyl)-6-0-methyl-3'-N-desmethyl- erythromycin A 11,12-carbonate, (0.01 g) which was dissolved in ethanol (10 mL) and dioxan (5 mL) and hydrogenated at 50 psl over palladium (10% on carbon, 0.1 g). After 3 h 28% aq. formaldehyde (1.5 mL), 0.7M pH 4.5 acetate buffer (2.5 mL) was added and the hydrogenation continued for 24 h. After filtration and evaporation, the residue was purified by chromatography (silica gel, 2-15% 2M methanolic ammonia in dichloromethane) giving impure product. Both batches of impure title product were purified by preparative HPLC (acetonitrlle/water/0.1% trifluoroacetic acid eluent) to give the title compound as a gum (0.004 g); ESMS m/z 1119 [M+H]+, Example 2: 4"-0-(3-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1.4-dihvdro- aulnolin-7-vlamlno)ethyl]-methvlamino)-propyl)-6-O-methyl-erythromvcin A 11.12- carbonate a) 2'-O,3'-N-bis(BenzyloxycarbonyI)-4"-O-(3-hydroxypropyl)-3'-N-desmethyl-6-O- methyl-erythromycin A 11,12-carbonate. Example 1c (0.97 g, 0.908mmol) in tetrahydrofuran (6 mL) was treated with 9-BBN (0.5M in tetrahydrofuran, 3.6 mL). After 1.5h the reaction was cooled to 0°C and sodium hydroxide (2 M, 1.5 mL) and hydrogen peroxide (27% in water, 2.1 mL) were added. After 5 min the cooling bath was removed and the reaction stirred for 15 m, then diluted with diethyl ether and water, the organic phase was washed with water and brine, dried (MgSO4), and evaporated to dryness. The residue was purified by chromatography (sllica gel, 0-50% ethyl acetate in dichloromethane) to give the title product as a white solid foam (0.80 g, 76%); ESMS m/z 1103 [M+NH4]+, 1108 [M+Na]+. b) 2'-0,3'-N-bis(Benzyloxycarbonyl)-4"-0-{3-[2-(3-carboxy-1-cyclopropyl-6-fluoro-4- oxo-1,4-dlhydro-quinolin-7-ylamino)-ethylamino]-propyl}]-6-0-methyl-3'-N- . desmethyl-erythromycin A 11,12-carbonate trifluoroacetate. To Example 2a (0.411 g, 0.378 mmol) in dichloromethane (6 mL) at 0°C under argon was added Dess-Martin periodlnane (0.176 g, 0.41 mmol). After 1.5 h, the cooling bath was removed and the reaction stirred for a further 30 min then diluted with dichloromethane, washed with saturated aq sodium hydrogen carbonate, dried (MgSO4), and evaporated to dryness to give the title product as a white solid foam (0.42 g). This material (0.169 g) in methanol (2 mL) and dimethylforrnarnlde (2 mL) was treated with acetic acid (0.2 mL), 7- (2-aminoethylamino)-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.048 g, 0.16 mmol) and sodium cyanoborohydride (0.02 g, 0.32 mmol). After 1.5 h the reaction was evaporated to dryness, and the residue purified by preparative HPLC (acetonitrile/water/0.1% trlfluoroacetic acid eluent) to give the title product (0.10 g); ESMS m/z 1373 [M+H]+. c) 4"-O-(3-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7- ylamIno)-ethyl]-methyiamino}-propyl)-6-0-methyl-erythromycin A11,12-carbonate. Example 2b (0.1 g) in ethanol (20 mL) and dioxan (10 mL) was hydrogenated at 50 psi over palladium (10% on carbon, 0.050 g) for 7 h. 28% aq. Formaldehyde (2.5 mL), 0.7 M pH 4.5 acetate buffer (5 mL) was added and the hydrogenation continued for 24 h. After filtration and evaporation, dichloromethane (10 mL) and methanol (2 mL) were added to the residue and insoluble material removed by filtration. The soluble material was passed down a silica gel column eluting with 2-15% 2 M methanolic ammonia in dichloromethane. The fractions containing the title material were dissolved in ethanol (10 mL), 28% aq. formaldehyde (1 mL) and 0.7 M pH 4.5 acetate buffer (2 mL) and the mixture hydrogenated at 50 psi over palladium (10% on carbon, 0.1 g) for 30 h. the catalyst was removed by filtration and the residue evaporated to dryness. Dichloromethane (10 mL) and methanol (2 mL) were added to the residue and insoluble material removed by filtration. The soluble material was passed down a silica gel column eluting with 2-15% 2 M methanolic ammonia in dichloromethane to give the title product, as a gum (0.012 g); 1H NMR (CD3OD) (inter alia) 1.8 (2H. m), 2.4 (3H, s), 2.6 (2H, m), 2.8 (2H, m), 3.5 (2H, m), 3.7 (2H, m), 4.55 (1H, d), 4.65 (1H, s), 4.85 (1H, d), 5.0 (1H, dd), 7.2 (1H, d), 7.8 (1H, d), 8.7 (1H,s); ESMS m/z 1133 [M+H]+. Example 3: 4'-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1.4 ethylamino]-proyl}-6-0-methyl-erythromycin A 11.12-carbonate bls triftuoroaeatate a) 4"-0-(3-Hydroxypropyl)-6-0-methyl-erythromycin A11,12-carbonate. Example 2a (2.57 g, 2.37 mmol) in ethanol (25 mL) and dioxan (25 mL) was hydrogenated at 50 psi over pailadium (10% on carbon, 0.2 g) for 26 h. The catalyst was removed by filtration and the soluble material taken up in ethanol (50 mL), pH 4.5 buffer (4 mL) and 37% aq formaldehyde solution (4 mL) were added and the mixture hydrogenated at 50 psi over palladium (10% on carbon, 0.5 g). After 18 h, the reaction mixture was filtered, and the catalyst washed well with ethanol and dloxan. The combined filtrates were purified by chromatography on silica gel eluting with 0-10% 2 M methanolic ammonia in dlchloromethane to give the title product as a white foam (1.21 g); ESMS m/z 832 [M+H]+. b) 4"-0-{3-[2-{3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-ethylamino]- propyl}-6-O-methyl-erythromycin A11,12-carbonate bis trlfluoroacetate. To Example 3a (0.099 g, 0.119 mmol) in dichloromethane (2 mL) at 0°C under argon was added Dess-Martin periodinane (0.176 g, 0.41 mmol). After 15 min the reaction was allowed to warm to 20°C. After a total reaction time of 100 min the rectlon mixture was diluted with dichloromethane, washed with saturated, aq sodium hydrogen carbonate, dried, and evaporated to dryness to give the crude aldehyde as a white solid foam. This material in DMF (1 mL) and methanol (1 mL) was treated with acetic acid (0.1 mL), intermediate 2 (0.038 g, 0.12 mmol), sodium acetate (0.01 g) and sodium cyanoborohydride (0.015 g, 0.24 mmol). After 14 h the reaction was evaporated to dryness, and the residue partially purified by chromatography on silica gel eluting with 5- 20% 2 M methanolic ammonia in dichloromethane followed by preparative HPLC (acetonitrile/water/0.1% trifluoroacetic acid eluent) to give the title product (0.013 g); ESMS m/z 1090 [M+H]+. Example 4: 4'-O{3-[2-(3-Carboxy-1-ethyl-4-dihydro-qulnolin-6-visulfanyl)- ethylamino)-propyl}-6-O-methyl-erythromycin A 11.12-carbonate bisformate To Example 3a (0.125 g, 0.119 mmol) in dichlorornethane (2.5 mL) under argon was added Dess-Martin pertodinane (0.095 g, 0.22 mmol). After 3.5 h, the reaction mixture was dlluted with dlchlorornethane, washed with saturated aq sodium hydrogen carbonate, dried, and evaporated to dryness to give the crude aldehyde as a white solid foam. This material was dissolved in dlmethylformamlde (1.5 mL) and methanol (1.5 mL) and treated with acetic acid (0.3 mL), Intermediate 3 (0.081 g, 0.2 mmol) sodium acetate (0.024 g) and sodium cyanoborohydride (0.015 g). After 3 h the reaction was evaporated to dryness, and the residue purified by preparative HPLC (acetonitrlle/water/0.1% formic acid eluent) to give the title product (0.024 g); 1H NMR δ (CDCI3) (inter alia) 1.6 (3H, t), 2.0 (2H, m), 3.05 (2H, m). 3.65 (1H, m). 3.85 (1H, m), 4.4 (2H, q), 4.55(1 H, d), 4.6 (1H, s), 4.85 (1H, d), 5.0 (1H, dd), 7.65 (1H, d), 7.85 (1H, d), 8.35 (2H, s), 8.4 (1H, s); ESMS m/z 1106[M+H]+. Example 5: 4'-O{3-[3-(3-Caoxy.1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)- a) 4"-O-(1-imdazo-1-yl-carbonyl)-6-O-methyl-erythromycin A, propylamino]propyl}-6-O-methyl-erythrormycin A blsformate 6-O-MethyI-erythromycin A (30 g, 40.1 mmol) in tetrahydrofuran (100 mL) was treated portionwise with carbonyidiimldazole (16 g, 97 mmol) with ice bath cooling. After 1 h the cooling bath was removed. After a futher 48 h, tetrahydrofuran (100 mL) and water (200 mL) were added slowly precipitating the title compound, which was collected by filtration and dried to give the title compound (24.7 g). Extraction of the mother liquors with diethyl ether gave further material (8.5 g) which was precipitated from tetrahydrofuran solution with water to give a further portion of the title compound (3.92 g, total of 28.64 g); ESMS m/z842[M+H]+. b) 4n-0-(AIIyloxycarbonyl)-6-0-methyl-erythromycin A. Example 5a (28.64 g, 34 mmol) in dichloromethana (100 mL) was cooled to 0°C and treated with allyl alcohol (13.6 mL) and DBU (5.23 mL). The reaction was stirred at 0°C for 2.5 h and at 20°C for 1.75 h. The reaction mixture was quenched with 3% aq citric acid (100 mL), the phases separated, and the organic phase washed with sat sodium hydrogen carbonate and brine. After drying and evaporation to dryness, the residue was triturated with petroleum ether (bp 40-60 °C) to give the title compound as a solid (25.08 g); ESMS m/z 832 [M+H]+. c) 4"-O-(AIIyloxycarbonyl)-9-dihydro-9-methoxy-2',11 -bis-O-trlmethylsilyl-6-O- methyt-9,12-anhydro-erythromycin A. Example 5b (22.29 g, 25.6 mmol) in pyridine (100 mL) was treated with chlorotrimethyisilane (26 mL). The reaction was stirred at 20°C for 6 h and left at 4°C for 16 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue taken up in methanol (100 mL) After 80 min at 20°C, the solvent was removed by evaporation under reduced pressure and the residue taken up in ethyl acetate and water, the phases were separated, the organic layer dried, and evaporated to dryness under reduced pressure. Toluene (two 500 mL portions) were added and evaporated under reduced pressure to give the crude title compound as a white foam (26.27 g). This material (5.8 g) was purified by chromatography on silica gel eluting with 0-3% 2 M methanolic ammonia in dichloromethana to give the title compound as a white foam (3.0 g); ESMS m/z 990 [M+H]+. d) 4"-O-Allyl-9-dihydro-9-nethoxy-2',11-bls-O-trimethyisllyl-6-O-methyl-0,12. anhydro-erythromycin A. Example 5c (3.0 g, 3.03 mmol) in tetrahydrofuran (20 mL) was treated with tetrakis triphenyiphosphine palladium (0.1 g) at reflux under argon. After 35 min, t-buty) ailyl carbonate (F. Houlihan et al, Can. J. Chew. 1985, 63, 153; 1.2 mL) and tetrakis(triphenyiphosphine) palladium (0.1 g) were added and the reflux continued for a further 1 h. The reaction was cooled and evaporated to dryness under reduced pressure, and the residue purified by chromatography on sillca gel eluting with 0-5% 2 M methanolic ammonia in dichloromethane to give the title product, 1.07 g, as a white foam; ESMS m/z 946 [M+H]+. e) 9-Dihydro-4' -O-(3-hydroxypropyl)-9-methoxy-2;11 -bis-O-trimethyisllyi-6-O- methyl-9,12-anhydro-erythromycin A. Example 5d (0.255 g, 0.27 mmol) in tetrahydrofuran (4 mL) under argon was treated with 9-BBN (0.5 M in tetrahydrofuran, 1.6 mL). After 30 mln, the reaction was cooled to 0°C and a precooled mixture of sodium hydroxide (2 M, 0.5 mL) and hydrogen peroxide (27% in water, 0.68 mL) were added. This was stirred at 0°C for 10 min before addition of cold diethyl ether and water. The phases were separated and the organic phase washed with water and brine. After drying and evaporation under reduced pressure the residue was purified by chromatography on silica gel eiuting with 0-10% 2 M methanolic ammonia In dichloromethane to give the title product as a white foam (0.16 g); ESMS m/z 964 [M+H]+. f) 4"-O-{3-{3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyiamino]- propyl}-6-O-methyl-erythromycin A blsformate. To Example 5e (0.16 g, 0.166 mmol) in dichloromethane (5 mL) under argon was added Dess-Marttn periodinane (0.085 g, 0.2 mmol). After 1 h, the rection mixture was diluted with dichloromethane, washed with sat aq sodium hydrogen carbonate, dried, and evaporated to dryness to give the crude aldehyde as a gum. This material was dissolved in methanol (2.5 mL) and dichloromethane (2.5 mL) and treated with acetic add (0.25 mL), sodium acetate (0.028 g), 3A molecular sieves (0.3 g), intermediate 4 (0.0625g, 0.16 mmol) and sodium cyanoborohydride (0.030 g). After 2 h the reaction was evaporated to dryness, and toluene (5 mL) added and evaporated. The residue was purified by preparative HPLC (aoetonitrlle/water/0.1% formlc acid eluent) and the fractions allowed to stand at 20°C for 1 h which resulted in loss of protection. A further preparative HPLC (acetonitrfle/water/0.1% formic add eluent) purification gave the title product (0.034 g); ESMS m/z 1062 [M+HJ+ Example 6: 4"-O-{3-[2-(2-Carfaoxy-1-oxo-6,dihydro-1H,5H-Pyrld[3,2,1-/ij]quinoline- 9-yioxy)-ethylamino]-propyl}-6-O-methyl-erythromycin A 11.12-carbonate blsformate To Example 3a (0.25 g, 0.33 mrnol) in dichloromethane (5 mL) under argon was added Dess-Martin periodinane (0.14 g, 0.33 mmol). After 2 h, more Dess-Martin periodinane (0.03 g) was added and the reaction stirred for a further 1.5 h. The reaction mixture was diluted with dichloromethane, washed with saturated, aq sodium hydrogen carbonate, dried, and evaporated to dryness to give the crude aldehyde as a white solid foam. This material (0.042 g, 0.05 mmol) in methanol / DCM (1:1, 2 mL) was added to sodium acetate (0.008 g, 0.1 mmol), acetic acid (0.1 mL), Intermediate 5 (0.02 g, 80% pure, 0.05 mmol), and 3A molecular sieves (0.1 g). The mixture was stirred for 15 min then a solution of sodium cyanoborohydride (0.0063 g, 0.1 mmol) in methanol (0.2 mL) was added and stirring continued for 3 h. The reaction was then filtered, washing well with methanol, and the filtrate evaporated. The residue was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound as a pale yellow solid (0.031 g);ESMSm/z 1102[M+H]+. Example 7: 4"-O-{3-[2-(3-Carboxy-1 -ethyl-4-oxo-1.4-dihydro-quinolin-6-yl)- propylamino1-propvl}-6-O-methyl-11 -desoxy-11 -(R)-methvlamino-ervthromycin A 11.12-carbamate formate a) 2'-O-Acetyl-4"-O-allyl-6-O-methyl-11-desoxy-11-(R)-methylamIno-erythromycin A 11,12-carbamate. intermediate 7 (0.315 g, 0.38 mmol), t-butyl allyl carbonate (0.079 g, 0.5 mmol) and tetrakis(triphenylphosphine) palladium (0.035 g, 0.03 mmol) in THF (10 mL) were refluxed for 4 h. More t-butyl allyl carbonate (0.079 g, 0.5 mmol) was added and refluxing continued for a further 2 h. More t-butyl allyl carbonate (0.04 g, 0.25 mmol) was added and refluxing continued for a further 1.5 h. The mixture was then evaporated to dryness and the residue purified by chromatography on sillca get (40 g). Button with 0-4.5% 2 M methanolic ammonia in dichloromethane, gave the tittle compound (0.294 g); ESMS m/z 869 [M+H]+. b) 4"-O-Allyt-6-O-methyt-11 carbamate. Example 7a (0.27 g, 0.31 mmol) in methanol (10 mL) was heated at 60°C for 8.5 h, 45°C for 15 h, and 60°C for 3 h. The mixture was then evaporated to dryness to give the title compound as a white solid (0.244 g); ESMS m/z 827 [M+H]+. c) r-O,3'-N-bis(Benzvk>xycarbonyl)-3'-N-desmethyl-4"-O-allyl-6-O-methyl-11 - desoxy-11-(R)-methylamino-erythromycin A 11,12-carbamate. Example 7b (0.24 g, 0.29 mmol) and sodium hydrogen carbonate (0.4 g) in benzyl chloroformate (2 mL) were heated at 60°C for 3 h. After cooling the mixture was purifled by chromatography on silica gel (50 g). Button with 0-50% ethyl acetate in petroleum ether gave the title compound as a white solid (0.272 g); ESMS m/z 1098 [M+NH4]+. djr-O.S'-W^lstBenzyloxycariwnyO-a'^-dMniethyi^-O^a-hydroxypfopyiJ-e^ m^yl-11-desoxy-11-(R)-methytamlno-erythromycln A 11,12-carbamate. Example 7c (0.27 g, 0.25 mmol) in THF (8 mL) was treated with 9- borablcycto[3.3.1lnonane (0.5 M in THF, 1.5 mL, 0.75 mmol). After 4 h more 9- borabicyck>{3.3.1)nonane (0.5 M In THF, 0.5 mL, 0.25 mmol) was added. Further 1 h then more 9-borablcyck>[3.3.1]nonane (0.5 M In THF, 1 mL, 0.5 mmol) was added. After 1 h more the solution was cooled In an Ice bath then pre-mixed hydrogen peroxide (30% aq, 1.7 mL, 15 mmol) In sodium hydroxide (2 N, 2.5 mL, 5 mmol) was added. The cooling bath was removed and the mixture stirred for 0.5 h. The reaction was diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried, and evaporated to give the crude product This was purified by chromatography on silica gel (40 g), elutJng with 30-80% ethyl acetate In petroleum ether, to give the title compound as a white solid (0.139 g); ESMS m/z 1116 (M+NH4]+. e) 4"-O-{3-Hydroxypropyl)-6-O-methyl-11-desoxy-11 -(R)-methyIamino-erythromycin A 11,12-carbamate. Example 7d (0.137 g, 0.125 mmol) was dissolved In ethanol (4 mL) and 1,4-dioxane (8 mL), and hydrogenated over 10% palladium on charcoal (50% aq paste, 0.06 g) for 6.5h. Formaldehyde (37% aq, 0.3 mL), pH 4.5 acetate buffer (0.3 mL) and more catalyst (0.05 g) were then added, and the mixture hydrogenated for 16 h. The mixture was then filtered, washing well with ethanol and 1,4-dloxane. The filtrate was evaporated, and the residue purified by chromatography on sillca gel (5 g). Elution with 0-6% 2 M methanollc ammonia in dichloromethane, gave the title compound as a white foam (0.083 g); ESMS m/z 845 [M+H]+. f) 4"-O-(3-Oxpropyl)-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycin A 11,12-carbamate. To Example 7e (0.082 g, 0.097 mmol) in DCM (3 mL) was added Dess-Martin periodinane (0.047 g, 0.11 mmol). The reaction was stirred for 1.75 h, then more oxidant (0.018 g) added. After a further 1.5 h, the reaction was diluted with DCM, washed with aq sodium hydrogen carbonate, dried and evaporated to give the crude title compound as a white foam (0.086 g), which was used without puriflcation; ESMS m/z 843 [M+H]+. g) 4"-O-{3-[2-(3-Carboxy-1 -ethyl-4-oxo-1 ,4-dlhydro-qulnolln-6-yl)-propyiamino]- propyf)-6-O-methyl-11-desoxy-11-(R)-methylaminco erythromycin A 11,12-carbamate formate. Example 7f (0.082 g, 0.097 mmol) in methanol / DCM (1:1, 4 mL) was added to sodium acetate (0.0164 g, 0.2 mmoi), acetic acid (0.2 mL), Intermediate 4 (0.0274 g, 0.1 mmoi), and 3A molecular sieves (0.2 g). The mixture was stirred for 20 min then a solution of sodium cyanoborohydride (0.0126 g, 0.2 mmoi) in methanol (0.3 mL) was added and stirring continued for 16 h. The reaction was then filtered, washing well with methanol and DCM, and the filtrate evaporated. The residue was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound as an off-white powder (0.038 g, 35%); ESMS m/z 1101 [M+H]+. Example 8: 4'-O-{3-(3-arboy--1ethyl-oxo-1.4-diydro-yl) propyminol-proyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycin A a) 2'-O,3'-N-bis(Benzycarbonyl)-3'-N-desmethyl-4'-O[3-(tert-butyidimethyisllyl]- oxy)proyt]6-O-methl-erythromycin A 11,12-carbonate. Example 2a (1.85 g, 1.71 mmol) in DMF(10mL) was treated sequentially with imidazole (0.128 g, 1.88 mmol) and tert-butydimethyisttyl chioride (0.283 g, 1.88 mmol). Mixture stirred for 20 h then evaporated. Water was added and the mixture extracted with diethyl ether. The combined organic extracts were washed with brine, dried, and evaoorated. The residue was purified by chromatography on silica gel (100 g), eluting with 12-42% ethyl acetate in petroleum ether, to give the title compound as a white foam (1.923 g); ESMS m/z1217 [M+NH4]+. b)2,-0,3'-N-bis(Benzyioxycarbonyl)-3'-N-desmethyl-4"-0-[3-(tert-butyldlmethylsilyl- oxy)propyl]-6-0-methyl-11 -desoxy-11 -(R)-amino-erythromycin A 11,12-carbamate. Example 8a (1.9 g, 1.58 mmol), carbonyldiimidazole (1.28 g, 7.2 mmol), Imidazole (0.01 g) and DBU (0.08 g, 0.52 mmol) were dissolved in THF (10 mL), heated to 40°C and stirred for 17 h. Further portions of carbonyidiimidazole and DBU were added, and reaction heated at 60°C for 6 h then 50°C for 16 h. The mixture was then cooled in an ice bath and ammonia gas bubbled in for 8 h. The reaction was then stored in the fridge for 14 h. Argon was then bubbled through the mixture before the addition of potassium tert-butoxide (1 M in THF, 1.74 mL, 1.74 mmol). After 5 h at room temperature more potassium tert-butoxide (1 M in THF, 1 mL, 1 mmol) was added. Further 2 h then more potassium tert-butoxide (1 M in THF, 0.5 mL, 0.5 mmol) added. The mixture was then stirred for 64 h. Aqueous sodium hydrogen carbonate was then added and the mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by chromatography on silica gel (100 g), eluting with 20-52% ethyl acetate in petroleum ether, to give the title compound as a white foam (1.3 g); ESMS m/z 1216 [M+NH4]+ c)4'-O-[3-(tert-butyldlmethylsiiyl-oxy)propyl]-6-0-methyl-11-desoxy-11-(R)-amino- erythromycin A11,12-carbamate. Example 8b (1.4 g, 1.17 mmol) was disolved in methanol (10 mL) and 1,4-dioxane (15 mL), and hydrogenated over 10% palladium on charcoal (50% aq paste, 0.4 g) for 6h. Formaldehyde (37% aq, 4 mL), pH 4.5 acetate buffer (4 mL) and more catalyst (0.2 g) were then added, and the mixture hydrogenated for 24 h. The mixture was then filtered, washing well with methanol and 1,4-dioxane. The filtrate was evaporated, and the residue purified by chromatography on silica gel (100 g). Elution with 0-7% 2 M methanoiic ammonia in dichloromethane, gave the title compound as a white foam (0.969 g); ESMS m/z 945 [M+H]+. d) 4"-O-(3-Hydroxypropyl)-6-O-methyl"11 -desoxy-11 -(R)-aminoerythromycin A 11,12-carbamate. Example 8c (0.17 g, 0.18 mmol) in THF (4 mL) and acetic acid (0.023 mL, 0.4 mmol) was treated with tetrabutylammonium fluoride (1 M in THF, 0.4 mL, 0.4 mmol). The mixture was stirred at 35°C for 72 h, then evaporated to dryness, and the residue purified by chromatography on silica gel (40 g). Elution with 0-11% 2 M methanolic ammonia in dlchloromethane, gave the title compound as a white foam (0.15 g); ESMS m/z 831 [M+H]+. e) 4"-O-(3-OxopropyI)-6-O-methyl-11-desoxy-11-(R)-aminoerythromycin A 11,12- carbamate. To Example 8d (0.085 g, 0.1 mmol) in DCM (2 ml) was added Dess-Martin periodinane (0.051 g, 0.12 mmol) in DCM (1 mL). Stirred for 1.3 h, then diluted with DCM, washed with aq sodium hydrogen carbonate, dried and evaporated to give the crude title compound as a white foam (0.097 g), which was used without purification; ESMS m/z 829 [M+H]+. f) 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyiamino]- propyl)-6-O-methyl-desoxy-11-(R)-amino-erythromycin A 11,12-carbamate formate. Example 8e (0.082 g, 0.1 mmol) in methanol / DCM (1:1, 4 mL) was added to sodium acetate (0.025 g, 0.3 mmol), acetic acid (0.2 mL), intermediate 4 (0.043 g, 0.11 mmol), and 3A moiecular sieves (0.2 g). The mixture was stirred for 30 min then a soiution of sodium cyanoborohydride (0.0126 g, 0.2 mmol) in methanol (0.3 mL) was added and stirring continued for 2.5 h. The reaction was then filtered, washing well with methanol and DCM, and the filtrate evaporated. The residue was purified by preparative reverse phase HPLC (MeCN/H2O/O.1%HCO2H eluent) to give the title compound as a pale yellow solid (0.054 g, 48%); ESMS m/z 1087 [M+H]+. Example 10: 4'-O-{3-[2-(3-Carboxy-7-chioro-1-cyclopropyl-4-oxo-1,4-dihydro- qulnolin-6-ylamino)proyl}-6-O-methyl-erythromycin A 11.12-carbonate formate Example 11: 4"-O-{3-[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro qulnolin-7-ylamin)ethyiamino]propyl}-6-methyl-erythromycin A 11,12-format Example 12: 4"-O-{3-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro- [1.8]naphthyridin-7-ylamin)ethlamino]-propy}-6-O-methyl-erythromycin A 11.12- carbonate formate To 4"-0^3^droxypropyl)^0-methy1eTythromydn A 11,12-carbonate (0.883 g, 1.08 mmol) in dlchloromethane (20 mL) under argon was added Dess-Martin periodlnane (0.495 g, 1.17 mmol). After 3 h, more Dess-Martin periodlnane (0.1 g, 0.24 mmoO was added, and after 1.5 h more Dess-Martin periodlnane (0.11 g, 0.26 mmol) was added. The mixture was stirred for a further 35 min then diiuted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate, dried, filtered, and concentrated in vacuo to give the crude aldehyde as a white solid foam. This material was dissolved in methanol (20 mL) and dichloromethane (20 ml), then split into four equal portions which were used in the general procedure for reductive amination. General Procedure for Reductive Amination To the solution of aldehyde in methanol (5 mL) and dichloromethane (5 mL) was.added sodium acetate (0.044 g, 0.54 mmol), acetic add (0.5 mL), 3A molecular sieves (0.5 g), and the amine (0.26 mmol). The mixture was stirred for 10 mln then a solution of sodium cyanoborohydride (0.033 g, 0.5 mmol in methanol (0.5 mL) was added and stirring continued for 20 h. The reaction was then filtered through Cellte, and concentrated in vacuo to give a residue which was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent), then further purified by chromatography (silica gel, 0- 20% 2 M methanollc ammonia in dichloromethane) to give the title compound. Example 13: 4'-O-(3-Carboxy-1-ethyl-4oxo-1,4-dihydro-qulnolin-6-yl] methylamino}propy)-6-Omethyl-erthromycin A 11.12-carbonate formate Example 14: 4'-O-(3-(2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro- qulnolin-6-ylamino)ethyl]-methylamino}propyl)-6-O-methyl-erythromycin A 11.12- carbonate Example 15: 4'-O-(3-{[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihvdro- [1,8]naphthyrtdin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycin A11.12-carbonate General Procedure for N-Methylation To a solution of amine starting material (0.072 mmol) as tabulated below in chloroform (2 ml) was added formic add (0.005 ml, 0.144 mmol), and formaldehyde (37% by weight in water) (0.011 mL, 0.144 mmol). The mixture was heated to 60°C for 3 h then concentrated in vacuo to give a residue which was purified by chromatography (silica gel, 0-20% 2 M methanolic ammonia in dichloromethane) or by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound. Example 16: 4"-O-{2-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6- yl)propylamino]etyl}azlthrornycin 11.12-carbonate a) 2'-O-Acetyl-azlthromycin 11,12-carbonate. To a suspension of azithromycin 11,12-carbonate (BA Jones et al., Tet Lett, 1993, 34, 4913; 100 g, 0.13 mol) and sodium hydrogen carbonate (44 g, 0.52 mol) In dichlromethan (400 mL) was added dropwise acetic anhydride (20.4 mL, 0.2 mol). After stirring overnight the mixture was diluted with water (400 mL) and the organic layer separated, dried and evaporated to yield the title compound as a white solid; ESMS m/z 818 (MH+). b) 2'-O-AcetyL-4"-O-aliyl-azltmromycin 11,12-carbonate. To a solution of Example 16a (0.408 g, 0.5 mmol) in dry THF (4 mL) and tetrakis(triphenyphosphine) palladium (0.057 mg, 0.05 mmol) was added aflyl t-butyl carbonate (0.300 g, 1.89 mmol). After heating at reflux under argon for 8 h the mixture was cooled and the solvent evaporated. Chromatography of the residue over silica gel eluting with dlchloromethane containing an increasing concentration of methanol (0-1%) gave the title compound as a pale yellow gum; ESMS m/z 857 (MH+). c) 2'-O-AcetYl-4'-O-(2-oxoethoxy)azlthromycin 11,12-carbonate. To a cooled solution of Example 16b (0.20 g, 0.23 mmol) in THF (1 mL) and water (1 mL) was added osmium tetraoxlde (15 µL of a 4% solution in water). After 5 mins solid sodium periodate (0.21 g, 1 mmol) was added in one portion and the resultant mixture stirred at room temperature for 4 h. Sodium hydrogen sulfite (0.19 g, 1 mmol) was added and the organic material extracted with ethyl acetate (2x15 mL). The combined organic fractions were dried and evaporated to yield the title compound as a brown gum; ESMS m/z 877 (MNH4+). d) 4"-O-{2-[3-(3-Carboxy-1 -ethyl-4-oxo-1,4-dihydro-qulnolin-6-yl)proylamino]ethyl} azithromycin 11,12-carbonate. A solution of Example 16c (0.054 g, 0.063 mmol), intermediate 4 (0.05 g, 0.127 mmol) and sodium acetate (0.011 g, 0.127 mmol) in 1% acetic acid/methanol (2 mL) was stirred for 0.5 h at room temperature. Sodium cyanoborohydride (0.016 mg, 0.25 mmol) was added. After 16 h the mixture was concentrated and purified by reverse phase liquid chromatography to yield the title compound as a white solid; ESMS m/z 1076 (MH+). Example 17: 4"-O-{2-[2-(3-Carboxy-1-ethyl-4-oxo-1.4-dihvdro-qulnolin-6- ylsulfanyl)ethylamino)ethyl}azithromvcin tris trifluoroacetate a) 2'-O-Acetyl-4"-O-{2-[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolln-6- vlsulfanyl)ethylamIno]ethyl}azIthromycln 11,12-carbonate. Using a similar procedure to that described in Example 16d, Example 16c (0.055 g, 0.063 mmol) and Intermediate 3 (0.030 g, 0.95 mmol) gave the title compound as a white solid; ESMS m/z 1136 (MH+). b)4"-O-{2-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6- ylsulfanyl)ethylamlno]ethyl}azithromycin tris trifluoroacetate. A solution of Example 17a in methanol (2 mL) containing sodium hydrogen carbonate (0.010g, 0.12 mmol) was stirred at 50°C. After 4 h the mixture was cooled, filtered and the solvent evaporated to yield the crude product. Purification by reverse phase liquid chromatography gave the title compound as a colourless gum; ESMS m/z 1094 (MH+). Example 18: 4"-O-{2-[2-(3-Carboxy-1-ethvl-6-fluoro-4-oxo-1.4-dihydro- [1.8]naphthvrldin-7-vlamino)ethvl]-amino}-ethvl-6-O-methvl-ervthromvcin A monoformate a) 9-Dihydro-9-methoxy-4'-O-2-oxoethyt-2',11-bis-O-trimethylsilyl-6-0-methyl-9,12- anhydro-erythromycin A. To Example 5d (0.6 g, 0.64 mmol) in THF (2.5 mL) and water (2.5 mL) under argon was added osmium tetroxlde (4% solution in water, 0.04 mL). After 5 min sodium periodate (0.535 g, 2.5 mmol) was added. After stirring for 4.5 h, the reaction was diluted with ethyl acetate (20 mL) and washed with sat. aq. sodium thlosulfate (5 mL) and brine (5 mL). After drying with magnesium sulfate, the solution was evaporated to give the title material as a white foam, (0.62 g); ESMS m/z 966 [M+H2O+H]+. b) 4"-O-{2-I2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1I4-dihydro-[1,8]naphthyrldln-7- ytamino)ethyl]-amino}-ethyl }-6-0-methyl-erythromycin A monoformate. To Example 18a (0.1 g, 0.1 mmol) in methanol / DCM (1:1, 3 mL) was added to sodium acetate (0.025 g, 0.3 mmol), acetic acid (0.15 mL), Intermediate 6 (0.041 g, 0.01 mmol), and 3A molecular sieves (0.2 g). The mixture was stirred for 45 min then a solution of sodium cyanoborohydride (0.0128 g, 0.2 mmol) in methanol (0.8 mL) was added and stirring continued for 3 h. The reaction was then filtered, washing well with methanol, and the combined filtrates evaporated. The residue was dissolved in acetonitrile (20 mL), and 1% aq. Formic acid (15 mL) for 10 min at 20 °C before evaporation to dryness. The crude product was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound as a yellow foam (0.037 g); ESMS m/z 1068 [M+H]+. Example 19: 4"-0-(2-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1^-dihvdro- [1.8]naDhthvridin-7-vlamino)ethyl]-methylamino}-ethyl} 1-6-O-methvl-erythromycin A To a solution of Example 18 (0.033g) in chloroform (1 mL) was added formic acid (0.005 mL, 0.144 mmol), and formaldehyde (37% by weight in water) (0.005 mL, 0.144 mmol). The mixture was heated to 60°C for 3 h when further 0.005 mL portions of the reagents were added. After a further 1.5 h heating the reaction mixture was concentrated in vacuo to give a residue which was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound, (0.016 g). ESMS m/z 1082 [M+H]+ Example 20: 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)- pripoxy]-propyl}-6-O-methyl-efythromycin A monoformate a) 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6-yl)-propoxy]-prop-1 - enyl}-6-O-methyl-erythromycin A ethyl ester. To Example 5e (0.12 g, 0.125 mmol) and Intermediate 8 (0.1 g) in THF (2 mL) under argon was added tetrakis(trlphenytphosphine) palladium (0.007 g). The reaction was heated to reflux for 15 min after which further intermediate 8 (0.1 g) and tetrakis(triphenyiphosphine) palladium (0.007 g). were added. After a further 40 min reflux, further intermediate 8 (0.075 g) and tetralds(triphenyiphosphine) palladium (0.007 g). were added. The reaction was refluxed for a further 35 mln cooled and evaporated to dryness. The residue was taken up in acetonltrile/0.2M aq. formic acid (50 mL, 50:50) and left at 20°C for 20 h. After evaporation to dryness, the residue was purified chromatography over silica gel eluting with 0-10% 2M methanolic ammonia in dlchloromethane to yield the title compound as a gum (0.175 g); ESMS m/z 1089 (M+H]+. b) 4"-0-{3-[3-(3-Carboxy-1 -ethyi-4-oxo-1,4-dihydro-qulnolin-6-yl)-propoxy]-propyl}- 6-O-methyl-erythromycin A ethyl ester. Example 20a (0.175 g), in ethanol was hydrogenated at 20 °C and 1 atm over 10% Pd/C (0.05g) for 3 h. The reaction was flltered, and the filtrate evaporated to give the title product (0.175g) as a gum, ESMS m/z 1091 [M+H]+. c)4"-O-{3-[3-Carboxy-1-ethyl-4-dihydro-qulnolin-6-yl)-propoxy]-proyl}-6- O-methyl-erythrornycin A. Example 20b (0.175 g), in 1,4-dioxan (5 mL) under argon was treated with water (1 mL) containing lithium hydroxide (0.012g). After stirring for 75 mln, the reaction mixture was evaporated to low volume, and the residue taken up in water and solid CO2 added. After evaporation to dryness, the residue was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound, (0.036 g) ESMS m/z [M+H]+ Example 21: 4'-O-{3-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro- [1.8]naphtyridin-7-ylamino)-ethylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)- amino-efythromycin A 11.12-carbamate formate Example 22: 4"-O-{3-[2-Carboxo-1-oxo-6,7-dihydro-1H,5H-pyrldo[3,2,1-ij]qulnoli- 9-yioxy)-ethlaino]-propyl}-6-O-methyl-11-desey-11-(R)-amino-erythromycin A 11.12-carbamate formate Example 22: 4'-O-{3-[2-(2-Carbixy-1-oxo-6,7-dihydro-1H,5H-Pyrldo[3,2,1-ij]qulnlin- 9-vioxy-ethylamino]-propyl}-6-O-methyl-11-desixy-11-(R)-amino-erythromycin A 11,12-acrbamate Example 24:4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-6-[1.8]naphthryldinyl)- piraylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycin A 11.12- Example 25:4"-O-{3-[3-[3-Carboxy-1-oxo-6,7-dihydro-1H.5H-Pyrido[3.2.1-ij]qulnolin- 9yl]-propylaminol]-propyl}-6-O-methyl-11-(R)-amino-erthromycin A Example 26:4"-O-{3-[3-[3-Carboxy-1-ethyl-4-oxo-4-H-qulnoizin-7-ylamino) ethylamino]-propyl}-6-O-methyl-11-(R)-amino-erthromycin A 11.12-carbamate formate 11.12-carbamate formate Using the method of Example 8f the amino adds tabulated below were converted to the title compounds. Purification was by chromatography (silica gel, 0-20% 2 M methanolic ammonia in dichloromethane) and/or by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) as appropriate. Exampl 27:4'-O-{3-{[2-(3-Carboxy-1-ethyl-6-fluro-4-oxo-1.4-dihydro- [1.8]naphtyridin-7-ylamino)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11- (R)-amino-erythromycin A 11.12-carbamate formate Example 28: 4"-O-{3-[[2-2-Carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1- ij]qulnolin-9-yloxy)-ethyl]-methiamino]-proyl}-6-O-methyl-11-desoxy-11-(R)- amino-erythromvcin A 11.12-carbamate formate Example 29: 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6yl)propyl] methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-mino-erthronycin A 11.12- carbamate formate Example 30:4"-O-{3-[3-(3-Carboxy-1-ethl-4-dihydro-6-[1.8]naphthryidinyl)- propyl]-methylmino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erthromycin A 11.12-carbamate Example 31:4"-O-{3-[[3-(2-Carboxo-6,7-dihydro-1H,5H-Puinolin- 9yl)-prpyl]-merhylamino]-propy}-6-O-methyl-11desoxy--11-(R)-amino- erythromycin A 11.12-carbamate Example 32:4"-O-{3-[[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yisulfanyl)- ethyl]-methylamino]-propyl}-6-O-methyl-11 -desoxy-l1 -(R)-amino-erythromycin A, 11.12-carbamate To a solution of starting material as tabulated below in chloroform (30 mUmmol) was added formic acid (4 equivalents), and formaldehyde (37% by weight in water) (2 equivalents). The mixture was heated to 60°C for 3 h then concentrated in vacuo to give a residue which was purified by chromatography (silica gel, 0-20% 2 M methanolic ammonia in dichloromethane) and/or by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound. Example 33: 4"-O{3-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihvdro- aulnolin-7-ylamino)-ethyicarbamoyl]-propyl}-azithromvcin DIPEA (201.4 L, 1.4 mol. equiv.) was added dropwise via a syringe at 0°C to a solution of intermediate 16c (181.7 mg, 0.22 mmoL) and HBTU (81.7 mg, 0.22 mmoL) in dry DMF (2.8 mL). The mixture was stirred for 15 minutes before 7-(2-amino-ethylamlno)-6- fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (48.7 mg, 0.18 mmoL),,4 was added over a period of 30 minutes. The reaction mixture was stirred at room temperature overnight, and then diluted with water (30 mL). The aqueous phase was extracted twice with EtOAc (2x50 mL), and the combined organic phases were washed sequentially with saturated aqueous NaHC03 (30 mL) and brine (30 mL). Drying with Na2S04 and evaporation afforded 127.5 mg (71%) of the title compound as a colourless solid. MS (m/z) 1122 (MH+). Example 34: 4"-O-{3-[2-(3-Carboxy-7-chloro-1-cvclopropyl-4-oxo-1.4-dihydro- qulnolin-6-ylamino)-ethylcarbamoyl]-propyl}-azrthromycin Starting from intermediate 16c (834 mg, 1.0 mmoL) and intermediate 1 (234.9 mg, 0.73 mmoL) using a similar procedure to that described in Example 33, the title compound (620.5 mg) was obtained. MS (m/z) 1138 (MH+). Example 35: 4"-O-{4-[4-(3-CarfaoxY-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihydro- auinolin-7-yl)-piperazin-1-yl]-4-oxo-butyl}azlthromvcin Starting from intermediate 16c (667.2 mg, 0.8 mmoL) and 1-cydopropyl-6-fluoro-4-oxo-7- piperazin-1-yI-1,4-dihydro-quinoline-3-carboxylic add (192.7 mg, 0.58 mmoL) using the similar procedure to that described in Example 33 the title compound (460.3 mg) was obtained. MS (m/z) 1148 (MH+). Example 36: 4"-O-{2-[4-(3-Carboxy-1-ethyl-4-oxo-1.4-dihydro-auinolin-6-yl)- piperazin-1-yl]-ethyl}-azithromycin 11,12-cyclic carbonate Intermediate 15 (114.4 mg, 0.14 mmoL) was dissolved in 0.9 mL of methanol. Three equivalents of Intermediate 17c (126.6 mg, 0.42 mmoL) were added as a 1 M solution in methanol (0.42 mL), followed by 0.43 mL of 1 M solution of acetic acid in methanol. The pH was checked and adjusted to about 6 with acetic acid, if necessary. NaCNBH3 was added as a freshly prepared 0.3 M solution in methanol (0.19 mL), and the mixture was stirred at room temperature for 2 h. The reaction was quenched with a few drops of water and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1-5% MeOH / 0.5-1% triethylamine / dichloromethane) to give 100.3 mg (75 %) of the title compound as a yellow solid. MS (m/z) 1102 (MH+). Example 37: 4"-O-{2-[2-(3-Carboxy-7-chloro-1 -cyclopropyl-4-oxo-1.4-dihydro- qulnolin-6-yiamino)-ethvlamino]-ethyl}-azithromycin 11.12-cyclic carbonate This method was adapted from the work of Debono et al. (J. Antlbfot. 1989, 42,1253- 1267). A solution of intermediate 15 (955.9 mg, 1.17 mmoL), intermediate 1 (563.1 mg, 1.75 mmoL), and 22.5 mL of EtOAc was heated to 70'C with stirring. Formic acid (58.9 mg, 1.28 mmoL) was added dropwise to the solution, and the temperature was lowered to 65°C. Stirring and heating was continued for 5 h. After cooling to room temperature, the reaction solution was washed twice with 25 mL portions of saturated aqueous NaHCO3 and then once with 20 mL of saturated aqueous NaCI. The combined extracts were dried over anhydrous MgS04, filtered, and evaporated under reduced pressure to furnish crude product as a yellow foam. This material was taken up in 100 mL of hot Et20; insolubles were filtered and saved. The filtrate was treated with 30 mL of hot hexane, and again the resulting insoluble matter was filtered and saved. The filtrate was concentrated to about 7.5 mL by boiling off excess solvent The resulting solution was allowed to cool to room temperature and then cooled to 5°C for several hours. A colorless precipitate formed (630.6 mg). The filtrate was combined with the insolubies that were saved, and the mixture was then chromatographed on silica gel. Elutlon with 9:1 CH2CI2-MeOH containing 1% NH4OH afforded an additional amount of the title product (420.3 mg, 80% overall yield). MS (m/z) 1122 (MH+). Example 38: 4"-O-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4>dihydro- quinolin-7-ylamino)-ethylamino]-ethyl}-azlthrornycin 11.12-cyclic carbonate To a magnetically stirred solution of Intermediate 15 (2.17 g, 2.65 mmoL) in 8 mL of methanol was added 7-(2-amino-ethylamino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid (1.62 g, 5.3 mmol). After being stirred at room temperature for 30 min, the solution was treated with 0.15 mL (2.65 mmoL) of HOAc and cooled to 0"C. in 2 mL of MeOH, 563.4 mg (2.66 mmoL) of NaBH(OAc)3 was then added over a period of 10 min. Stirring and cooling was continued for 10 min. The reaction mixture was worked up and the crude product was chromatographed on silica gel to furnish 1.99 g (68%) of the title product MS (m/z) 1108 (MH+). Example 39: 4"-O-{2-[4-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihydro. quinolin-7-yl)-piperazin-1-yl]-ethyl}-azithromycin 11.12-cyclic carbonate Starting from Intermediate 14 (817 mg, 1.0 mmoL) and 1-cyclopropyl-6-fluoro-4-oxo-7- piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid (994.1 mg, 3.0 mmoL) using a similar procedure to that described in Example 36 the title compound (702.1 mg) was obtained. MS (m/z) 1132 (MH+). Example 40; 4"-O-{2-[4-(3-CarboxY-1-ethyl-4-oxo-1.4-dihydro-quinolin-6-yl)- plperazin-1-yl]-ethyl}-azlthromycin To a solution of Example 36 (1.101 g, 1.0 mmoL) in a THF-water mixture (1:1,10.0 mL), was added LIOH (192 mg, 4.6 mmoL) at room temperature, and the resulting reaction mixture was stirred at the same temperature for 12 hours. The solvent was removed under reduced pressure, and the solid was azeotroped with toluene (5X5 mL) and finally dried under vacuum. The acid salt was dissolved in water and the resulting solution was made acidic by dropwie addition of aqueous HCI (2 M). The precipitate was filtered off to give 688.9.mg (64 %) of the title compound as colourless solid. MS (m/z) 1076 (MH+). Example 41: 4"-O-{2-[2-(3-Carboxy-7-chloro-1 -cyclopropyl-4-oxo-1.4-dihvdro- quinolin-6-viamino)-ethvtamino]-ethyl}-azithromycin Starting from Example 37 (504.9 mg, 0.45 mmoL) according to the procedure of Example 40, the title compound (399.8 mg) was obtained. MS (m/z) 1096 (MH+)- Example 42: 4"-O-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihydro- quinolin-7-vlamino)-ethylamino]-ethyl}-azlthromycin Starting from Example 38 (686.3 mg, 0.62 mmoL) according to the procedure of Example 40, the title compound (671.1 mg) was obtained. MS (m/z) 1082 (MH+). 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. feecalis ATCC 29212, H. influenzae ATCC 49247, M. catarrhalis ATCC 23246. Examples 1,2,5-7,13,15,18-23,25 and 27-32 have an MIC ≤1 µg/mL against S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565 and E faecalis ATCC 29212. Examples 1, 2, 4, 6, 13-16, 18-21, 23 and 27-32 have an MIC ≤4 µg/mL against H. influenzae ATCC 49247 and M. catarrhalis ATCC 23246. Examples 1-4,6,7,9-15 and 18-32 have an MIC ≤1 µg/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: WE CLAIM: 1. A macrolide compound of formula (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-0(CH2)dXR11; R2 is hydrogen or a hydroxyl protecting group; R3 is hydrogen, C1-4alkyl, or C3_6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl; R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or -0(CH2)eNR7R12 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(R13)- and -CH (SR13)-; R8 is hydrogen or fluorine; R7 is hydrogen or C1-6alkyl; R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or -C(O) R14, or R8 and R9 together form =CH(CR14R15)faryl, =CH(CR14R15)fheterocyclyl, =CR14R15 or =C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16; R10 is -OR17, C1_6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)iOR7, wherein each R10 group is optionally substituted by up to three groups independently selected from R16; R11 is a heterocyclic group having the following structure: R12 is hydrogen or C1-6galkyl; R13 is hydrogen or C1-4alkyl 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; R14 and R15 are each independently hydrogen or C1-6alkyl; R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R21, -C(O)OR21, -OC(O)R21, -OC(O)OR21, -NR22C(O)R23, -C(O)NR22R23, -NR22R23, hydroxy, C1-6alkyl, -S(O) kC1-6alkyl, C1-6alkoxy, -(CH2)maryl or -(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from -NR14R15, halogen and -OR14, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O)R24, -C(O)OR24, -OC(O)OR24, -NR25C(O)R26, -0(O)NR25R26, -NR25R26, hydroxy, C1-6alkyl and C1-6alkoxy; R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl 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, -OR27, -S(O)nR27, -NR27R28, -CONR27R28, halogen and cyano; R18 is hydrogen, -C(O)OR29, -C(O)NHR29, -C(O)CH2NO2 or -C(O)CH2S02R7; R19 iS hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3- 7cycloalkyl, or optionally substituted phenyl or benzyl; R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1- 4alkyl)2; R21 is hydrogen, C1-10alkyl, -(CH2)paryl or -(CH2)pheteroaryl; R22 and R23 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or -(CH2) qheterocyclyl; R24 is hydrogen, C1-10alkyl, -(CH2)raryl or -(CH2)rheteroaryl; R25 and R26 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or -(CH2) sheterocyclyl; R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl; R29 is hydrogen, C1-6alkyl optionally substituted by up to three groups independently selected from halogen, cyano, C1-4alkoxy optionally substituted by phenyl or C1-4alkoxy, -C(O) C1-6alkyl, -C(O)OC1-6alkyl, -OC(O)C1-6alkyl, -OC(O)OC1-6alkyl, -C(O) NR32R33 -NR32R3 phenyl optionally substituted by nitro or -C(O)OC1- 6alkyl, -(CH2)wC3-7cycloalkyl, -(CH2)wheterocyclyl, -(CH2)wheteroaryl, -(CH2)waryl, C3-6alkenyl, or C3-6alkynyl; R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl; R31 is hydrogen or R20 or R31 and R19 are linked to form the bivalent radical -O(CH2) 2- or -(CH2)t-; R32 and R33 are each independently hydrogen or C1-6alkyl optionally substituted by phenyl or -C(O)OC1-6alkyl, or R32 and R33, 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; X is -U(CH2)VB-, -U(CH2)V- or a group selected from: U and B are independently a divalent radical selected from -N(R30)-, -0-, -S(O)z-, -N (R30)C(O)-, -C(O)N(R30)- and -N[C(O)R30]-; W is -C(R31)- or a nitrogen atom; d is an integer from 2 to 6; 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. 2. A compound as claimed in claim 1 wherein A is -C(O)- or -N(R7)-CH2- 3. A compound as claimed in claim 1 or claim 2 wherein X is -U(CH2)VB- or -U(CH2) V' 4. A compound as claimed in any one of the preceding claims wherein d is 2 or 3. 5. A compound as claimed in any one of the preceding claims wherein R11 is a heterocyclic group of the following formula: wherein the heterocyclic is linked in the 6 or 7 position and j, R18, R19 and R20 are as defined in claim 1; a heterocyclic group of the following formula: wherein the heterocylic is linked in the (ii) or (iii) position, W is -C(R31)- and R31 and R19 are linked to form the bivalent radical -(CH2)t- as defined in claim 1, and j, R18, R19 and R20 are as defined in claim 1; or a heterocyclic group of the following formula: wherein the heterocyclic is linked in the 7 or 8 position and j, R18, R19 and R20 are as defined in claim 1. 6. A compound as claimed in claim 1 as defined in any one of Examples 1 to 42, or a pharmaceutically acceptable derivative thereof. 7. A compound selected from: 4"-0-(2-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]- methylamino}-ethyl)-6-0-methyl-erythromycin A 11,12-carbonate; 4"-0-(3-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)ethyl]- methylamino}-propyl)-6-0-methyl-erythromycin A 11,12-carbonate; 4"-0-{3-[2-(2-carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-(ij]quinoline-9-yloxy)- ethylamino]-propyl}-6- O-methyl-erythromycin A 11,12-carbonate; 4"-0-(3-{[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino}- propyl)-6-O-methyl-erythromycin A 11,12-carbonate; 4"-0-(3-{[2-(3-carboxy-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino) ethyl]-methylamino}-propyl)-6-O-methyl-erythromycin A 11,12-carbonate; 4"-0-{2-[2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino) ethyl]-methylamino}-ethyl }-6-O-methyl-erythromycin A; 4"-O-{3-[[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamino]- propyl}-6-0-methyl-11 -desoxy-11 -(R)-amino-erythromycin A 11,12-carbamate; 4"-0-{3-[[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethyl]- methylamino]-propyl}-6-O-methyt-11-desoxy-11-(R)-amino-erythromycin A 11,12- carbamate; 4"-0-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)- ethylcarbamoyl]-propyl}-azithromycin; 4"-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)- ethylamino]-ethyl}-azithromycin 11,12-cyclic carbonate; 4"-0-{2-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinotin-6-ylamino)- ethylamino]-ethyl}-azithromycin; and 4"-0-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)- ethylamino]-ethyl}-azithromycin; or a pharmaceutically acceptable derivative thereof. 8. A process for the preparation of a macrolide compound as claimed in claim 1 which comprises: a) reacting a compound of formula (II) with a suitable amine (IlIa) or (IIIb), wherein Ba and R11a are B and R11 as defined in claim 1 or groups convertible to B and R11; b) reacting a compound of formula (V) (V) with a compound of formula XaR11a (IV), wherein R11a is R11 as defined in claim 1 or a group convertible to R11 and Xa is -U(CH2)V- or -U(CH2)VB-, or a group convertible to -U(CH2)V- or -U(CH2)VB-, in which U is a group selected from -N(R30)- and -S-, and L is suitable leaving group, to produce a compound of formula (I) wherein U is a group selected from -N(R30)- and -S-; a) converting one compound of formula (I) into another compound of formula (I); d) where U is -O-, reacting a compound of formula (VII) with a suitable compound of formula XaR11a in the presence of a catalyst; or e) where U is -C(O)N(R30)-, reacting a compound of formula (VIII) with a suitable amine compound, 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 XaR11 a to XR11, iii) conversion of BaR11a to R11, iv) conversion of R11a to R11, 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. A compound as claimed in any one of claims 1 to 7 for use in the manufacture of a medicament capable of being used in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body. 11. A compound as claimed in any one of claims 1 to 7 for the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body. 12. 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. 13. A pharmaceutical composition as claimed in claim 12 for the treatment of the human or non-human animal body to combat microbial infection. 14. A compound of formula (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-0(CH2)dXR11; R2 is hydrogen or a hydroxyl protecting group; R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl; R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6galkoxy or -O(CH2)eNR7R12. 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(R13)- and -CH (SR13)-; R6 is hydrogen or fluorine; R7 is hydrogen or C1-6alkyl; R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or -C(O) R14 or R8 and R9 together form =CH(CR14R15)faryl, =CH(CR14R15)fheterocyclyl, =CR14R15 or =C(R-14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16; R10 is -OR17, C1-6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)jOR7, wherein each R10 group is optionally substituted by up to three groups independently selected from R16 R11 is a heterocyclic group having the following structure: or R12 is hydrogen or C1-6alkyl; R13 is hydrogen or C1-4alkyl 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; R14 and R15 are each independently hydrogen or C1-6alkyl; R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R21, -C(O)OR21, -OC(O)R21, -OC(O)OR21, -NR22C(O)R23, -C(O)NR22R23, -NR22R23, hydroxy, C1_6alkyl, -S(O) kC1-6alkyl, C1-6alkoxy, -(CH2)maryl or -(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from -NR14R15, halogen and -OR14, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O)R24, -C(O)OR24, -OC(O)OR24, -NR25C(O)R26, -C(O)NR25R26, -NR25R26, hydroxy, C1-6alkyl and C1-6alkoxy; R17 is hydrogen, C1-6alkyl, C3-7cycloaikyl, C3-6alkenyl 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, -OR27, -S(O)nR27, -NR27R28, -CONR27R28, halogen and cyano; R18 is hydrogen, -C(O)OR29, -C(O)NHR29 or -C(O)CH2NO2; R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-6alkoxy, C3- 7cycloalkyl, or optionally substituted phenyl or benzyl; R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1- 4alkyl)2; R21 is hydrogen, C1-10alkyl, -(CH2)paryl or -(CH2)pheteroaryl; R22 and R23 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or -(CH2) qheterocyclyl; R24 is hydrogen, C1-10alkyl, -(CH2)raryl or-(CH2)rheteroaryl; R25 and R26 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or -(CH2) sheterocyclyl; R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl; R29 is hydrogen or C1-6alkyl optionally substituted by up to three groups independently selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and -OC(O)OC1-6alkyl; R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl; R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical -O(CH2) 2-or-(CH2)t-; X is -U(CH2)VB-, -U(CH2)V- or a group selected from; U and B are independently a divalent radical selected from -N(R30)-, -O-, -S(O)z-, -N (R30)C(O)-, -C(O)N(R30)- and -N[C(O)R30]-; W is -C(R31)- or a nitrogen atom; d is an integer from 2 to 6; 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. The present invention relates to 14- or 15-membered macrolides substituted at the 4" 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.

Full Text

NOVEL 14 AMD 15 MEMBERED-RING COMPOUNDS
The present Invention relates to novel semt-synthetic macrolides having antimicrobial
activity, in particular antibacterial activity. More particularly, the invention relates to 14-
and 15-membered macrolldes substituted at the 4" 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-reslstant bacterial strains has"
resulted in the need to develop new macrolide compounds. For example, EP 0 895 999
describes derivatives modified at the 4" position of the macrolide ring having antibacterial
activity.
According to the present invention, we have now found novel 14- and 15-membered
macrolldes substituted at the 4" position which also have antimicrobial activity.
Thus, the present invention provides compounds of general formula (I)

wherein
A is a bivalent radical selected from -C(O)-, -C(0)NH-, -NHC(0)-, -N(R7)-CH2-, -CH2-
N(R7)-, -CH(NR8R9)- and -C(=NR10)-;
R1is-0(CH2)dXR11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C1-4alkyl, or C3alkenyl optionally substituted by 9 to 10 membered
fused blcyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic
heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or -o(CH2)eNR7R12,
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)-, -0-, -N(R13)- and -
CH(SR13)-;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or -
C(O)R14, or
R8 and R9 together form CH (CR14R15)faryl, =CH(CR14Rl5)fheterocyclyl, =CR14R15
or =C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally
substituted by up to three groups independently selected from R16;
R10 is -OR17, C1-6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)iOR7,
wherein each R10 group is optionally substituted by up to three groups independently
selected from R16;
R11 Is a heterocyclic group having the following structure:

R12 is hydrogen or C1-6halkyl;
R13 IS hydrogen or C1-4alkyl 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;
R14 and R15 are each independently hydrogen or C1-6alkyl;
R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(0)R21, .C(0)OR21, -OC(0)R21, -
OC(O)OR21. -NR22C(O)R23, -C9(O)NR22R23, -NR22R23 hydroxy, C1-6alkyl, -S(O)kC1_

6alkyl. C1-6alkoxy, -(CH2)maryl or -(CH2)mheteroaryl, wherein the alkoxy group is
optionally substituted by up to three groups independently selected from -NR14R15
halogen and -OR14, and the aryl and heteroaryl groups are optionally substituted by up to
five groups Independently selected from halogen, cyano, nifro, trifluoromethyl, azido, -
C(O)R24 -C(O)OR24, -OC(O)OR24, -NR25C(O)R26, -C(O)NR25R26 -NR25R26,
hydroxy, C1-6alkyL and C1-6alkoxy;
R17 is hydrogen, C1-6alkyL, C3-7cycloalkyl, C3-6alkenyl 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, -OR27 -S(O)nR27, -NR27R28 -CONR27R28 halogen and cyano;
R18 is hydrogen, -C(O)OR29 -C(O)NHR29 -C(O)CH2NO2 or-C(O)CH2S02R7;
R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3-
7cycloalkyl, or optionally substituted phenyl or benzyl;
R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1-
4alkyl)2;
R21 is hydrogen, C1-10alkyl, -(CH2)parylor-(CH2)pheteroaryl;
R22 and R23 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or -
(CH2)qheterocyclyl;
R24 is hydrogen, C1-10nalkyl, -(CH2)raryl or-(CH2)rheteroaryl;
R25 and R26 are each Independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or -
(CH2)sheterocyclyl;
R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
R29 IS hydrogen,
C1-6alkyl optionally substituted by up to three groups independently selected from
halogen, cyano, C1-4alkoxy optionally substituted by phenyl or C1-4alkoxy, -
C(O)C1-6alkyl, -C(O)OC1-6alkyl. -OC(O)C1-6alkyl, -OC(O)OC1-6alkyl, -
C(O)NR32R33, -NR32R33 and phenyl optionally substituted by nltro or -C(O)OC1-
6alkyl.
-(CH2)wC3-7cycloalkyl,
-(CH2)wheferocyclyl,
-(CH2)wheteroaryl,
-(CH2)waryl,
C3-6alkenyl, or
C3-6alkynyl;
R30 IS hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl
or benzoyl;
R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical -0(CH2)2-
or-(CH2)t-;
R32 and R33 are each independently hydrogen or C1-6alkyl optionally substituted by
phenyl or-C(O)OC1-6alkyl, or

R32 and R33, 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 suifur;
X is -U(CH2)yB-, -U(CH2)v- or a group selected from:

U and B are independently a divalent radical selected from -N(R30)-, -0-, -S(O)z-, -
N(R30)C(O)-, -C(O)N(R30)- and -N[C(O)R3°]-;
W is -C(R31)- or a nitrogen atom;
d is an integer from 2 to 6;
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 another embodiment the present invention provides compounds of general
formula (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)-;
R1is-O(CH2)dXR11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C1-4alkyl. or C3-6alkenyl optionally substituted by 9 to 10 membered
fused bicydic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused blcyclic
heteroaryl, or C1-6alkoxy optionally substituted by C1-6lkoxy or -O(CH2)eNR7R12,
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(R13)- and -
CH(SR13).;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or -
C(O)R14, or
R8 and R9 together form CH(CRl4Rl5)faryl, =CH(CR14R15)fheterocyclyl, =CR14R15
or C(Rl4)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally
substituted by up to three groups independently selected from R16;
R10 is -OR17 C1_6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)|OR7
wherein each R10 group is optionally substituted by up to three groups independently
selected from R16;

R11 is a heterocyclic group having the following structure:

R12 is hydrogen or C1-6alkyl;
R13 is hydrogen or C1-4alkyl substituted by a group selected from optionally substituted
phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to
10 membered fused bicyclc heteroaryl;
R14 and R15 are each independently hydrogen or C1-6alkyl;
R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R21, -C(O)0R21 -OC(O)R21, -
OC(O)OR21, -NR22C(O)R23, -C(O)NR22R23, -NR22R23, hydroxy, C3-6alkyl, S(O)KC1-
6alkyl, C1-6alkoxy, -(CH2)aryl or -(CH2)mheteroaryl, wherein the alkoxy group is
optionally substituted by up to three groups Independently selected from -NR14R15,
halogen and -OR14, and the aryi and heteroaryl groups are optionally substituted by up to
five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -
C(O)R24 -C(O)OR24 -OC(O)OR24, -NR25C(O)R26, -C(O)NR25R26 -NR25R26
hydroxy, C1-6alkyl and.C1-6alkoxy;
R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl or a 5 or 6 membered
heterocyclic group, wherein the alkyi, 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, -OR27, -S(O)nR27, -NR27R28, -CONR27R28, haiogen and cyano;
R18 iS hydrogen, -C(O)OR29, -C(O)NHR29 or -C(O)CH2N02;
R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3.
7cycloalkyl, or optionally substituted phenyl or benzyl;
R20 is halogen, C1-4alkyl, C1-4thioalkvl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1-
4alkyl)2;
R21 is hydrogen, C1-10alkyl, -(CH2)paryl or-(CH2)pheteroaryl;
R22 and R23 are each Independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or -
(CH2)qheterocyclyl;

R24 is hydrogen, C1-10alkyl. -(CH2)raryl or -(CH2)rheteroaryl;
R25 and R26 are each Independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or -
(CH2)sheterocyclyl;
R27 and R28 are each Independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
R29 is hydrogen or C1-6alkyl optionally substituted by up to three groups Independently
selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and -OC(O)OC1-6alkyl;
R30 is hydrogen, C1-4alkyl, C3-10cycloalkyl, optionally substituted phenyl or benzyl, acetyl
or benzoyl;
R31 Is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical -O(CH2)2-
or-(CH2)t-;
X is -U(CH2)vB-, -U(CH2)v- or a group selected from:

U and B are Independently a divalent radical selected from -N(R30)-, -0-, -S(O)Z-, -
N(R30)C(O)-, -C(O)N(R30)- and -N[C(O)R30]-;
W is -C(R31)- or a nitrogen atom;
d is an Integer from 2 to 6;
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 is2or3;
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 counterforts 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 pharmaceutJcally acceptable salts and solvates.

Compounds of the Invention may have both a basic and an acidic centre may therefore
be inihe 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., "Bioreverslble 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 covalentty 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 sulfhydryi groups. Thus, representative examples of prodrugs Include (but are
not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryi 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

The term "pharmaceutlcally acceptable derivative" as used herein means any
pharmaceutlcally 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, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein
by reference to the extent of teaching such derivatives. Preferred pharmaceutlcally
acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters.
Particularly preferred pharmaceutlcally acceptable derivatives are salts, solvates and
esters. Most preferred pharmaceutlcally 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 pharmaceutlcally acceptable salt. For a review on suitable salts see
Berge et al., J. Pharm. Scl., 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 (lyophlllsed)
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 dllsopropyl 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, hydrobromlde, hydroiodide, sulphate, bisulphate,
nitrate, phosphate, hydrogen phosphate, acetate, trlfluoroacetate, maleate, malate,
fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate,
oxaloacetate, trlfluoroacetate, saccharate, benzoate, alkyl or aryl sulphonates (eg
methanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate)
and isethlonate. Representative examples include trlfluoroacetate and formate salts, for
example the bis or tris trlfluoroacetate salts and the mono or dlformate salts.
Pharmaceutlcally 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-glucamlne.

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 substltuents on the macrollde may also have one or more
asymmetric carbon atoms. Thus, the compounds of structure (I) may occur as individual
enantiomers or dlastereomers. All such isomeric forms are included within the present
invention, including mixtures thereof.
Where a compound of the invention contains an alkenyl group, cls (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 chlral support or by fractional crystallisation of the dlastereoisomeric salts
formed by reaction of the corresponding mixture with a suitable optically active acid or
base, as appropriate.
The compounds of structure (1) 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. trimethylsllyl). 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 R11is a heterocyclic group having the following structure:

sald 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 R20 group or groups
may be attached at any position on the ring. In one embodiment, an R20 group is
attached at the 6 or 7 position.
When R11 is a heterocyclic group having the following structure:

wherein W is -C(R31)- where R31 is R20 or R31 and R19 are linked to form the bivalent
radical -0(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 R11 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. The R20 group or groups may be attached at any
position on the ring. In one embodiment, an R20 group is attached at the 6 position.
When R11 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 R11 is a heterocyclic group having the following structure:

wherein W is -C(R31)- where R31 is R20 or R31 and R19 are linked to form the bivalent
radical -0(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 R11is 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, C1-10alkyl 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, isopropvl. t-butvl. hexvl. heDtyl, octyl,

nonyl and decyl. A C1-4alkyl group is preferred, for example methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl or t-butyl.
The term "C3-7cycloalkyl" Qroup 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, C1-6alkoxy 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 C1-4alkoxy 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 "C2-6alkenyl" 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 "C3-6alkenyl" 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-enyi. It will be appreciated that in
groups of the form -0-C2-6alkenyl, 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 'C3-6alkenyl' 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,

triazolyi, oxadiazolyl, tetrazolyl, thiadiazolyl, pyridyi, pyridazlnyl, pyrazinyl, pyrimldlnyl,
trlazlnyl, quinolinyt, isoquinollnyl, 1,2,3,4-tetrahydrolsoquinolinyl, benzofuranyl,
benzimldazolyl, benzothienyl, benzoxazolyl, 1,3-benzodioxazolyl, indolyl, benzothlazolyl,
furylpyrldine, oxazolopyrfdyl and benzothlophenyl.
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, thlophenyl, pyrrolyl, pyrazolyl, imldazolyl, oxazolyl,
isoxazolyl, thlazolyl, Isothlazolyl, triazolyi, oxadiazolyl, tetrazolyl, pyridyl, pyridazlnyl,
pyrazinyl, pyrimldlnyl 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 quinolinyt, lsoquinolinyl, 1,2,3,4-tetrahydrolsoquinolinyl, benzofuranyl,
benzimldazolyl, benzothienyl, benzoxazoiyl, 1,3-benzodloxazolyl, indolyl, benzothlazolyl,
furylpyrldine, oxazolopyridyl or benzothlophenyl.
The term "heterocyclyT as used herein, unless otherwise defined, refers to a monocyclic
or blcyclic 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, tetrahydrothlophenyl,
Imldazoildlnyl, pyrazolldinyl, piperidyl, piperazinyl, morphollno, tetrahydropyranyl and
thlomorphollno.
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,
tetrahydrothlophenyl, Imldazoildlnyl, pyrazolldinyl, piperidyl, piperazinyl, morpholino,
tetrahydropyranyl and thlomorphollno.
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 substltuted 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, C1-4alkyl, C1-4alkoxy, hydroxy, nitro, cyano, amino, C1-
4alkylamlno or diC1-4alkylamino, phenyl and 5 or 6 membered heteroaryl.

In one embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, -N(R7)CH2-, -CH2N(R7)- or -
CH(NR8R9)-. In another embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, -CH2-N(R7)-,-
CH(NR8R9)- or -C(=NR10)-. In a further embodiment, A is -C(O)-, -C(O)NH-, -NHC(O)-, -
CH2-NR7- or -CH(NR8R9)-. Representative examples of A include -C(O)- and -N(R7).
CH2-. In particular, A is-C(O)-.
A representative example of R2 is hydrogen.
Representative examples of R3 Include hydrogen and C1-4alkyl, for example hydrogen
and methyl. In particular, R3 is methyl.
In one embodiment, R4 and R5 are hydroxy. Alternatively, 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 -O- and -N(R13)-.
A representative example of R6 is hydrogen.
A representative example of R7 is C1-6alkyl, for example Chalkyl, in particular methyl.
In one embodiment, R1 1 Includes heterocyclic groups having the following structures:

wherein the heterocyclic is linked in the 8 or 7 position to the defined;

heterocyclic groups having the following structure:

wherein W is -C(R31)- and R31 and R19 are linked to form the bivalent radical -(CH2)t-,
and the heterocyllc Is linked in the (ii) or (iii), position to the X group as above defined; and
heterocyclic groups having the following structure:

the heterocyclic is linked in the 7 or 8 position to the X group as above defined.
Representative examples of R11 Include heterocyclic groups having the following
structures:

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

wherein W is -C(R31)- and R31 and R19 are linked to form the bivalent radical -(CH2)t-,
and the heterocylic is linked in the (ii) or (iii), position to the X group as above defined.
A further representative example of R11 is a heterocyclic group having the following
structure:

said heterocyclic is linked in the 7 or 8 position to the X group as above defined.
In one embodiment, R13 is hydrogen or C1-4alkyl substituted by a group selected from
optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and
optionally substituted 9 to 10 membered fused blcyciic heteroaryl. Representative
examples of R13 include hydrogen and C1-4alkyl, for example hydrogen and methyl.
In one embodiment, R18 iS hydrogen, -C(O)OR29, -C(O)NHR29 or -C(O)CH2NO2. In a
further embodiment, R18 is -C(O)OR29, -C(O)NHR29 or -C(O)CH2NO2. A representative
example of R18 is -C(O)OR29, wherein R29 is hydrogen.
Representative examples of R19 include C1-4alkyl, in particular ethyl, and C3-7cycioalkyl,
in particular cyclopropyl.
In one embodiment, R20 is halogen or C1-4alkyl. Representative examples of R20
include halogen, in particular chlorine or fluorine. Further representative examples of R20
Include C1-4alkyl, In particular methyl.
In one embodiment, R29 is hydrogen or C1-6alkyl optionally substituted by up to three
groups independently selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and
OC(O)OC1-6alkyl. A representative example of R29 is hydrogen.
Representative examples of R30 include hydrogen and C1-4alkyl, in particular hydrogen
and methyl.

A representative example of R31 is hydrogen, or R31 and R19 are linked to form the
divatent radical -CH2)t-
In one embodiment, X is -U(CH2)vB-. -U(CH2)V- or a group selected from:

In another embodiment, X is -U(CH2)VB-, -U(CH2)V- or a group selected from:

Representative examples of X are -U(CH2)VB- and -U(CH2)v-
Further representative examples of X are

In one embodiment, U and B are independently a divalent radical selected from -N(R30)-,
-0-, -S(O)z- and -C(O)N(R30)-. Representative examples of U and B Include the dlvalenf
radicals -N(R30)-, -O- and -S(O)z-. A further representative example of U and B is -
C(O)N(R30)-.
in one embodiment, when X is -U(CH2)VB-, U is selected from the divalent radicals -
N(R30) and -C(O)N(R30)- and B is selected from the divalent radicals -N(R30)-, -O- and
-S(O)z-. In particular, U is -N(R30)- and B is selected from the divalent radicals -N(R30)-,
-0- and -S(O)Z-. For example, U is -N(R30)- and B is selected from the divalent radicals -
N(R30)-and-S(O)Z-.
In one embodiment, when X is -U(CH2)v-, U is selected from the divalent radicals -
N(R30)- and-O-. For example, U is-N(R30)-.
Representative examples of Y include the bivalent radicals -0- and -N(R13)-.
Representative examples of d include 2 and 3.
A representative example of t Is 3.
In one embodiment, v Is an Integer of from 2 to 8. A representative example of v is 2 to 4,
in particular 2 or 3.
A representative example of z is 0.
Representative examples of j include 0 and 1.
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 Rl4, R15, R16, R20, R21, R22 R23 R24, R25 R26 R27
R28, R30, R32, R33, k, m, n, p, q, r, 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:
4"-O(2{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-
methylamino}-ethyl)-6-0-methyl-etythromycin A 11,12-carbonate;
4"-0-(3{[2-(3-^arboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-qulnolin-7-ylamlno)ethyl]-
methylamlno}-propyi)-6-0-methyl-erythromycIn A 11,12-carbonate;
4"-0-{3-[2-(2-carboxy-1 -oxo-6,7-dihydro-1 H,5W-pyrido[3,2,1 -lquinoline-9-yloxy)-
ethylamlno]-propyl}-6-0-methyl-erythromycin A11,12-carbonate;

4"-0-(3-{[3-(3-arboxy-1-ethyl-4-xo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino}
propyl)-6-0-methyl-erythromycln A 11,12-carbonate;
4"-0-(3-{I2-(3-carboxy-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridirn-7-
ylamlno)ethyl]-methylamIno}-propyl)-6-0-methyl-erythromycIn A 11,12-carbonate;
and pharmaceutically acceptable derivatives thereof.
Further particularly preferred compounds of the invention are:
4"-0-{2-[2-(3-carboxy-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridfn-7-
ylamlno)ethyl]-methylamino}-ethyl }-6-O-methyl-erythromycin A;
4"-0-{3-[[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamlno]-
propyl}-6-0-methyl-11-desoxy-11-(R)amino-erythromycin A 11,12-carbamate;
4"-0-{3-[[2-(3-carboxy-1-ethvl-4-oxo-1,4dihydro-quinolin-6-ylsulfanyl)-ethyl]-
methylamlno]-propyl}-6-0-methyl-11-desoxy-11-(R)-amino-erythromycin A 11,12-
carbamate;
4"-0-{3-[2-(3-rarboxy-7-chloro-1-cyciopropyl-4-oxc>-1,4-dihydro-quinolin-6-ylamlno}-
ethylcarbamoyl]-propyl}-azithromycin;
4"-{2-[2-(3-raitoxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydr6-quinolin-7-ylamlno)-
ethylamino]-ethyl}-azithromycln 11,12-cyclic carbonate;
4"-0-{242-(3-rarboxy-7-chIoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yfamino)-
ethylamlno]-ethyl}-azithromycin;
4"-Q-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-
ethylamlno]-ethyl}-azithromycin;
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 mlcroorganisims. 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 01
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 (l) 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 therapetlc 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),
solubillsing 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-cyclodextrln 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 solublliser.
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 blle.
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
route. 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 genlto-urinary use.
For some applications, the agents of the present Invention are delivered systemlcally
(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, intraarterlally,
Intraperitoneally, intrathecally, intraventricularly, intraurethraily, intrasternalfy,
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 olly or aqueous vehicles, and may contain
formulatory agents such as suspending, stabilising, solubilislng and/or dispersing
agents. Alternatively the active Ingredient may be In sterile powder form for
reconstitutlon 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 pharmaceuticatly acceptable carriers and
exciplents which may be in solid or liquid form.
The tablets may contain exciplents such as mlcrocrystalline cellulose, lactose, sodium
citrate, calcium carbonate, dibasic calcium phosphate and glycine, dlsintegrants 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), hydroxypropylcellulose
(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 exclplents 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 exdplent.
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, poiysorbate 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 micronlsed 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 benzylalkonlum
chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
As Indicated, the compound of the present invention can be administered intranasally 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 nebullser with
the use of a suitable propellant, e. g. dichlorodifluoromethane, trichlorofluoromethane,
dlchlorotetrafluoroethane, 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 nebullser.
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 R33, A, B, X, Y, U, 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 R11a, BaR11a and XaR11a are R11, BR11 and XR11 as defined for formula
(I) or groups convertible to R11, BR11 and XR11. Conversion of such groups 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 2nd ed., John Wiley &
Son, Inc 1991 and by P.J. Koclenskl 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, trifiuoroacetyl and acetyl), aromatic
urethane type protecting groups (e.g. benzyioxycarbonyl (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 trimethylsllyl or tert-
butyldimethylsllyl; 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 trialkylsllyl chloride in an aprotlc solvent. Examples of aprotic
solvents are dichioromethane, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran
and the like.
Compounds of formula (I) wherein U is -N(R30)- may be prepared by reaction of a 4"
aldehyde compound of formula (II) wherein A, R2, R3, R4 and R5 may be suitably
protected, for example by cyclic protection between the 9 and 12 positions when A is -
C(O)- and d is an integer from 1 to 5, with a suitable protected derivative of the amine
(Illa) or (lllb), followed where necessary by subsequent removal of the hydroxyl protecting
group R2 and conversion of the BaR11a or R11a group to BR11 orR11.

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.
Compounds of formula (II) where d' is 1 or 2 may be prepared from suitably protected
compounds of formula (IV) by hydroboration with 9-BBN, or other suitable boranes,
followed by treatment with peroxide and then oxidation (d' = 2), or by osmlum
tetroxide/peridoate cleavage (d' = 1). Compounds of formula (IV) can be formed by
palladium-catalysed allylation of suitably protected 4" hydroxy compounds.

In another embodiment of the invention, compounds of formula (I) wherein U is a group
selected from -N(R30)- and -S-, may be prepared by reaction of compounds of formula (V)

wherein d is an integer from 2 to 6 and L is a suitable leaving group, with XaR11a (VI) in
which U is a group selected from -N(R30)- 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,
dimethyisulfoxide, N.N-dimethylformamlde 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 XaR11a group to XR11. Examples of the bases which may be used
include organic bases such as diisopropylethylamine, triethylamine and 1,8-
dlazabicyclo[5.4.0]undec-7-ene (DBU), 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 hallde (e.g. chloride, bromide or
iodide) or a sulfonyloxy group (e.g. tosyloxy or methanesulfonyloxy).
Compounds of formula (I) may be converted into other compounds of formula (I). Thus
compounds of formula (I) wherein U or B 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 U or B is -N(R30)-
and R30 is C1-4alkyl can be prepared from compounds wherein R30 is hydrogen by
reductive alkylatlon.
with a suitable compound of formula XaR11a, in the presence of a catalyst such as
tetrakis(triphenylphosphine) palladium.
In another embodiment of the Invention, compounds of formula (I) wherein U is -0-, may
be prepared by reaction of compounds of formula (VII)

In a further embodiment of the invention, compounds of formula (i) wherein U is -
C(O)N(R30)-, may be prepared by reaction of compounds of formula (VIII)

with a suitable amine compound.
Compounds of formula (II) wherein A is -C(O)NH- or -NHC(O)-, R4 or R5 are hydroxy, R3
Is hydrogen and R6 is hydrogen are known compounds or they may be prepared by
analogous methods to those known in the art. Thus they can be prepared according to the
procedures described in EP 507595 and EP 503932.
Compounds of formula (II), wherein A is -C(O)NH- or -NHC(O)-, R4 or R5 are hydroxy and
R3 is C1-4alkyl or C3-6alkenyl optionally substituted by 9 to 10 membered fused blcyclic
heteroaryl and R6 is hydrogen are known compounds or they may be prepared by
analogous methods to those known in the art. Thus they can be prepared according to the
procedures described in WO 9951616 and WO 0063223.
Compounds of formula (II), wherein A is -C(O)NH-, R4 and R5 taken together with the
intervening atoms form a cyclic group having the following structure:

R3 is C1-4alkyl, or C3-6ealkenyl optionally substituted by 9 to 10 membered fused blcyclic
heteroaryl and R6 is hydrogen are known compounds or they may be prepared by
analogous methods to those known in the art Thus they can be prepared according to the
procedures described in US 6262030.

Compounds of formula (II), wherein A is -C(O)-, -C(O)NH-, -NHC(O)-, -N(R7)-CH2-, -CH2-
N(R7)- or-CH(NR8R9)-. R4 or R5 are 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 -O- and -N(R13)- and R3 IS C1-4alkyl, or C3.
6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl are known
compounds or they may be prepared by analogous methods to those known In the art
Thus they can be prepared according to the procedures described in EP 307177, EP
248279, WO 0078773, WO 9742204.
Compounds of formula (II), wherein A is -C(O)NH-, -NHC(O)-, -N(CH3)-CH2- or -CH2-
N(CH3)-, R4 or R5 are hydroxy or R4 and R5 taken together with the intervening atoms
form a cycllc group having the following structure:

and R6 is hydrogen are known compounds or they may be prepared by analogous
methods to those known in the art Thus they can be prepared according to the
procedures described In EP 508699 and J.Chem. Res.Synop (1988 pages 152-153), US
6262030.
Compounds of formula (II), wherein A is -C(=NR10)-, R4 or R5 are hydroxy or R4 and R5
taken together with the Intervening atoms form a cyclic group having the following
structure:

and R6 is hydrogen, are known compounds or they may be prepared by analogous
methods to those known in the art Thus they can be prepared according to the
procedures described in EP 284203.
Compounds of formula (II), wherein A is -C(O), R4 and R5 taken together with the
Intervening atoms form a cyclic group having the following structure:

R6 is hydrogen and R3 is C1-4alkyl may be prepared by decarboxylation of a compound
of formula (IX), wherein R34 is amino protecting group followed, if required, by removal of
the protecting group R2 or R34.

The decarboxylation may be carried out in the presence of a lithium salt such as lithium
chloride, preferably in an organic solvent such as dlmethylsulfoxide.
Compounds of formula (II), wherein A is -C(O)-, R4 and R5 taken together with the
intervening atoms form a cyclic group having the following structure:

and R3 is C1-4 alkyl may be prepared according to the procedures described in WO
02/50091 and WO 02/50092.
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 Ac for acetyl, AC2O for acetic anhydride,
9-BBN for 9-borablcyclo[3.3.1]nonane, BINAP for 2,2,-bls(dlphenyiphosphlno)-1,1'-
binaphthyl, BOC for t-butoxycarbonyl, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene, DCM
for dlchloromethane, D1PEA for N.N-dllsopropylethvlamine. DMF for N,N-

dimethylformamide, DMSO for dimethyl sulfoxide, Et2O for diethyl ether, EtOAc for ethyl
acetate, EtOH for ethanol, HBTU for2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronlum
hexafluorophosphate, HOAc for acetic acid, LDA for lithium diisopropylamlde, MeCN for
acetonitrile, MeOH for methanol and THF for tetrahydrofuran.

2-O-Acetyl-azithromycrn11,12-carbonate may be prepared by the procedure described
by S. Djokic et al. in J. Chem. Res. (S) 1988,152.
Nomenclature
In the Examples, compounds of formula (I) in which R11 is a tricyclic heterocyclic group
are referred to using the numbering system below:

Intermediate 1; 6[(2-Amlnoethvl)amino]-7chlro-1cyclopropyl-4-oxo-1.4-dlhydro
qulnollne-3-carboxyllc acid
7-Chloro-1-cyclopropyl-1,4-dihydro-oxo-quinollne-3-carboxyllc acid (56.3 g) and
ethylenedlamlne (36 g) were dissolved in N.N-dimethytacetamide (650 mL) at 100°C and
stirred for 8.5 h at 115oC. 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 110oC 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 35-40oC 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]-.
Intermedlat 2:6-(2-Amlno-ethoxy)-1-ethyi-4-oxo-1,4dlhydro qulnollne-3-
carboxyllc acid hydrochloride
a) 6-(2-Dibenzamlno-thoxy)-1-ethyl-4-oxo-1,4-dlhydro-qulnollne-3-carboxyiic acid
2-dibenzytamlno-ethyl aster.
1Ethyl-6-hydroxy-4-oxo-1,4-dihydro-qulnollne-3-carboxyllc acid (GB 1433774) (1.4 g. 6
mmol) was dissotved In dry DMF (80 mL). To this was added potassium carbonate (5 g,
36 mmol) and dlbenzyl-(2-chloroethyl)amlne 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 IM+H]+ (100%).
b) 6-(2-Dlbenzylamlno-ethoxy)-1-ethyl-4-oxo-1,4-dlhydro-qulnoIlne-3-carboxyllc acid
sodium salt.
Intermediate 2a (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-quinoiine-3-carboxylic acid.
Intermediate 2b (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(ll) hydroxide on carbon (0.6 g) at 50 psl for 18 h. The mixture was filtered
through kleselguhr, 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 3: 6-(2-Aminoethvlsulfanyn-1 -ethyl-oxo-1,4-dlhvdro-quinollne-3-
carboxyiic acid trlfluoroacetate salt
a) 6-Bromo-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxyiic acid ethyi ester.
A mixture of potassium carbonate (2.95 g, 21.2 mmol) and 6-bromoquinolone-3-carboxylic
acid (2.84g, 10.6 mmol) in dimethylformamlde (25 mL) was heated to 40°C under argon
for 10 minutes and lodoethane (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 5oC and filtered under vacuum. The resultant cream-coloured solid was dried under
vacuum to yield the title compound; 1H NMR 5 [(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 (1H, dd, J = 2.4 & 9 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.49 (1H, s).
b) 6-(2-t-Butoxycarbonylamlnoethylsulfany1)-1 -ethyl-4-oxo-1,4-dlhydro-qulnollne-3-
carboxyllc acid ethyl ester.

A mixture of N-Bocsteinamine (0.35 g. 2 mmol), Intermediate 3a (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-chromatograpny over slilca gal editing with diotoromethane containing an
increasing concentration of methanol/emmonium hydroxide the title compound was
obtained as a white solid; ESMS m/z 421 [M+H]+ (100%).
c)6-(2-t-Butoxycarbonytamlnoethyisulfanyl)-1-ethyl-4-oxo-1,4-dlhydro-quinoilne-3-
carboxyiic add sodium salt
To a solution of Intermediate 3b (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-Aminethyisulfanyl)-1-ethyl-4-oxo-1,4-dihydro-quinollne-3carboxiic acid
trtfluoroacetate salt
To Intermediate 3c (0.068 g, 0.17 mmol) was added trifluoroacetic acid (1 mL). After 1 h
the solvent was evaporated to yleid 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).
Intermedlated 4: 6-(3-Amlnopropyl)-1-ethyl-4-oxo-1,4-dlhydro-3-quinoilne-3-carboxilc
acid trlfluoroacetate salt
a) 1-Ethyl-6-odo-4-oxo-1,4-dihydro-quinollne-3-carboxylic acJd ethyl ester.
A mixture of 1,4-dihydro-6-iodo-4-oxo quinollne-3-carboxyilc acid (J. Eills et a/, 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 8 (CDCl3) 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-t-Butoxycarbonylamino-prop-1-ynyl)-1-ethyl-4-oxo-1,4-dihydro-quinline-3-
carboxylic acid ethyl ecter.
Intermediate 4a (0.371g, 1 mmol), copper (I) iodide (26 mg, 0.13 mmol) and triethyiamine
(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 mfn.
dicniorobte(triphenylphosphine)paliadium (II) (0.026g, 0.0379 mmol) and
t-butoxycanbonyipropargytarnine (0.264 g, 1.7 mmol) were added and the brown
suspension was heated under reflux. After 2 h 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-t-Butoxycarbonylamlnopropyl)-1-ethyl-4-oxo-1,4-dlhydro-quinollne-3-
carboxylic acid ethyl ester.
Intermediate 4b (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-dlhydro-qulnoilne-3-carboxylic acid ethyl
ester.
Using a similar procedure to that described in intermediate 3d, Intermediate 4c (355 mg,
0.88 mmol) gave the title compound as a yellow oil; ESMS m/z 303 [M+H]+.
e) 6-(3-Aminopropyl)-1-9thyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium
salt.
Using a similar procedure to that described in intermediate 3c, intermediate 4d (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-quinoIine-3-carboxylic acid
trifluoroacetate salt.
Intermediate 4e (0.06 g, 0.2 mmol) was subjected to reverse phase HPLC purification to
give the title compound as white solid; 1H NMR 5 [(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,(1H, 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 5: 9-(2-Amino-ethoxy)-1-oxo-8.7'dihvdro-1H,5H-pyridor[3.2.1-
ll]qulnoline-2-carboxylic acid hydrochloride
a) 9-(2-Dlbenzylamino-ethoxy)-1-oxo-6,7-dlhydro-1W,5W-pyrldo[3,2,1-ij]quinoline-2-
carboxylic acid 2-dibenzylamino-sthyl ester.
9-Hydroxy-1-oxo-6,7-dihydro-1H,5H-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-chioroethyl)amine
hydrochloride (2.37 g, 8 mmol). The mixture was heated at 60°C for f6 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+HJ+ (100%).
b) 9-(2-DlbenzyIamlno-ethoxy)-1-oxo-6,7-dihydro-1 //,5//-pyrido[3,2,1-ij]quinoline-2-
carboxyllc acid sodium salt.
Intermediate 5a (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]qulnollne-2-
carboxyllc acid hydrochloride.
Intermediate 5b (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 6: 7-(2-AmIno-ethvlamlno)-1 -ethvl-6-fluoro-4-oxo-1,4-dlhvdro-
[1.8]naphthyridine-3-carboxylic acid trifluoroacetate
a) 7-(2-tert-Butoxycarbonylamino-ethylamino)-1-ethyi-6-fluoro-4-oxo-1,4-dihydro-
[1,8]naphthyrldine-3-carboxylic acid ethyl ester.
7-Chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl
ester (2.20 g, 7.37 mmol) in THF (20 mL) and MeCN (20 mL) was treated with
triethylamine (3.07 mL, 22.0 mmol), followed by (2-amino-ethyI)-carbarnic acid terf-butyl
ester (1.41 g, 8.80 mmol) and the mixture heated to 70°C. After 26 h (2-amino-ethyl)-
carbamic acid fert-butyl ester (300 mg, 1.87 mmol) was added. After a further 15 h the
heating was stopped and the solvent removed In vacuo. The residue was taken up in
ethyl acetate, washed with water, dried filtered, and concentrated In vacuo to give a
residue which was purified by chromatography (silica gel, 30-100% ethyl acetate in
petroleum ether (b.p. 40-60°C)) to give the title compound (2.89 g); ESMS m/z 423
IM+H]+.
b) 7-(2-fert-Butoxycarbonylamino-ethylamino)-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-
[1,8]naphthyridlne-3-carboxylic acid.
To Intermediate 6a (2.89 g, 6.84 mmol) in THF (30 mL) was added 2 N aqueous sodium
hydroxide (3.4 mL, 6.8 mmol), and the mixture stirred at room temperature. After 24 h 2 N

aqueous sodium hydroxide (0.6 mL, 1.2 mmol) was added and stirring continued for a
further 24 h. The solvent was then removed in vacuo, and the residue taken up in water
(10 mL). Solid carbon dioxide-was added, and the resulting precipitate filtered off and
dried in vacuo to give the title compound (2.65 g); ESMS m/z 395 [M+Hf.
c) 7-(2-Amino-ethylamino)-1 -ethyl-6-fluoro-4-oxo-1,4-dlhydro-[1,8]naphthyridine-3-
carboxyllc acid trlfluoroacetate.
Intermediate 6b (2.65 g, 6.72 mmol) was suspended in dichloromethane (30 mL),
trtfluoroacetlc acid (15 mL) added, and the solution stirred for 35 min. The mixture was
concentrated in vacuo, and again from toluene, and again from hexane to give the title
compound as a tan powder (2.92 g); ESMS m/z 295 [M+Hf.
Intermediate 7: 2'O-Acetvl-6-0-metyl-11-desoxv-11-fR)-methyiamino-
erythromycin A 11.12-carbamate
6rO-Methyl-11 desoxy-11-(R)-methylamino-erythromycin A 11,12-carbamate (W. R.
Baker ef al., J. Org. Chem:, 1988, 53(10), 2340-5) (0.87 g) was dissolved in DCM (20
mL) and acetone (3 mL). Solid NaHC03 (0.6 g) and AczO (0.6 mL) were added and the
reaction mixture was stirred for 1 h, then DCM (50 mL) and water (50 mL) were added.
The organic phase was separated, washed with brine (20 mL), dried over K2C03, filtered
and concentrated under reduced pressure, affording the title compound (0.875 g); ESMS
m/z 829 [MH]+.
Intermediate 8; 6-((Z)-34ert-Butoxvcarbonyloxvprop-1-enyl)-1.4-dihydro-1-ethyl-4.
oxo-quinoline-3-carboxylic acid ethyl ester
a) 1,4-Dlhydro-1-ethyl-6-lodo-4-oxo-qulnoline-3-carboxyIic acid ethyl ester.
A mixture of 1,4-dlhydro-6-lodo-4-oxo-qulnoline-3-carboxylic acid (J. Ellis, E. Gellert, J.
Robson, AusL 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), 8.88 (1H. d, J = 2.1
Hz).
b) 6-(3-Hydroxyprop-1-ynyl)-1,4-dihydro-1-ethyl-4-oxo-qulnoline-3-carboxylic acid
ethyl ester.
Intermediate 8a (3.71 g, 10 mmol), copper (I) iodide (0.209 g, 1.1 mmol) were
suspended in dry acetonitrile (100 mL) and triethylamine (49 mL). The light green
suspension was heated to 50°C whilst argon was bubbled through. After 20 mln,

dichlorobis(triphenylphosphine)palladlum (II) (0.21 g, 0.3 mmol) and propargyl alcohol
(0.92 mL,. 17 mmol) were added and the brown suspension was heated under argon at
50°C for 3.5 h. The crude product was purified by chromatography on silica gel elutlng
with a gradient of dichloromethane in hexane followed by a gradient of methanol in
dichloromethane. Product containing fractions were evaporated to dryness and the
residue dissolved in chloroform and filtered. The filtrate was evaporated to drynes to yield
the title compound as a beige solid, (1.62 g, 54%); ESMS m/z 300 [M+H]+.
c) 6-((Z)-3-Hydroxyprop-1-enyl)-1,4-dihydro-1-ethyl-4-oxo-quinoIine-3-carboxylic
acid ethyl ester.
Intermediate 8a (0.39 g, 1.3 mmol) in ethanol (10 mL) and 1,4-dioxan (5 mL) was
hydrogenated at 20°C and 1 atm over Lindlar catalyst (0.05g). After 5 h, dichloromethane
(10 mL) was added, and the hydrogenation continued for 18 h. The catalyst was filtered
off and washed well with ethanol / dichloromethane. The combined filtrates were
evaporated to dryness and the residue taken up in ethanol (4 mL) and dichloromethane
(12 mL), and re hydrogenated at 20°C and 1 atm over Lindiar catalyst (0.2 g) for 3 h. The
catalyst was filtered off and washed well with ethanol / dichloromethane. The combined
filtrates were evaporated to dryness to give the title product as a white solid, (0.394g)
ESMS m/z 302 [M+H]+.
d) 6-((Z)-3-tert-Butoxycarbonyloxyprop-1-enyl)-1,4-dlhydro-1-ethyl-4-oxo-quinoline-
3-carboxylic acid ethyl ester.
Intermedlate 8a (0.393 g, 1.3 mmol) in dichloromethane (10 mL) was treated with di-tert-
butyl dicarbonate (0.327 g, 1.5 mmol) and N-methylimidazole (0.01 g). After 4 d at 20 °C
the crude product was purified by chromatography on silica gel elutlng with a gradient of
ethyl acetate in hexane to give the title product, (0.40g, 77%). 1H NMR δ (CDCI3) 1.42
(3H, t,J = 7.1 Hz), 1.49 (9H, s), 1.51 (3H, t, J = 7.2 Hz), 4.26 (2H, q, J = 7.2 Hz), 4.41 (2H,
q, J = 7.1 Hz), 4.89 (2H, dd, J = 6.4,2.0 Hz), 5.93 (1H, dt, J = 11.8,6.4 Hz), 6.73 (1H, bd,
J= 11.8 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.58 (1H, dd, J= 8.8, 2.2 Hz), 8.35 (1H, d, J= 2.2
HZ), 8.49 (1H, s).
Intermediate 9:6-(3-Aminopropyl)-ethvl-5-methvl-4-oxo-1.4-dihvdro-3-
qulnolinecarboxvlic acid trifluoroacetate
a) Diethyl {[4-iodo-3-methyiphenyl)amino]methylidene}propanedioate.
4-lodo-3-methylanlline (5.75 g) was suspended in diethyl ethoxymethylenemalonate (5.5
mL). The mixture was heated at 130°C for 2.5 h. After cooling to ~90*C, hexane was
added and the mixture stirred while cooling to room temperature. The product crystallised
out, and was filtered off, washing well with more hexane. The solid was dried in vacuo to
yield the title compound as a pale grey powder (7.947 g);1H NMR δ (CDCI3) 1.33 (3H, t),
1.38 (3H, t), 2.43 (3H, s), 4.25 (2H, q), 4.3 (2H, q), 6.69 (1H, dd), 7.01 (1H, d), 7.75 (1H,
d), 8.46 (1H, d). and 10.95 (1H, brd).

b) Ethyl 6-iodo-5-methyl-4-oxo-1,4-dlhydro-3-quinolinecarboxylate.
Intermediate 9a (8.73 g) was suspended in Dowtherm (30 mL) then heated at 250oC for 1
h. The mixture cooled, petroleum ether added, and the solid filtered off, washing well with
more petroleum ether. The solid was dried in vacuo to give the title compound and the 7-
methyl isomer as a pale grey powder (7.8 g).
c) Ethyl 1-ethyl-6-iodo-5-methyl-4-oxo-1,4-dlhydro-3-quinolinecarboxylate.
Intermediate 9b (3.57 g) was suspended in DMF (25 mL), potassium carbonate (1.66 g)
and lodoethane (3.2 mL) added, and the mixture heated at 55°C - 60°C for 89 h. More
lodoethane (2x2 mL) being added after 64 and 69 h. The mixture was evaporated,
diluted with water and extracted with ethyl acetate (x 7). The combined organic extracts
were washed with aqueous sodium thiosulphate solution then brine, dried and
evaporated. The residue was purified by chromatography on silica gel (100 g), eluting with
40 -100% ethyl acetate in petroleum ether followed by 5% methanol in dichloromethane,
to give the title compound as a pale brown solid (0.492 g); ESMS m/z 386 [M+H]+.
d) Ethyl 6-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amlno)-1-propyn-1-yl]-1-ethyl-5-
methyl-4-oxo-1,4-dihydro-3-qulnolinecarboxylate.
Using a similar procedure to that described in intermediate 4b, intermediate 9c (0.485 g)
and t-butoxycarbonylpropargylamine (0.332 g) gave the title compound as a yellow solid
(0.62 g); ESMS m/z 413 [M+H]+.
e) Ethyl 6-[3-{[(1,1dimethyiethyl)oxy]carbonyl}amino)propyi]-1-ethyl-5-methyl-4.
oxo-1,4-dihydro-3-quinoilnecarboxylate.
Intermediate 9d (0.52 g) in DCM (30 mL) was treated with 10% Pd/C (0.4 g). The mixture
filtered then hydrogenated over 10% Pd/C (0.4 g) for 1 h. The resultant mixture was
filtered and the solvent evaporated to give the title compound as a yellow foam (0.58 g);
ESMS m/z 417 [M+H]+
f)6-[3-({I(1,1-Dimethylethyl)oxylcarbonyl}amino)propyf]-1-ethyi-5-methyl-4-oxo-1,4-
dlhydro-3-qulnolinecarboxylic acid.
Using a similar procedure to that described in intermediate 6b, intermediate 9e (0.524 g)
was reacted to give the title compound as a cream powder (0.457 g); ESMS m/z 389
[M+H]+.
g) 6-(3-Amlnopropyr)-1-ethyl-5-methyl-4-oxo-1,4-dlhydro-3>quinolinecarboxylic acid
trlfluoroacetate.
Using a similar procedure to that described in intermediate 6c, intermediate 9f (0.453 g)
was reacted to give the title compound as a pale brown powder (0.505 g); ESMS m/z 289
[M+H]+.

Intermediate 10:7-(2-Amino-ethyiamino)-1-ethyl-4-oxo-4-H-quinoline-3-carboxylic
acid
a) 4-Chloro-2-propyipyridine
To a solution of LDA (0.13 motes) in THF/hexanes (40 mL/40 mL) at -60°C under argon
was added a solution of 4-chloro-2-plcoline (15 g) in THF (250 mL) over 20 min. After a
further 30 mln at -60°C iodoethane (10.4 mL) In THF (60 mL) was added over 20 min,
the reaction stirred at -60°C for 1.5 h and then allowed to warm to -30°C. The mixture
was poured into brine and extracted with dichloromethane. After drying (MgS04) and
purification by chromatography elutlng with dichloromethane in petroleum ether (70-100%)
followed by dichloromethane containing methanol (0 to 5%) the title compound was
obtained as a brown oil (12.35 g). 1H NMR δ (CDCI3) 0.97 (3H, t), 1.75 (2H. m), 2.75
(2H, t), 7.12 (1H, m), 7.16 (1H, d), 8.42 (1H, d).
b) [2-(4-Chloro-pyrIdln-2-yl)-1-ethoxy-butyri-malonic acid diethyl ester.
To a solution of LDA (87.5 mmoles) in THF/hexanes (40 mL/40 mL) at-60°C under argon
was added a solution of Example 10a (12.31g) in dry THF (150 mL) over 20 min. After a
further 30 mln at -80°C diethyl ethoxymethylene malonate (18.81 g) in THF (40 mL))
was added over 20 min, the reaction stirred at -60°C for 1.5 h and then allowed to warm
to -30°C. The mixture was poured into brine and extracted with ethyl acetate. After drying
(MgSO4) and purification by chromatography eluting with dichloromethane in petroleum
ether (70-100%) followed by dichloromethane containing methanol (0 to 5%) gave the title
compound as an oil (27.38 g). ESMS m/z 372 [M+H].
c) 7-Chloro-1-ethyl-4-oxo-4-H-quinolizine-3-carboxylic acid ethyl ester.
A solution of intermediate 10b (27.38 g) and DBU (10 drops) in xylene was heated at
reflux. After 16 h the mixture was cooled and purifled by chromatography eluting with
dichloromethane containing methanol (0 to 10%). The resultant yellow/brown solid was
triturated with diethyl ether and filtered to yield the title compound as a yellow solid.
ESMS m/z 280 (M+H).
d) 7-(2-t-Butoxycarbonylamlnoethylamino)-1 -ethyl-4-oxo-4-H-qulnolbine-3-
carboxylic acid ethyl ester.
A solution of intermediate 10c (0.63 g), mono Boc ethylene diamine (0.45 g) and
triethylamlne (0.9 mL) in pyridine (15 mL) was heated at 60 °C for 16 h. After evaporation
the crude product was purified by chromatography eluting with dichloromethane
containing methanol (0 to 5%) to give the title product as a yellow solid (0.37g. ESMS m/z
404 (M+H).
e) 7-{2-t-Butoxycarbonylaminoethylamino)-1 -ethyl-4-oxo-4-H-quInolizine-3-
carboxylic acid.

Using a similar procedure to that described for the preparation of Intermediate 6b,
intermediate 10d (0.334 g) gave the title compound as yellow solid ESMS m/z 376(M+H).
f) 7-(2-AmInoethylamino)-1-ethyl-4-oxo-4-H-qulnolizine-3-carboxylic acid.
Using a similar procedure to that described for the preparation of intermediate 6c
Intermediate 10e ( 0.172 g) gave the title compound as yellow solid. ESMS m/z 276
(M+H).
Intermediate 11: 6-(3-Amlnopropyl)-1-ethyl-4-oxo-1.4-dlhvdro-1.8-naphthvridine-3-
carboxylic acid trifluoroacetate salt
a)EthyI 2-[(2-chloro-5-iodo-3-pyrldinyl)carbonyl]-3-(ethylamino)-2-propenoate.
5-lodo-2-hydroxypyridine-3-carboxylic acid (T. R. Elworthy et a/., J.Med.Chem., 40, 17,
1997,2674-2687) (7.95 g) was suspended in thionyl chloride (40 mL). DMF (4 drops) was
added and the mixture refluxed for 4 h. The resultant solution was evaporated to dryness.
This acid chloride was then dissolved in 1,4-dioxane (40 mL) and added dropwise to a
solution of ethyl 3-(ethylamino)-2-propenoate (5.15 g) and triethyiamine (10.5 mL) in 1,4-
dioxane at 0°C. After 1 h the cooling bath was removed, and the reaction stirred at room
temperature for 16 h. The mixture was then evaporated, saturated sodium hydrogen
carbonate solution added, and extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried and evaporated to give a dark oil. This was purified
by chromatography on silica gel, eluting with 33 - 45% diethyl ether in petroleum ether, to
give the title compound (5.35 g); ESMS m/z 409 [M+H]+.
b) Ethyl 1 -ethyl-6-lodo-4-oxo-1,4-dlhydro-1,8-naphthyridlne-3-carboxylate.
Intermediate 11a (4.92 g) was dissolved in DMF (50 mL), potassium carbonate.(1.662 g)
added, and the mixture heated at 50°C for 16 h and 60oC for 2 h. After evaporation the
mixture was diluted with water and extracted with DCM. The combined organic extracts
were dried and evaporated to give an oil. This was purified by chromatography on silica
gel, eluting with 0 - 20% diethyl ether in DCM, to give the title compound as a pale yellow
solid (4.33 g); ESMS m/z 373 [M+H]+.
c) Ethyl 6-[3-(t-butoxycarbonylamino)-1 -propyn-1 -yl]-1 -ethyl-4-oxo-1,4-dihydro-1,8-
naphthyrldine-3-carboxylate.
A mixture of Intermediate 11b (2.176 g), copper (I) Iodide (115 mg, 0.6 mmol) and
triethylamine (27.9 mL, 200 mmol) were suspended in dry acetonitrile (40 mL). The light
green suspension was heated to 43°C whilst argon was bubbled through. After 30 min,
dlchlorobis(triphenylphosphine)palladium (II) (0.127g, 0.018 mmol) and N-t-
butoxycarbonylpropargylamine (1.542 g) were added and the mixture was heated at
43°C for 25 min. 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 dark solid which was purified by chromatography on silica

gel eluting with 0-25% (methanol/diethyl ether [1:24]) in dichloromethane to yield the title
compound-as a pale yellow solid (1.8 g); ESMS m/z 400 [M+H]+.
d) Ethyl 6-[3-(t-butoxycarbonylamino)-1-propyl]-1-ethyl-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carboxylate.
intermediate 11c (0.91 g)) in dichloromethane (50 mL) was treated with 10% palladium
on carbon (60 mg) and hydrogenated at room temperature and atmospheric pressure for
75 mln. The reaction mixture was filtered and concentrated, and the residue purified by
chromatography on silica gel eluting with 0-4% methanol in dichloromethane to give the
title compound as an off-white solid (0.83 g); ESMS m/z 404 [M+H]+.
e) 6-[3-(t-Butoxycarbonylamino)-1 -propyl]-1 -ethyl-4-oxo-1,4-dlhydro-1,8-
naphthyridine-3-carboxylic acid.
intermediate 11 d (0.825 g) was dissolved in THF (15 mL), 0.2 N sodium hydroxide (15
mL) added, and the reaction stirred for 16 h at room temperature. The mixture was
evaporated to a small volume then solid carbon dioxide added. The precipitate which
formed was filtered off, washed well with water, and dried in vacuo over phosphorous
pentoxide to give the title compound as an off-white powder (0.709 g); ESMS m/z 376
[M+H]+.
f) 6-(3-Aminopropyl)-1 -ethyl-4-oxo-1,4-dlhydro-1,8-naphthyridine-3-carboxylic acid
trifluoroacetate salt.
intermediate 11e (0.72 g) was dissolved in DCM (12 mL), trifluoroacetic acid (4 mL) was
added and the reaction stirred under argon at room temperature for 0.75 h. The solution
was evaporated to dryness, and the residue triturated with diethyl ether to give, after
drying, the title compound as an off-white powder (0.859 g). NMR data: 1H NMR
(DMSO-d6) 1.43 (3H,t), 1.95 (2H, m), 2.84 (2H, m), 2.92 (2H, t), 4.68 (2H, q), 7.78 (3H, br
s), 8.63 (1H, d), 8.95 (1H, d), 9.24 (1H, s) and 14.8 (1H, br s).
Intermediate 12: 9-(3-Amino-propyl)-1-oxo-6.7-dlhvdro-1H,5H-pyrido [3.2.-ij]
qulnoline-2-carboxyllc acid trifluoroacetate salt
a) Diethyl 2-((3,4-dlhydro-2H-qulnolin-1-yl)methylene)malonate.
A mixture of tetrahydroquinoline (13.32g, 100mmol) and diethyl ethoxymethylenemalonate
(21.62g, 100mmol) is heated to 130°C using a Dean-Stark apparatus. After 1 hour the
reaction mixture was concentrated to give the title compound as a brown oil. ESMS m/z
304 (MH+).
b) Ethyl 1-oxo-6,7-dlhydro-1H,5W-pyrldo [3,2,1-ij] qulnoline-2-carboxylate.
Diethyl 2-((3,4-dihydro-2H-qulnolin-1-yl)methylene)malonate (2.5g, 8.24mmol) was
dissolved in polyphosphoric acid and the viscous mixture stirred for 4hours at 110°C. The
reaction mixture was cooled down before adding ice. The resuiting precipitate was filtered

off, washed with water then dried In a dessicator in the presence of phosphorous
pentoxide. togive the title compound as a beige solid. ESMS m/z 258 (MH+). 1H NMF
(DMSO-d6) δ 8.55(s, 1H), 8.05 (dd, 1H), 7.54 (dd, 1H). 7.38 (dd, 1H), 4.27 (q, 2H), 4.Z
(q, 2H), 3.00 (t, 2H), 2.10 (tt, 2H), 1.28 (t, 3H).
c) Ethyl 9-romo-1-oxo-6,7-dlhydro-1H,5H-pyrkido [3,2,1-ij] qulnoline-2-carboxylate.
Ethyl 1-oxo-6,7-dihydro-1H,5W-pyrido [3,2,1-ij] quinoiine-2-carboxyiate (290mg,
1.13mmol) was dissoived in acetic acid (3mL) and bromine (197mg, 1.23mmol) was
added dropwise. The reaction was followed by LC/MS, additional bromine (2 X 197mg)
was added. After 24 hours water was added and the precipitate was filtered off, washed
with diethyl ether then dried in a dessicator in the presence of phosphorous pentoxide to
provide an orange solid which was purifled by chromatography on silica gel eluting with 0-
1.5% (9:1 MeOH/20 M NH3) in dlchloromethane to yield the title compound as a white
solid. ESMS m/z 336/338 (MH+). 1H NMR (CDCI3) δ 8.34(d, 1H), 8.31 (s, 1H), 7.48 (d,
1H), 4.37 (q, 2H), 4.17 (t, 2H), 3.03 (t, 2H), 2.23 (tt, 2H), 1.40 (t, 3H).
d) Ethyl 9-(3-tert-butoxycarbonylamino-prop-1-oxo-6,7-dlhydro-1H,5H-Pyrido
[3,2,1-ij] qulnoline-2-carboxylate.
A yellow suspension of palladium acetate (73mg, 0.32 mmol) and triphenylphosphine
(191mg, 0.72mmol) in dry tetrahydrofuran (6ml) under argon was cooled to 0°C. A
solution of n-butyllithium (2.5M in hexanes, 284uL) was added dropwise and after 15
minutes the dark green suspension is warmed to room temperature for 15 minutes. This
suspension is then cannulated under argon into a white suspension of ethyl 9-bromo-1-
oxo-6,7-dlhydro-1H,5W-pyrido [3,2,1-ij] quinoline-2-carboxylate (337mg, 1mmol), copper
Iodide (84mg, 0.44mmol) and t-butoxycarbonylpropargylamine (198mg, 1.28 mmol) in
diethylamine (6mL). The brown suspension is warmed to 45°C for 2 hours then filtered
off and preabsorbed on silica gel. Chromatography on silica gel elutlng with 0-5% (9:1
MeOH/20 M NH3) in dlchloromethane provided the title compound as a brown oil. ESMS
m/z 411 (MH+). 1H NMR (CDCI3) δ 8.23(s, 1H), 8.12 (d, 1H). 7.29 (d, 1H). 5.1 (m, 1H),
4.35 (q, 2H), 4.15 (m, 2x2H), 2.97 (t, 2H), 2.19 (tt, 2H), 1.49 (s, 9H), 1.38 (t, 3H).
e) Ethyl 9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7dlhydro-1/y,5H-pyrido
[3,2,1-ij] qulnollne-2-carboxytate.
Ethyl 9-(3-fert-butoxycarbonylamin--prop-1-ynyl)-1-oxo-6,7-dlhydro- 1H,5H-pyri [3,2,1-ij]
qulnoline-2-carboxylate (318 mg, 0.77 mmol) was dissolved In dlchloromethane (50 mL),
treated with 10% palladiun on carbon (200 mg) and hydrogenated at room temperature
and atmospheric pressure overnight The reaction mixture was filtered and concentrated
to provide a brown oil which was purified by chromatography on silica gel elutlng with 0-
1% (9:1 MeOH/20 M NH3) in dlchloromethane to yield the title compound as a brown oil.
ESMS m/z 415 (MH+). 1H NMR (CDCI3) δ 8.34 (s, 1H), 8.11 (bs, 1H), 7.25 (bs, 1H), 4.60
(m, 1H), 4.37 (q, 2H), 4.17 (t, 2H), 3.13 (q, 2H), 3.02 (t, 2H). 2.71 (t,2H). 2.20 (tt, 2H).
1.85 (tt, 2H), 1.44 (s, 9H), 1.40 (t, 3H).

f) 9-(3-tert-butoxycarbonylamino-propyl)-1 -oxo-6,7-dihydro-1 H,5H-pyrido [3,2,1 -ij]
qulnoline-2-carboxylic acid sodium salt.
Ethyl 9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrldo [3,2,1-ij]
qulnollne-2-carboxylate (240 mg, 0.59 mmol) was dissolved in tetrahydrofuran (3 mL) and
treated with 2N aqueous sodium hydroxide (0.32 mL). The solution was heated to 50°C
overnight then treated with excess solid carbon dioxide. Evaporation of the solvent gave
the title compound as a beige solid. ESMS m/z 387 (MH+). NMR (DMSO-d6) δ 8.83 (s,
1H), 8.11 (bs, 1H), 7.99 (s, 1H), 7.57 (s, 1H), 6.89 (bt, 1H), 4.41 (bt 2H), 3.04'(t, 2H), 2.94
(q, 2H), 2.71 (t,2H), 2.13 (m, 2H), 1.74 (m, 2H), 1.37 (s, 9H).
g) 9-(3-Amlno-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido [3,2,1-ij] quinoline-2-
carboxylic acid trifluoroacetate salt
9-(3-terf-Butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido [3,2,1-ij]
quinoline-2-carboxylic acid sodium salt (224 mg, 0.58 mmol) was dissolved in
trifluoroacetic acid (3 mL). After 0.5 h at room temperature the reaction mixture was
concentrated to provide the title compound as a beige solid. ESMS m/z 287 (MH+).
NMR (MeOD-d4) δ 8.83 (s, 1H), 8.15 (d, 1H), 7.62 (d, 1H), 4.43 (t, 2H), 3.14 (t, 2H), 2.98
(t, 2H), 2.89 (t,2H), 2.66 (tt, 2H), 2.05 (tt, 2H).
Intermediate 13:4"-0-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1.4-dihvdro-quinoiin-6-
yisulfanyl)-ethylamino]-propyl}-6-0-methyl-11 -desoxy-11 -(R)-amino-erythromycin A
11.12-carbamate formate
The title compound was prepared from intermediate 3 by the procedure described below
(see Table following Example 26).
Intermediate 14: 4"-O-AIlyl-2'-O-acetvlazithromvcin-11.12-cvclic carbonate
To a solution of 2'-0-acetyl azithromycin-11,12-carbonate (0.408 g, 0.5 mmoL) in dry THF
(4 mL) under an atmosphere of nitrogen, was added tetraklstriphenylphosphine palladium
(0.057 g, 0.05 mmol) and allyl t-butyl carbonate (0.30 g, 1.9 mmoL). The resulting mixture
was stirred under reflux. After 18 h of reflux TLC indicated 50% conversion of the desired
product. The solvent was evaporated and the crude product dissolved in 4 mL of
methanol. The mixture was stirred overnight at room temperature and then concentrated
under reduced pressure. The crude product was purified by flash chromatography over
silica gel eluting with 90:9:0.5; dichloromethane/MeOH/aq. NH3 to yield 0.24 g (56%) of a
pale yellow crystals. MS (m/z) 815 (MH*).
Intermediate 15: 4"-(2-Oxo-ethoxy)-azithromvcin 11.12-cvclic carbonate
To a solution of intermediate 14 (0.20g, 0.23 mmoL) in THF (1ml) and water (1ml), was

added osmium tetraoxide (2.0 mL of a 2.5% solution in THF). After stirring for 5 minutes,
sodium periodate (0.213 g, 1 mmoL) was added in one portion. The mixture was
vigorously stirred for 12h at 25°C before being quenched with saturated aqueous Na2S03
(10mL). The resulting solution was stirred at 25°C for 2 h and then partitioned between
EtOAc (22 mL) and water (5.0 mL). The organic phase was separated and the aqueous
phase was extracted with EtOAc (2x10 mL). The combined organic extracts were dried
(K2CO3) and the solvents were removed under reduced pressure. Flash column
chromatography (silica gel, 90:9:0.5; dichloromethane/MeOH/aq. NH3) provided the
corresponding aldehyde as a bright yellow solid (ca. 160 mg; 81% yield). MS (m/z) 817
(MH+).
Intermediate 16: 4"-(3-Carboxv-propoxy)-azithromvcin
a) 4"-(3-Methoxycarbonyl-aliyloxy)-azithromycin 11,12-cycllc carbonate.
A mixture of Intermediate 15 (587.6 mg, 0.719 mmoL) and methoxycarbonylmethylene
triphenyl phosphorane (360 mg, 1.08 mmoL, 1.5 mol equiv.) in benzene (7.2 mL) was
heated at reflux for 18 h. After cooling to 25°C the solvent was removed under reduced
pressure. Flash column chromatography (silica gel, 90:9:0.5 Ch2CI2:MeOH: aq. NH3)
furnished unsaturated methyl ester 313,8 mg, 50%) as a mixture of Z and E isomers in
1:1 ratio according LC/MS analysis. MS (m/z) 873 (MH+).
b) 4"-(3-Methoxycarbonyl-propoxy)-azithromycin 11,12-cyclic carbonate.
The mixture of intermediate 16a from above (200 mg, 0.23 mmoL) was dissolved in
MeOH (5 mL), treated with Pd/C (50 mg, 10 wt% Pd) and catalytically hydrogenated in
Parr apparatus for 5 h. After filtration through a Celite pad, the filtrate was concentrated in
vacuo and the residue purified by column chromatography (eluting with 90:9:0.5;
dichloromethane/MeOH/aq. NH3) to give 125 mg (62%) of pure ester as a colourless
crystalline solid. MS (m/z) 875 (MH+).
c) 4"-(3-Carboxy-propoxy)-azithromycin.
To a solution of intermediate 16b (875 mg, 1.0 mmoL) in 1:1 THF-water (10.0 mL) at
room temperature, was added LIOH (192 mg, 4.57 mmoL), and the resulting reaction
mixture was stirred at the same temperature for 12h. The solvent was removed under
reduced pressure, and the solid was azeotroped with benzene (5 mL x 5) and finally dried
under vacuum. The acid salt was dissolved in water and the resulting solution was made
acidic by dropwise addition of 2M aqueous HCI. The precipitate was filtered of to give 787
mg (90%) of pure title compound. MS (m/z) 835 (MH+).
Intermediate 17: 1 -Ethyl-4-oxo-6-plperazin-1 -yl-1.4-dihvdro-quinoline-3-carboxylic
acid
a) 6-(4-tert-Butoxycarbonyl-plperezin-1-yl)-1-ethyl-4-oxo-1,4-dihydro-qulnoline-3-

carboxylic acid ethyl ester.
An oven-dried Pyrex flask was charged with sodium tert-butoxide (134.5 mg, 1.4 mmoL),
Pd2(dba)3 (2.3-9.2 mg, 0.0025-0.01 mmoL) and BINAP (47-18.7 mg, 0.0075-0.03
mmoL). The Pyrex tube was fitted with a septum, and the air atmosphere was replaced
with argon, dry THF (2-9 mL), 6-iodo-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
ethyl ester (371.2 mg, 1.0 mmoL), and N-Boc-piperazine (223.5 mg, 1.2 mmoL) were
added by syringe. The reaction was heated to 80°C with stirring until the starting material
was consumed as judged by LC-MS analysis. The reaction mixture was cooled to room
temperature, diluted with ether (15 mL), filtered, and concentrated. The crude reaction
mixture was then purifled further by flash chromatography on silica gel to give 356.5 mg
(83%) of the title compound as a pale yelow solid. MS (m/z) 430 (MH+).
b) 1-Ethyl-4-oxo-6-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester.
A solution of intermediate 17a (429.5 mg, 1.0 mmoL) in 10 mL of CH2CI2 and
trifluoroacetic acid (1:1) was stirred at 0°C for 5 hours. The volatile materials were
evaporated under reduced pressure, and the residue was triturated with diethylether and
filtered. The resulting product (354.7 mg, 80%) was used without further purification in the
next step. MS (m/z) 330 (MH+).
c) 1-Ethyl-4-oxo-6-plperazln-1-yl-1,4-dihydro-quinoline-3-carboxylic acid.
intermediate 17b was dissolved in a mixture of THF, water and 5 eq of NaOH and stirred
at 80 °C until TLC showed a complete conversion to the title compound. MS (m/z) 302
(MH+).
Example 1: 4"-O-(2-{(2-(3-Carboxy-1 -cyclopropyl-6-fluoro-4-oxo-1 t4-dihydro-
qulnolin-7-vlamino)-ethyl]-methylamlno}-ethyn-6-0-methyl-erythromycin A 11.12-
carbonate bis trifluor oacetate

a)2'-Ol3'-N-bis(Benzyloxycarbonyl)-3'-N-desmethyl-6-O-methyl-erythromycin A.
To a stirred mixture of 6-O-methyl-erythromycin A (20 g, 26.8 mmol) and sodium
hydrogen carbonate (30 g) cooled in an ice bath was added portionwise benzyl
chloroformate (60 mL). After 10 min the ice bath was removed and the mixture was stirred

for 15 min. The reaction was then heated at 60-70°C for 1 h. After cooling, the reaction
mixture was loaded onto a silica gel column (150 g) and eluted with a gradient of 10-50%
ethyl acetate in hexane. Evaporation of the product containing fractions gave the title
product as a white solid foam (20.22 g); ESMS m/z 1024 [M+Na]+, 1060
[M+NH4+acetonitrile]+.
b) 4"-0-Allyloxycarbonyl-2'-0,3,-N-bis(benzyioxycarbonyl)-3,-N-desmethyl-6-0-
methyl-erythromycin A 11,12-carbonate.
Example 1a (13 g, 12.97 mmol) in dichloromethane (50 mL) at 0°C under argon was
added pyridine (11.5 mL) and a solution of phosgene in toluene (20%, 30 mL). After 30
min the mixture was allowed to warm to 20°C. After 2.5 h the reaction was recooled to 0°C
and allyl alcohol (5 mL) was added dropwise. After stirring at 0°C for 15 min and 20°C for
30 min the mixture was poured onto ice. Extraction with diethyl ether and washing with
water, 5% aq citric acid, and saturated aq sodium hydrogen carbonate gave a crude
product solution which was dried, evaporated and purified by chromatography (silica gel,
20-50% ethyl acetate in hexane) to give the title product as a white solid foam (12.5 g);
ESMS m/z 1129 [M+NH4]+, 1134 [M+Na]+, 1170 [M+NH4+acetonitrile]+.
c) 40'-O-Allyl-2'-O,3'-A/-bls(benzyloxycarbonyI)-3'-N-desmethyl-6-O-methyl-
erythromycin A 11,12-carbonate.
Example 1b (7.9 g, 7.1 mmol) in tetrahydrofuran (50 mL) was treated with
tetrakis(triphenylphosphine) palladium (0.16 g). The reaction was heated to reflux for 30
min after which time methyl allyl carbonate (1.7 mL) was added. After a further 1.75 h
reflux, the reaction was cooled and evaporated to dryness. The residue was purified by
chromatography (silica gel, 0-30% ethyl acetate in dichloromethane) to give the title
product as a white solid foam (3.93 g); ESMS m/z 1085 [M+NH4]+, 1090 [M+Na]+, 1126
[M+NH4+acetonitrile]+.
d) 2'-O, 3'-N-bis(Benzyloxycarbonyl)-4"-O-{2-[2-(3-Carboxy-1 -cyclopropyl-6-fluoro-4-
oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-6-0-methyl-3'-N-desmethyl-
erythromycln A 11,12-carbonate.
To Example 1c (0.256 g, 0.25 mmol) in tetrahydrofuran (1 mL) and water (1 mL) under
argon was added osmium tetroxlde (4% in water, 0.015 mL). After 5 min sodium periodate
(0.213 g, 1 mmol) was added. After 2.5 h the mixture was diluted with diethyl ether and
water. The organic phase was washed with saturated aq. sodium thiosulphate, dried, and
evaporated to dryness to give the crude aldehyde as a white solid foam (0.255 g). This
material (0.094 g) in methanol (1.5 mL) and dimethylformamide (1.5 mL/was treated with
acetic acid (0.15 mL), 7-(2-amlnoethylamino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-
qulnoline-3-carboxylic acid (Yoshida et al, J. Pharm. Soc. Japan, 1990, 110, 258) (0.031
g, 0.1 mmol) and sodium cyanoborohydride (0.013 g, 0.2 mmol). After 3 h the reaction
was evaporated to dryness, and the residue purified by chromatography (silica gel, 0-10%

2 M methanolic ammonia in dichioromethane) to give the title product as a white solid
foam (0.066g); ESMS m/z 1359 [M+H]+.
e) 4"-O-(2-{[2-{3-Carboxy-1 -cyciopropyl-6-fiuoro-4-oxo-1,4-dihydro-quinolin-7-
ylamlno)-ethyl]-methylamino}-ethyl)-6-0-methyl-erythromycin A 11,12-carbonate
blstrifluoroacetate.
Example 1d (0.066 g) in ethanol (20 mL) and dioxan (10 mL) was hydrogenated at 50 psi
over paliadium hydroxide (20% on carbon, 0.080 g) for 72 h. The catalyst was removed by
filtration, washed well with dioxan and ethanol, and the combined filtrates evaporated to
dryness. The residue was taken up in ethanol (20 mL) and dioxan (10 mL), and 28% aq
formaldehyde (2 mL), 0.7min pH 4.5 acetate buffer (2 mL) and palladium hydroxide (20%
on carbon, 0.080 g) added. The mixture was hydrogenated at 50 psi for a further 5 days,
then the catalyst was removed by filtration, washed well with dioxan and ethanol, and the
combined filtrates evaporated to dryness. The residue was purified by chromatography
(silica gel, 5-10% methanol in dichloromethane then 10-20% 2 M methanolic ammonia in
dichloromethane). Later fractions contained impure title product. Early eluted fractions
contained 3'-/V-benzyloxycarbonyl-4'-0-(2-{[2-(3-carbbxy-1-cyclopropyl-6-fluoro-4-oxo-
1,4-dihydro-quinolin-7-ylamino)-ethy]-methylamino}-ethyl)-6-0-methyl-3'-N-desmethyl-
erythromycin A 11,12-carbonate, (0.01 g) which was dissolved in ethanol (10 mL) and
dioxan (5 mL) and hydrogenated at 50 psl over palladium (10% on carbon, 0.1 g). After 3
h 28% aq. formaldehyde (1.5 mL), 0.7M pH 4.5 acetate buffer (2.5 mL) was added and
the hydrogenation continued for 24 h. After filtration and evaporation, the residue was
purified by chromatography (silica gel, 2-15% 2M methanolic ammonia in
dichloromethane) giving impure product. Both batches of impure title product were
purified by preparative HPLC (acetonitrlle/water/0.1% trifluoroacetic acid eluent) to give
the title compound as a gum (0.004 g); ESMS m/z 1119 [M+H]+,
Example 2: 4"-0-(3-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1.4-dihvdro-
aulnolin-7-vlamlno)ethyl]-methvlamino)-propyl)-6-O-methyl-erythromvcin A 11.12-
carbonate

a) 2'-O,3'-N-bis(BenzyloxycarbonyI)-4"-O-(3-hydroxypropyl)-3'-N-desmethyl-6-O-
methyl-erythromycin A 11,12-carbonate.
Example 1c (0.97 g, 0.908mmol) in tetrahydrofuran (6 mL) was treated with 9-BBN (0.5M
in tetrahydrofuran, 3.6 mL). After 1.5h the reaction was cooled to 0°C and sodium
hydroxide (2 M, 1.5 mL) and hydrogen peroxide (27% in water, 2.1 mL) were added. After
5 min the cooling bath was removed and the reaction stirred for 15 m, then diluted with
diethyl ether and water, the organic phase was washed with water and brine, dried
(MgSO4), and evaporated to dryness. The residue was purified by chromatography (sllica
gel, 0-50% ethyl acetate in dichloromethane) to give the title product as a white solid foam
(0.80 g, 76%); ESMS m/z 1103 [M+NH4]+, 1108 [M+Na]+.
b) 2'-0,3'-N-bis(Benzyloxycarbonyl)-4"-0-{3-[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-
oxo-1,4-dlhydro-quinolin-7-ylamino)-ethylamino]-propyl}]-6-0-methyl-3'-N- .
desmethyl-erythromycin A 11,12-carbonate trifluoroacetate.
To Example 2a (0.411 g, 0.378 mmol) in dichloromethane (6 mL) at 0°C under argon was
added Dess-Martin periodlnane (0.176 g, 0.41 mmol). After 1.5 h, the cooling bath was
removed and the reaction stirred for a further 30 min then diluted with dichloromethane,
washed with saturated aq sodium hydrogen carbonate, dried (MgSO4), and evaporated to
dryness to give the title product as a white solid foam (0.42 g). This material (0.169 g) in
methanol (2 mL) and dimethylforrnarnlde (2 mL) was treated with acetic acid (0.2 mL), 7-
(2-aminoethylamino)-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
(0.048 g, 0.16 mmol) and sodium cyanoborohydride (0.02 g, 0.32 mmol). After 1.5 h the
reaction was evaporated to dryness, and the residue purified by preparative HPLC
(acetonitrile/water/0.1% trlfluoroacetic acid eluent) to give the title product (0.10 g); ESMS
m/z 1373 [M+H]+.
c) 4"-O-(3-{[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-
ylamIno)-ethyl]-methyiamino}-propyl)-6-0-methyl-erythromycin A11,12-carbonate.
Example 2b (0.1 g) in ethanol (20 mL) and dioxan (10 mL) was hydrogenated at 50 psi
over palladium (10% on carbon, 0.050 g) for 7 h. 28% aq. Formaldehyde (2.5 mL), 0.7 M
pH 4.5 acetate buffer (5 mL) was added and the hydrogenation continued for 24 h. After
filtration and evaporation, dichloromethane (10 mL) and methanol (2 mL) were added to
the residue and insoluble material removed by filtration. The soluble material was passed
down a silica gel column eluting with 2-15% 2 M methanolic ammonia in dichloromethane.
The fractions containing the title material were dissolved in ethanol (10 mL), 28% aq.
formaldehyde (1 mL) and 0.7 M pH 4.5 acetate buffer (2 mL) and the mixture
hydrogenated at 50 psi over palladium (10% on carbon, 0.1 g) for 30 h. the catalyst was
removed by filtration and the residue evaporated to dryness. Dichloromethane (10 mL)
and methanol (2 mL) were added to the residue and insoluble material removed by
filtration. The soluble material was passed down a silica gel column eluting with 2-15% 2
M methanolic ammonia in dichloromethane to give the title product, as a gum (0.012 g);
1H NMR (CD3OD) (inter alia) 1.8 (2H. m), 2.4 (3H, s), 2.6 (2H, m), 2.8 (2H, m), 3.5 (2H,

m), 3.7 (2H, m), 4.55 (1H, d), 4.65 (1H, s), 4.85 (1H, d), 5.0 (1H, dd), 7.2 (1H, d), 7.8 (1H,
d), 8.7 (1H,s); ESMS m/z 1133 [M+H]+.
Example 3: 4'-O-{3-[2-(3-Carboxy-1-ethyl-4-oxo-1.4 ethylamino]-proyl}-6-0-methyl-erythromycin A 11.12-carbonate bls triftuoroaeatate

a) 4"-0-(3-Hydroxypropyl)-6-0-methyl-erythromycin A11,12-carbonate.
Example 2a (2.57 g, 2.37 mmol) in ethanol (25 mL) and dioxan (25 mL) was
hydrogenated at 50 psi over pailadium (10% on carbon, 0.2 g) for 26 h. The catalyst was
removed by filtration and the soluble material taken up in ethanol (50 mL), pH 4.5 buffer (4
mL) and 37% aq formaldehyde solution (4 mL) were added and the mixture hydrogenated
at 50 psi over palladium (10% on carbon, 0.5 g). After 18 h, the reaction mixture was
filtered, and the catalyst washed well with ethanol and dloxan. The combined filtrates were
purified by chromatography on silica gel eluting with 0-10% 2 M methanolic ammonia in
dlchloromethane to give the title product as a white foam (1.21 g); ESMS m/z 832 [M+H]+.
b) 4"-0-{3-[2-{3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yloxy)-ethylamino]-
propyl}-6-O-methyl-erythromycin A11,12-carbonate bis trlfluoroacetate.
To Example 3a (0.099 g, 0.119 mmol) in dichloromethane (2 mL) at 0°C under argon was
added Dess-Martin periodinane (0.176 g, 0.41 mmol). After 15 min the reaction was
allowed to warm to 20°C. After a total reaction time of 100 min the rectlon mixture was
diluted with dichloromethane, washed with saturated, aq sodium hydrogen carbonate,
dried, and evaporated to dryness to give the crude aldehyde as a white solid foam. This
material in DMF (1 mL) and methanol (1 mL) was treated with acetic acid (0.1 mL),
intermediate 2 (0.038 g, 0.12 mmol), sodium acetate (0.01 g) and sodium
cyanoborohydride (0.015 g, 0.24 mmol). After 14 h the reaction was evaporated to
dryness, and the residue partially purified by chromatography on silica gel eluting with 5-
20% 2 M methanolic ammonia in dichloromethane followed by preparative HPLC
(acetonitrile/water/0.1% trifluoroacetic acid eluent) to give the title product (0.013 g);
ESMS m/z 1090 [M+H]+.

Example 4: 4'-O{3-[2-(3-Carboxy-1-ethyl-4-dihydro-qulnolin-6-visulfanyl)-
ethylamino)-propyl}-6-O-methyl-erythromycin A 11.12-carbonate bisformate

To Example 3a (0.125 g, 0.119 mmol) in dichlorornethane (2.5 mL) under argon was
added Dess-Martin pertodinane (0.095 g, 0.22 mmol). After 3.5 h, the reaction mixture
was dlluted with dlchlorornethane, washed with saturated aq sodium hydrogen carbonate,
dried, and evaporated to dryness to give the crude aldehyde as a white solid foam. This
material was dissolved in dlmethylformamlde (1.5 mL) and methanol (1.5 mL) and treated
with acetic acid (0.3 mL), Intermediate 3 (0.081 g, 0.2 mmol) sodium acetate (0.024 g)
and sodium cyanoborohydride (0.015 g). After 3 h the reaction was evaporated to
dryness, and the residue purified by preparative HPLC (acetonitrlle/water/0.1% formic acid
eluent) to give the title product (0.024 g); 1H NMR δ (CDCI3) (inter alia) 1.6 (3H, t), 2.0
(2H, m), 3.05 (2H, m). 3.65 (1H, m). 3.85 (1H, m), 4.4 (2H, q), 4.55(1 H, d), 4.6 (1H, s),
4.85 (1H, d), 5.0 (1H, dd), 7.65 (1H, d), 7.85 (1H, d), 8.35 (2H, s), 8.4 (1H, s); ESMS m/z
1106[M+H]+.
Example 5: 4'-O{3-[3-(3-Caoxy.1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-
a) 4"-O-(1-imdazo-1-yl-carbonyl)-6-O-methyl-erythromycin A,
propylamino]propyl}-6-O-methyl-erythrormycin A blsformate

6-O-MethyI-erythromycin A (30 g, 40.1 mmol) in tetrahydrofuran (100 mL) was treated
portionwise with carbonyidiimldazole (16 g, 97 mmol) with ice bath cooling. After 1 h the
cooling bath was removed. After a futher 48 h, tetrahydrofuran (100 mL) and water (200
mL) were added slowly precipitating the title compound, which was collected by filtration
and dried to give the title compound (24.7 g). Extraction of the mother liquors with diethyl
ether gave further material (8.5 g) which was precipitated from tetrahydrofuran solution
with water to give a further portion of the title compound (3.92 g, total of 28.64 g); ESMS
m/z842[M+H]+.
b) 4n-0-(AIIyloxycarbonyl)-6-0-methyl-erythromycin A.
Example 5a (28.64 g, 34 mmol) in dichloromethana (100 mL) was cooled to 0°C and
treated with allyl alcohol (13.6 mL) and DBU (5.23 mL). The reaction was stirred at 0°C for
2.5 h and at 20°C for 1.75 h. The reaction mixture was quenched with 3% aq citric acid
(100 mL), the phases separated, and the organic phase washed with sat sodium
hydrogen carbonate and brine. After drying and evaporation to dryness, the residue was
triturated with petroleum ether (bp 40-60 °C) to give the title compound as a solid (25.08
g); ESMS m/z 832 [M+H]+.
c) 4"-O-(AIIyloxycarbonyl)-9-dihydro-9-methoxy-2',11 -bis-O-trlmethylsilyl-6-O-
methyt-9,12-anhydro-erythromycin A.

Example 5b (22.29 g, 25.6 mmol) in pyridine (100 mL) was treated with
chlorotrimethyisilane (26 mL). The reaction was stirred at 20°C for 6 h and left at 4°C for
16 h. The reaction mixture was evaporated to dryness under reduced pressure and the
residue taken up in methanol (100 mL) After 80 min at 20°C, the solvent was removed by
evaporation under reduced pressure and the residue taken up in ethyl acetate and water,
the phases were separated, the organic layer dried, and evaporated to dryness under
reduced pressure. Toluene (two 500 mL portions) were added and evaporated under
reduced pressure to give the crude title compound as a white foam (26.27 g). This
material (5.8 g) was purified by chromatography on silica gel eluting with 0-3% 2 M
methanolic ammonia in dichloromethana to give the title compound as a white foam (3.0
g); ESMS m/z 990 [M+H]+.

d) 4"-O-Allyl-9-dihydro-9-nethoxy-2',11-bls-O-trimethyisllyl-6-O-methyl-0,12.
anhydro-erythromycin A.
Example 5c (3.0 g, 3.03 mmol) in tetrahydrofuran (20 mL) was treated with tetrakis
triphenyiphosphine palladium (0.1 g) at reflux under argon. After 35 min, t-buty) ailyl
carbonate (F. Houlihan et al, Can. J. Chew. 1985, 63, 153; 1.2 mL) and
tetrakis(triphenyiphosphine) palladium (0.1 g) were added and the reflux continued for a
further 1 h. The reaction was cooled and evaporated to dryness under reduced pressure,
and the residue purified by chromatography on sillca gel eluting with 0-5% 2 M methanolic
ammonia in dichloromethane to give the title product, 1.07 g, as a white foam; ESMS m/z
946 [M+H]+.
e) 9-Dihydro-4' -O-(3-hydroxypropyl)-9-methoxy-2;11 -bis-O-trimethyisllyi-6-O-
methyl-9,12-anhydro-erythromycin A.
Example 5d (0.255 g, 0.27 mmol) in tetrahydrofuran (4 mL) under argon was treated with
9-BBN (0.5 M in tetrahydrofuran, 1.6 mL). After 30 mln, the reaction was cooled to 0°C
and a precooled mixture of sodium hydroxide (2 M, 0.5 mL) and hydrogen peroxide (27%
in water, 0.68 mL) were added. This was stirred at 0°C for 10 min before addition of cold
diethyl ether and water. The phases were separated and the organic phase washed with
water and brine. After drying and evaporation under reduced pressure the residue was
purified by chromatography on silica gel eiuting with 0-10% 2 M methanolic ammonia In
dichloromethane to give the title product as a white foam (0.16 g); ESMS m/z 964 [M+H]+.
f) 4"-O-{3-{3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyiamino]-
propyl}-6-O-methyl-erythromycin A blsformate.
To Example 5e (0.16 g, 0.166 mmol) in dichloromethane (5 mL) under argon was added
Dess-Marttn periodinane (0.085 g, 0.2 mmol). After 1 h, the rection mixture was diluted
with dichloromethane, washed with sat aq sodium hydrogen carbonate, dried, and
evaporated to dryness to give the crude aldehyde as a gum. This material was dissolved
in methanol (2.5 mL) and dichloromethane (2.5 mL) and treated with acetic add (0.25
mL), sodium acetate (0.028 g), 3A molecular sieves (0.3 g), intermediate 4 (0.0625g,
0.16 mmol) and sodium cyanoborohydride (0.030 g). After 2 h the reaction was
evaporated to dryness, and toluene (5 mL) added and evaporated. The residue was
purified by preparative HPLC (aoetonitrlle/water/0.1% formlc acid eluent) and the fractions
allowed to stand at 20°C for 1 h which resulted in loss of protection. A further preparative
HPLC (acetonitrfle/water/0.1% formic add eluent) purification gave the title product (0.034
g); ESMS m/z 1062 [M+HJ+
Example 6: 4"-O-{3-[2-(2-Carfaoxy-1-oxo-6,dihydro-1H,5H-Pyrld[3,2,1-/ij]quinoline-
9-yioxy)-ethylamino]-propyl}-6-O-methyl-erythromycin A 11.12-carbonate
blsformate

To Example 3a (0.25 g, 0.33 mrnol) in dichloromethane (5 mL) under argon was added
Dess-Martin periodinane (0.14 g, 0.33 mmol). After 2 h, more Dess-Martin periodinane
(0.03 g) was added and the reaction stirred for a further 1.5 h. The reaction mixture was
diluted with dichloromethane, washed with saturated, aq sodium hydrogen carbonate,
dried, and evaporated to dryness to give the crude aldehyde as a white solid foam. This
material (0.042 g, 0.05 mmol) in methanol / DCM (1:1, 2 mL) was added to sodium
acetate (0.008 g, 0.1 mmol), acetic acid (0.1 mL), Intermediate 5 (0.02 g, 80% pure, 0.05
mmol), and 3A molecular sieves (0.1 g). The mixture was stirred for 15 min then a solution
of sodium cyanoborohydride (0.0063 g, 0.1 mmol) in methanol (0.2 mL) was added and
stirring continued for 3 h. The reaction was then filtered, washing well with methanol, and
the filtrate evaporated. The residue was purified by preparative reverse phase HPLC
(MeCN/H2O/0.1%HCO2H eluent) to give the title compound as a pale yellow solid (0.031
g);ESMSm/z 1102[M+H]+.
Example 7: 4"-O-{3-[2-(3-Carboxy-1 -ethyl-4-oxo-1.4-dihydro-quinolin-6-yl)-
propylamino1-propvl}-6-O-methyl-11 -desoxy-11 -(R)-methvlamino-ervthromycin A
11.12-carbamate formate

a) 2'-O-Acetyl-4"-O-allyl-6-O-methyl-11-desoxy-11-(R)-methylamIno-erythromycin A
11,12-carbamate.
intermediate 7 (0.315 g, 0.38 mmol), t-butyl allyl carbonate (0.079 g, 0.5 mmol) and
tetrakis(triphenylphosphine) palladium (0.035 g, 0.03 mmol) in THF (10 mL) were refluxed
for 4 h. More t-butyl allyl carbonate (0.079 g, 0.5 mmol) was added and refluxing

continued for a further 2 h. More t-butyl allyl carbonate (0.04 g, 0.25 mmol) was added
and refluxing continued for a further 1.5 h. The mixture was then evaporated to dryness
and the residue purified by chromatography on sillca get (40 g). Button with 0-4.5% 2 M
methanolic ammonia in dichloromethane, gave the tittle compound (0.294 g); ESMS m/z
869 [M+H]+.
b) 4"-O-Allyt-6-O-methyt-11 carbamate.
Example 7a (0.27 g, 0.31 mmol) in methanol (10 mL) was heated at 60°C for 8.5 h, 45°C
for 15 h, and 60°C for 3 h. The mixture was then evaporated to dryness to give the title
compound as a white solid (0.244 g); ESMS m/z 827 [M+H]+.
c) r-O,3'-N-bis(Benzvk>xycarbonyl)-3'-N-desmethyl-4"-O-allyl-6-O-methyl-11 -
desoxy-11-(R)-methylamino-erythromycin A 11,12-carbamate.
Example 7b (0.24 g, 0.29 mmol) and sodium hydrogen carbonate (0.4 g) in benzyl
chloroformate (2 mL) were heated at 60°C for 3 h. After cooling the mixture was purifled
by chromatography on silica gel (50 g). Button with 0-50% ethyl acetate in petroleum
ether gave the title compound as a white solid (0.272 g); ESMS m/z 1098 [M+NH4]+.
djr-O.S'-W^lstBenzyloxycariwnyO-a'^-dMniethyi^-O^a-hydroxypfopyiJ-e^
m^yl-11-desoxy-11-(R)-methytamlno-erythromycln A 11,12-carbamate.
Example 7c (0.27 g, 0.25 mmol) in THF (8 mL) was treated with 9-
borablcycto[3.3.1lnonane (0.5 M in THF, 1.5 mL, 0.75 mmol). After 4 h more 9-
borabicyck>{3.3.1)nonane (0.5 M In THF, 0.5 mL, 0.25 mmol) was added. Further 1 h then
more 9-borablcyck>[3.3.1]nonane (0.5 M In THF, 1 mL, 0.5 mmol) was added. After 1 h
more the solution was cooled In an Ice bath then pre-mixed hydrogen peroxide (30% aq,
1.7 mL, 15 mmol) In sodium hydroxide (2 N, 2.5 mL, 5 mmol) was added. The cooling
bath was removed and the mixture stirred for 0.5 h. The reaction was diluted with water
and extracted with ethyl acetate (x3). The combined organic extracts were washed with
brine, dried, and evaporated to give the crude product This was purified by
chromatography on silica gel (40 g), elutJng with 30-80% ethyl acetate In petroleum ether,
to give the title compound as a white solid (0.139 g); ESMS m/z 1116 (M+NH4]+.
e) 4"-O-{3-Hydroxypropyl)-6-O-methyl-11-desoxy-11 -(R)-methyIamino-erythromycin
A 11,12-carbamate.
Example 7d (0.137 g, 0.125 mmol) was dissolved In ethanol (4 mL) and 1,4-dioxane (8
mL), and hydrogenated over 10% palladium on charcoal (50% aq paste, 0.06 g) for 6.5h.
Formaldehyde (37% aq, 0.3 mL), pH 4.5 acetate buffer (0.3 mL) and more catalyst (0.05
g) were then added, and the mixture hydrogenated for 16 h. The mixture was then filtered,
washing well with ethanol and 1,4-dloxane. The filtrate was evaporated, and the residue
purified by chromatography on sillca gel (5 g). Elution with 0-6% 2 M methanollc ammonia

in dichloromethane, gave the title compound as a white foam (0.083 g); ESMS m/z 845
[M+H]+.
f) 4"-O-(3-Oxpropyl)-6-O-methyl-11-desoxy-11-(R)-methylamino-erythromycin A
11,12-carbamate.
To Example 7e (0.082 g, 0.097 mmol) in DCM (3 mL) was added Dess-Martin
periodinane (0.047 g, 0.11 mmol). The reaction was stirred for 1.75 h, then more oxidant
(0.018 g) added. After a further 1.5 h, the reaction was diluted with DCM, washed with aq
sodium hydrogen carbonate, dried and evaporated to give the crude title compound as a
white foam (0.086 g), which was used without puriflcation; ESMS m/z 843 [M+H]+.
g) 4"-O-{3-[2-(3-Carboxy-1 -ethyl-4-oxo-1 ,4-dlhydro-qulnolln-6-yl)-propyiamino]-
propyf)-6-O-methyl-11-desoxy-11-(R)-methylaminco erythromycin A 11,12-carbamate
formate.
Example 7f (0.082 g, 0.097 mmol) in methanol / DCM (1:1, 4 mL) was added to sodium
acetate (0.0164 g, 0.2 mmoi), acetic acid (0.2 mL), Intermediate 4 (0.0274 g, 0.1 mmoi),
and 3A molecular sieves (0.2 g). The mixture was stirred for 20 min then a solution of
sodium cyanoborohydride (0.0126 g, 0.2 mmoi) in methanol (0.3 mL) was added and
stirring continued for 16 h. The reaction was then filtered, washing well with methanol and
DCM, and the filtrate evaporated. The residue was purified by preparative reverse phase
HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound as an off-white powder
(0.038 g, 35%); ESMS m/z 1101 [M+H]+.
Example 8: 4'-O-{3-(3-arboy--1ethyl-oxo-1.4-diydro-yl)
propyminol-proyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycin A

a) 2'-O,3'-N-bis(Benzycarbonyl)-3'-N-desmethyl-4'-O[3-(tert-butyidimethyisllyl]-
oxy)proyt]6-O-methl-erythromycin A 11,12-carbonate.
Example 2a (1.85 g, 1.71 mmol) in DMF(10mL) was treated sequentially with imidazole
(0.128 g, 1.88 mmol) and tert-butydimethyisttyl chioride (0.283 g, 1.88 mmol). Mixture
stirred for 20 h then evaporated. Water was added and the mixture extracted with diethyl
ether. The combined organic extracts were washed with brine, dried, and evaoorated. The

residue was purified by chromatography on silica gel (100 g), eluting with 12-42% ethyl
acetate in petroleum ether, to give the title compound as a white foam (1.923 g); ESMS
m/z1217 [M+NH4]+.
b)2,-0,3'-N-bis(Benzyioxycarbonyl)-3'-N-desmethyl-4"-0-[3-(tert-butyldlmethylsilyl-
oxy)propyl]-6-0-methyl-11 -desoxy-11 -(R)-amino-erythromycin A 11,12-carbamate.
Example 8a (1.9 g, 1.58 mmol), carbonyldiimidazole (1.28 g, 7.2 mmol), Imidazole (0.01
g) and DBU (0.08 g, 0.52 mmol) were dissolved in THF (10 mL), heated to 40°C and
stirred for 17 h. Further portions of carbonyidiimidazole and DBU were added, and
reaction heated at 60°C for 6 h then 50°C for 16 h. The mixture was then cooled in an
ice bath and ammonia gas bubbled in for 8 h. The reaction was then stored in the fridge
for 14 h. Argon was then bubbled through the mixture before the addition of potassium
tert-butoxide (1 M in THF, 1.74 mL, 1.74 mmol). After 5 h at room temperature more
potassium tert-butoxide (1 M in THF, 1 mL, 1 mmol) was added. Further 2 h then more
potassium tert-butoxide (1 M in THF, 0.5 mL, 0.5 mmol) added. The mixture was then
stirred for 64 h. Aqueous sodium hydrogen carbonate was then added and the mixture
extracted with ethyl acetate. The combined organic extracts were washed with brine,
dried, and evaporated. The residue was purified by chromatography on silica gel (100 g),
eluting with 20-52% ethyl acetate in petroleum ether, to give the title compound as a white
foam (1.3 g); ESMS m/z 1216 [M+NH4]+
c)4'-O-[3-(tert-butyldlmethylsiiyl-oxy)propyl]-6-0-methyl-11-desoxy-11-(R)-amino-
erythromycin A11,12-carbamate.
Example 8b (1.4 g, 1.17 mmol) was disolved in methanol (10 mL) and 1,4-dioxane (15
mL), and hydrogenated over 10% palladium on charcoal (50% aq paste, 0.4 g) for 6h.
Formaldehyde (37% aq, 4 mL), pH 4.5 acetate buffer (4 mL) and more catalyst (0.2 g)
were then added, and the mixture hydrogenated for 24 h. The mixture was then filtered,
washing well with methanol and 1,4-dioxane. The filtrate was evaporated, and the residue
purified by chromatography on silica gel (100 g). Elution with 0-7% 2 M methanoiic
ammonia in dichloromethane, gave the title compound as a white foam (0.969 g); ESMS
m/z 945 [M+H]+.
d) 4"-O-(3-Hydroxypropyl)-6-O-methyl"11 -desoxy-11 -(R)-aminoerythromycin A
11,12-carbamate.
Example 8c (0.17 g, 0.18 mmol) in THF (4 mL) and acetic acid (0.023 mL, 0.4 mmol) was
treated with tetrabutylammonium fluoride (1 M in THF, 0.4 mL, 0.4 mmol). The mixture
was stirred at 35°C for 72 h, then evaporated to dryness, and the residue purified by
chromatography on silica gel (40 g). Elution with 0-11% 2 M methanolic ammonia in
dlchloromethane, gave the title compound as a white foam (0.15 g); ESMS m/z 831
[M+H]+.

e) 4"-O-(3-OxopropyI)-6-O-methyl-11-desoxy-11-(R)-aminoerythromycin A 11,12-
carbamate.
To Example 8d (0.085 g, 0.1 mmol) in DCM (2 ml) was added Dess-Martin periodinane
(0.051 g, 0.12 mmol) in DCM (1 mL). Stirred for 1.3 h, then diluted with DCM, washed with
aq sodium hydrogen carbonate, dried and evaporated to give the crude title compound as
a white foam (0.097 g), which was used without purification; ESMS m/z 829 [M+H]+.
f) 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyiamino]-
propyl)-6-O-methyl-desoxy-11-(R)-amino-erythromycin A 11,12-carbamate
formate.
Example 8e (0.082 g, 0.1 mmol) in methanol / DCM (1:1, 4 mL) was added to sodium
acetate (0.025 g, 0.3 mmol), acetic acid (0.2 mL), intermediate 4 (0.043 g, 0.11 mmol),
and 3A moiecular sieves (0.2 g). The mixture was stirred for 30 min then a soiution of
sodium cyanoborohydride (0.0126 g, 0.2 mmol) in methanol (0.3 mL) was added and
stirring continued for 2.5 h. The reaction was then filtered, washing well with methanol and
DCM, and the filtrate evaporated. The residue was purified by preparative reverse phase
HPLC (MeCN/H2O/O.1%HCO2H eluent) to give the title compound as a pale yellow solid
(0.054 g, 48%); ESMS m/z 1087 [M+H]+.

Example 10: 4'-O-{3-[2-(3-Carboxy-7-chioro-1-cyclopropyl-4-oxo-1,4-dihydro-
qulnolin-6-ylamino)proyl}-6-O-methyl-erythromycin A 11.12-carbonate
formate

Example 11: 4"-O-{3-[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro
qulnolin-7-ylamin)ethyiamino]propyl}-6-methyl-erythromycin A 11,12-format

Example 12: 4"-O-{3-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-
[1.8]naphthyridin-7-ylamin)ethlamino]-propy}-6-O-methyl-erythromycin A 11.12-
carbonate formate

To 4"-0^3^droxypropyl)^0-methy1eTythromydn A 11,12-carbonate (0.883 g, 1.08
mmol) in dlchloromethane (20 mL) under argon was added Dess-Martin periodlnane
(0.495 g, 1.17 mmol). After 3 h, more Dess-Martin periodlnane (0.1 g, 0.24 mmoO was
added, and after 1.5 h more Dess-Martin periodlnane (0.11 g, 0.26 mmol) was added.

The mixture was stirred for a further 35 min then diiuted with dichloromethane, washed
with saturated aqueous sodium hydrogen carbonate, dried, filtered, and concentrated in
vacuo to give the crude aldehyde as a white solid foam. This material was dissolved in
methanol (20 mL) and dichloromethane (20 ml), then split into four equal portions which
were used in the general procedure for reductive amination.
General Procedure for Reductive Amination
To the solution of aldehyde in methanol (5 mL) and dichloromethane (5 mL) was.added
sodium acetate (0.044 g, 0.54 mmol), acetic add (0.5 mL), 3A molecular sieves (0.5 g),
and the amine (0.26 mmol). The mixture was stirred for 10 mln then a solution of sodium
cyanoborohydride (0.033 g, 0.5 mmol in methanol (0.5 mL) was added and stirring
continued for 20 h. The reaction was then filtered through Cellte, and concentrated in
vacuo to give a residue which was purified by preparative reverse phase HPLC
(MeCN/H2O/0.1%HCO2H eluent), then further purified by chromatography (silica gel, 0-
20% 2 M methanollc ammonia in dichloromethane) to give the title compound.

Example 13: 4'-O-(3-Carboxy-1-ethyl-4oxo-1,4-dihydro-qulnolin-6-yl]
methylamino}propy)-6-Omethyl-erthromycin A 11.12-carbonate formate

Example 14: 4'-O-(3-(2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-
qulnolin-6-ylamino)ethyl]-methylamino}propyl)-6-O-methyl-erythromycin A 11.12-
carbonate

Example 15: 4'-O-(3-{[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihvdro-
[1,8]naphthyrtdin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycin
A11.12-carbonate

General Procedure for N-Methylation
To a solution of amine starting material (0.072 mmol) as tabulated below in chloroform (2
ml) was added formic add (0.005 ml, 0.144 mmol), and formaldehyde (37% by weight in
water) (0.011 mL, 0.144 mmol). The mixture was heated to 60°C for 3 h then
concentrated in vacuo to give a residue which was purified by chromatography (silica gel,
0-20% 2 M methanolic ammonia in dichloromethane) or by preparative reverse phase
HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound.

Example 16: 4"-O-{2-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6-
yl)propylamino]etyl}azlthrornycin 11.12-carbonate

a) 2'-O-Acetyl-azlthromycin 11,12-carbonate.
To a suspension of azithromycin 11,12-carbonate (BA Jones et al., Tet Lett, 1993, 34,
4913; 100 g, 0.13 mol) and sodium hydrogen carbonate (44 g, 0.52 mol) In
dichlromethan (400 mL) was added dropwise acetic anhydride (20.4 mL, 0.2 mol). After
stirring overnight the mixture was diluted with water (400 mL) and the organic layer
separated, dried and evaporated to yield the title compound as a white solid; ESMS m/z
818 (MH+).
b) 2'-O-AcetyL-4"-O-aliyl-azltmromycin 11,12-carbonate.
To a solution of Example 16a (0.408 g, 0.5 mmol) in dry THF (4 mL) and
tetrakis(triphenyphosphine) palladium (0.057 mg, 0.05 mmol) was added aflyl t-butyl
carbonate (0.300 g, 1.89 mmol). After heating at reflux under argon for 8 h the mixture
was cooled and the solvent evaporated. Chromatography of the residue over silica gel
eluting with dlchloromethane containing an increasing concentration of methanol (0-1%)
gave the title compound as a pale yellow gum; ESMS m/z 857 (MH+).
c) 2'-O-AcetYl-4'-O-(2-oxoethoxy)azlthromycin 11,12-carbonate.
To a cooled solution of Example 16b (0.20 g, 0.23 mmol) in THF (1 mL) and water (1 mL)
was added osmium tetraoxlde (15 µL of a 4% solution in water). After 5 mins solid sodium
periodate (0.21 g, 1 mmol) was added in one portion and the resultant mixture stirred at
room temperature for 4 h. Sodium hydrogen sulfite (0.19 g, 1 mmol) was added and the
organic material extracted with ethyl acetate (2x15 mL). The combined organic fractions
were dried and evaporated to yield the title compound as a brown gum; ESMS m/z 877
(MNH4+).
d) 4"-O-{2-[3-(3-Carboxy-1 -ethyl-4-oxo-1,4-dihydro-qulnolin-6-yl)proylamino]ethyl}
azithromycin 11,12-carbonate.
A solution of Example 16c (0.054 g, 0.063 mmol), intermediate 4 (0.05 g, 0.127 mmol)
and sodium acetate (0.011 g, 0.127 mmol) in 1% acetic acid/methanol (2 mL) was stirred
for 0.5 h at room temperature. Sodium cyanoborohydride (0.016 mg, 0.25 mmol) was

added. After 16 h the mixture was concentrated and purified by reverse phase liquid
chromatography to yield the title compound as a white solid; ESMS m/z 1076 (MH+).
Example 17: 4"-O-{2-[2-(3-Carboxy-1-ethyl-4-oxo-1.4-dihvdro-qulnolin-6-
ylsulfanyl)ethylamino)ethyl}azithromvcin tris trifluoroacetate

a) 2'-O-Acetyl-4"-O-{2-[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolln-6-
vlsulfanyl)ethylamIno]ethyl}azIthromycln 11,12-carbonate.
Using a similar procedure to that described in Example 16d, Example 16c (0.055 g,
0.063 mmol) and Intermediate 3 (0.030 g, 0.95 mmol) gave the title compound as a white
solid; ESMS m/z 1136 (MH+).
b)4"-O-{2-[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6-
ylsulfanyl)ethylamlno]ethyl}azithromycin tris trifluoroacetate.
A solution of Example 17a in methanol (2 mL) containing sodium hydrogen carbonate
(0.010g, 0.12 mmol) was stirred at 50°C. After 4 h the mixture was cooled, filtered and the
solvent evaporated to yield the crude product. Purification by reverse phase liquid
chromatography gave the title compound as a colourless gum; ESMS m/z 1094 (MH+).
Example 18: 4"-O-{2-[2-(3-Carboxy-1-ethvl-6-fluoro-4-oxo-1.4-dihydro-
[1.8]naphthvrldin-7-vlamino)ethvl]-amino}-ethvl-6-O-methvl-ervthromvcin A
monoformate

a) 9-Dihydro-9-methoxy-4'-O-2-oxoethyt-2',11-bis-O-trimethylsilyl-6-0-methyl-9,12-
anhydro-erythromycin A.
To Example 5d (0.6 g, 0.64 mmol) in THF (2.5 mL) and water (2.5 mL) under argon was
added osmium tetroxlde (4% solution in water, 0.04 mL). After 5 min sodium periodate
(0.535 g, 2.5 mmol) was added. After stirring for 4.5 h, the reaction was diluted with ethyl
acetate (20 mL) and washed with sat. aq. sodium thlosulfate (5 mL) and brine (5 mL).
After drying with magnesium sulfate, the solution was evaporated to give the title material
as a white foam, (0.62 g); ESMS m/z 966 [M+H2O+H]+.
b) 4"-O-{2-I2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1I4-dihydro-[1,8]naphthyrldln-7-
ytamino)ethyl]-amino}-ethyl }-6-0-methyl-erythromycin A monoformate.
To Example 18a (0.1 g, 0.1 mmol) in methanol / DCM (1:1, 3 mL) was added to sodium
acetate (0.025 g, 0.3 mmol), acetic acid (0.15 mL), Intermediate 6 (0.041 g, 0.01 mmol),
and 3A molecular sieves (0.2 g). The mixture was stirred for 45 min then a solution of
sodium cyanoborohydride (0.0128 g, 0.2 mmol) in methanol (0.8 mL) was added and
stirring continued for 3 h. The reaction was then filtered, washing well with methanol, and
the combined filtrates evaporated. The residue was dissolved in acetonitrile (20 mL), and
1% aq. Formic acid (15 mL) for 10 min at 20 °C before evaporation to dryness. The crude
product was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H
eluent) to give the title compound as a yellow foam (0.037 g); ESMS m/z 1068 [M+H]+.
Example 19: 4"-0-(2-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1^-dihvdro-
[1.8]naDhthvridin-7-vlamino)ethyl]-methylamino}-ethyl} 1-6-O-methvl-erythromycin A

To a solution of Example 18 (0.033g) in chloroform (1 mL) was added formic acid (0.005
mL, 0.144 mmol), and formaldehyde (37% by weight in water) (0.005 mL, 0.144 mmol).
The mixture was heated to 60°C for 3 h when further 0.005 mL portions of the reagents
were added. After a further 1.5 h heating the reaction mixture was concentrated in vacuo

to give a residue which was purified by preparative reverse phase HPLC
(MeCN/H2O/0.1%HCO2H eluent) to give the title compound, (0.016 g). ESMS m/z 1082
[M+H]+
Example 20: 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-
pripoxy]-propyl}-6-O-methyl-efythromycin A monoformate

a) 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6-yl)-propoxy]-prop-1 -
enyl}-6-O-methyl-erythromycin A ethyl ester.
To Example 5e (0.12 g, 0.125 mmol) and Intermediate 8 (0.1 g) in THF (2 mL) under
argon was added tetrakis(trlphenytphosphine) palladium (0.007 g). The reaction was
heated to reflux for 15 min after which further intermediate 8 (0.1 g) and
tetrakis(triphenyiphosphine) palladium (0.007 g). were added. After a further 40 min reflux,
further intermediate 8 (0.075 g) and tetralds(triphenyiphosphine) palladium (0.007 g).
were added. The reaction was refluxed for a further 35 mln cooled and evaporated to
dryness. The residue was taken up in acetonltrile/0.2M aq. formic acid (50 mL, 50:50)
and left at 20°C for 20 h. After evaporation to dryness, the residue was purified
chromatography over silica gel eluting with 0-10% 2M methanolic ammonia in
dlchloromethane to yield the title compound as a gum (0.175 g); ESMS m/z 1089 (M+H]+.
b) 4"-0-{3-[3-(3-Carboxy-1 -ethyi-4-oxo-1,4-dihydro-qulnolin-6-yl)-propoxy]-propyl}-
6-O-methyl-erythromycin A ethyl ester.
Example 20a (0.175 g), in ethanol was hydrogenated at 20 °C and 1 atm over 10% Pd/C
(0.05g) for 3 h. The reaction was flltered, and the filtrate evaporated to give the title
product (0.175g) as a gum, ESMS m/z 1091 [M+H]+.
c)4"-O-{3-[3-Carboxy-1-ethyl-4-dihydro-qulnolin-6-yl)-propoxy]-proyl}-6-
O-methyl-erythrornycin A.
Example 20b (0.175 g), in 1,4-dioxan (5 mL) under argon was treated with water (1 mL)
containing lithium hydroxide (0.012g). After stirring for 75 mln, the reaction mixture was
evaporated to low volume, and the residue taken up in water and solid CO2 added. After
evaporation to dryness, the residue was purified by preparative reverse phase HPLC

(MeCN/H2O/0.1%HCO2H eluent) to give the title compound, (0.036 g) ESMS m/z
[M+H]+
Example 21: 4'-O-{3-[2-(3-Carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-
[1.8]naphtyridin-7-ylamino)-ethylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-
amino-efythromycin A 11.12-carbamate formate

Example 22: 4"-O-{3-[2-Carboxo-1-oxo-6,7-dihydro-1H,5H-pyrldo[3,2,1-ij]qulnoli-
9-yioxy)-ethlaino]-propyl}-6-O-methyl-11-desey-11-(R)-amino-erythromycin A
11.12-carbamate formate

Example 22: 4'-O-{3-[2-(2-Carbixy-1-oxo-6,7-dihydro-1H,5H-Pyrldo[3,2,1-ij]qulnlin-
9-vioxy-ethylamino]-propyl}-6-O-methyl-11-desixy-11-(R)-amino-erythromycin A
11,12-acrbamate

Example 24:4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-6-[1.8]naphthryldinyl)-
piraylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycin A 11.12-

Example 25:4"-O-{3-[3-[3-Carboxy-1-oxo-6,7-dihydro-1H.5H-Pyrido[3.2.1-ij]qulnolin-
9yl]-propylaminol]-propyl}-6-O-methyl-11-(R)-amino-erthromycin A
Example 26:4"-O-{3-[3-[3-Carboxy-1-ethyl-4-oxo-4-H-qulnoizin-7-ylamino)
ethylamino]-propyl}-6-O-methyl-11-(R)-amino-erthromycin A
11.12-carbamate formate
11.12-carbamate formate

Using the method of Example 8f the amino adds tabulated below were converted to the
title compounds. Purification was by chromatography (silica gel, 0-20% 2 M methanolic
ammonia in dichloromethane) and/or by preparative reverse phase HPLC
(MeCN/H2O/0.1%HCO2H eluent) as appropriate.

Exampl 27:4'-O-{3-{[2-(3-Carboxy-1-ethyl-6-fluro-4-oxo-1.4-dihydro-
[1.8]naphtyridin-7-ylamino)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-
(R)-amino-erythromycin A 11.12-carbamate formate

Example 28: 4"-O-{3-[[2-2-Carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-
ij]qulnolin-9-yloxy)-ethyl]-methiamino]-proyl}-6-O-methyl-11-desoxy-11-(R)-
amino-erythromvcin A 11.12-carbamate formate

Example 29: 4"-O-{3-[3-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-qulnolin-6yl)propyl]
methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-mino-erthronycin A 11.12-
carbamate formate

Example 30:4"-O-{3-[3-(3-Carboxy-1-ethl-4-dihydro-6-[1.8]naphthryidinyl)-
propyl]-methylmino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erthromycin A
11.12-carbamate

Example 31:4"-O-{3-[[3-(2-Carboxo-6,7-dihydro-1H,5H-Puinolin-
9yl)-prpyl]-merhylamino]-propy}-6-O-methyl-11desoxy--11-(R)-amino-
erythromycin A 11.12-carbamate

Example 32:4"-O-{3-[[2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yisulfanyl)-
ethyl]-methylamino]-propyl}-6-O-methyl-11 -desoxy-l1 -(R)-amino-erythromycin A,
11.12-carbamate

To a solution of starting material as tabulated below in chloroform (30 mUmmol) was
added formic acid (4 equivalents), and formaldehyde (37% by weight in water) (2
equivalents). The mixture was heated to 60°C for 3 h then concentrated in vacuo to give a
residue which was purified by chromatography (silica gel, 0-20% 2 M methanolic ammonia
in dichloromethane) and/or by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H
eluent) to give the title compound.

Example 33: 4"-O{3-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihvdro-
aulnolin-7-ylamino)-ethyicarbamoyl]-propyl}-azithromvcin

DIPEA (201.4 L, 1.4 mol. equiv.) was added dropwise via a syringe at 0°C to a solution
of intermediate 16c (181.7 mg, 0.22 mmoL) and HBTU (81.7 mg, 0.22 mmoL) in dry
DMF (2.8 mL). The mixture was stirred for 15 minutes before 7-(2-amino-ethylamlno)-6-
fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (48.7 mg, 0.18 mmoL),,4
was added over a period of 30 minutes. The reaction mixture was stirred at room
temperature overnight, and then diluted with water (30 mL). The aqueous phase was
extracted twice with EtOAc (2x50 mL), and the combined organic phases were washed
sequentially with saturated aqueous NaHC03 (30 mL) and brine (30 mL). Drying with
Na2S04 and evaporation afforded 127.5 mg (71%) of the title compound as a colourless
solid. MS (m/z) 1122 (MH+).
Example 34: 4"-O-{3-[2-(3-Carboxy-7-chloro-1-cvclopropyl-4-oxo-1.4-dihydro-
qulnolin-6-ylamino)-ethylcarbamoyl]-propyl}-azrthromycin

Starting from intermediate 16c (834 mg, 1.0 mmoL) and intermediate 1 (234.9 mg, 0.73
mmoL) using a similar procedure to that described in Example 33, the title compound
(620.5 mg) was obtained. MS (m/z) 1138 (MH+).

Example 35: 4"-O-{4-[4-(3-CarfaoxY-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihydro-
auinolin-7-yl)-piperazin-1-yl]-4-oxo-butyl}azlthromvcin

Starting from intermediate 16c (667.2 mg, 0.8 mmoL) and 1-cydopropyl-6-fluoro-4-oxo-7-
piperazin-1-yI-1,4-dihydro-quinoline-3-carboxylic add (192.7 mg, 0.58 mmoL) using the
similar procedure to that described in Example 33 the title compound (460.3 mg) was
obtained. MS (m/z) 1148 (MH+).
Example 36: 4"-O-{2-[4-(3-Carboxy-1-ethyl-4-oxo-1.4-dihydro-auinolin-6-yl)-
piperazin-1-yl]-ethyl}-azithromycin 11,12-cyclic carbonate

Intermediate 15 (114.4 mg, 0.14 mmoL) was dissolved in 0.9 mL of methanol. Three
equivalents of Intermediate 17c (126.6 mg, 0.42 mmoL) were added as a 1 M solution in
methanol (0.42 mL), followed by 0.43 mL of 1 M solution of acetic acid in methanol. The
pH was checked and adjusted to about 6 with acetic acid, if necessary. NaCNBH3 was
added as a freshly prepared 0.3 M solution in methanol (0.19 mL), and the mixture was
stirred at room temperature for 2 h. The reaction was quenched with a few drops of water
and concentrated under reduced pressure. The residue was purified by silica gel
chromatography (1-5% MeOH / 0.5-1% triethylamine / dichloromethane) to give 100.3 mg
(75 %) of the title compound as a yellow solid. MS (m/z) 1102 (MH+).
Example 37: 4"-O-{2-[2-(3-Carboxy-7-chloro-1 -cyclopropyl-4-oxo-1.4-dihydro-

qulnolin-6-yiamino)-ethvlamino]-ethyl}-azithromycin 11.12-cyclic carbonate

This method was adapted from the work of Debono et al. (J. Antlbfot. 1989, 42,1253-
1267). A solution of intermediate 15 (955.9 mg, 1.17 mmoL), intermediate 1 (563.1 mg,
1.75 mmoL), and 22.5 mL of EtOAc was heated to 70'C with stirring. Formic acid (58.9
mg, 1.28 mmoL) was added dropwise to the solution, and the temperature was lowered to
65°C. Stirring and heating was continued for 5 h. After cooling to room temperature, the
reaction solution was washed twice with 25 mL portions of saturated aqueous NaHCO3
and then once with 20 mL of saturated aqueous NaCI. The combined extracts were dried
over anhydrous MgS04, filtered, and evaporated under reduced pressure to furnish crude
product as a yellow foam. This material was taken up in 100 mL of hot Et20; insolubles
were filtered and saved. The filtrate was treated with 30 mL of hot hexane, and again the
resulting insoluble matter was filtered and saved. The filtrate was concentrated to about
7.5 mL by boiling off excess solvent The resulting solution was allowed to cool to room
temperature and then cooled to 5°C for several hours. A colorless precipitate formed
(630.6 mg). The filtrate was combined with the insolubies that were saved, and the
mixture was then chromatographed on silica gel. Elutlon with 9:1 CH2CI2-MeOH
containing 1% NH4OH afforded an additional amount of the title product (420.3 mg, 80%
overall yield). MS (m/z) 1122 (MH+).
Example 38: 4"-O-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4>dihydro-
quinolin-7-ylamino)-ethylamino]-ethyl}-azlthrornycin 11.12-cyclic carbonate

To a magnetically stirred solution of Intermediate 15 (2.17 g, 2.65 mmoL) in 8 mL of
methanol was added 7-(2-amino-ethylamino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-

quinoline-3-carboxylic acid (1.62 g, 5.3 mmol). After being stirred at room temperature for
30 min, the solution was treated with 0.15 mL (2.65 mmoL) of HOAc and cooled to 0"C.
in 2 mL of MeOH, 563.4 mg (2.66 mmoL) of NaBH(OAc)3 was then added over a period
of 10 min. Stirring and cooling was continued for 10 min. The reaction mixture was worked
up and the crude product was chromatographed on silica gel to furnish 1.99 g (68%) of
the title product MS (m/z) 1108 (MH+).
Example 39: 4"-O-{2-[4-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihydro.
quinolin-7-yl)-piperazin-1-yl]-ethyl}-azithromycin 11.12-cyclic carbonate

Starting from Intermediate 14 (817 mg, 1.0 mmoL) and 1-cyclopropyl-6-fluoro-4-oxo-7-
piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid (994.1 mg, 3.0 mmoL) using a
similar procedure to that described in Example 36 the title compound (702.1 mg) was
obtained. MS (m/z) 1132 (MH+).
Example 40; 4"-O-{2-[4-(3-CarboxY-1-ethyl-4-oxo-1.4-dihydro-quinolin-6-yl)-
plperazin-1-yl]-ethyl}-azlthromycin

To a solution of Example 36 (1.101 g, 1.0 mmoL) in a THF-water mixture (1:1,10.0 mL),
was added LIOH (192 mg, 4.6 mmoL) at room temperature, and the resulting reaction
mixture was stirred at the same temperature for 12 hours. The solvent was removed
under reduced pressure, and the solid was azeotroped with toluene (5X5 mL) and finally
dried under vacuum. The acid salt was dissolved in water and the resulting solution was

made acidic by dropwie addition of aqueous HCI (2 M). The precipitate was filtered off to
give 688.9.mg (64 %) of the title compound as colourless solid. MS (m/z) 1076 (MH+).
Example 41: 4"-O-{2-[2-(3-Carboxy-7-chloro-1 -cyclopropyl-4-oxo-1.4-dihvdro-
quinolin-6-viamino)-ethvtamino]-ethyl}-azithromycin

Starting from Example 37 (504.9 mg, 0.45 mmoL) according to the procedure of Example
40, the title compound (399.8 mg) was obtained. MS (m/z) 1096 (MH+)-
Example 42: 4"-O-{2-[2-(3-Carboxy-6-fluoro-1-cyclopropyl-4-oxo-1.4-dihydro-
quinolin-7-vlamino)-ethylamino]-ethyl}-azlthromycin

Starting from Example 38 (686.3 mg, 0.62 mmoL) according to the procedure of Example
40, the title compound (671.1 mg) was obtained. MS (m/z) 1082 (MH+).
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. feecalis
ATCC 29212, H. influenzae ATCC 49247, M. catarrhalis ATCC 23246.
Examples 1,2,5-7,13,15,18-23,25 and 27-32 have an MIC ≤1 µg/mL against S. aureus
Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565 and E faecalis ATCC
29212.
Examples 1, 2, 4, 6, 13-16, 18-21, 23 and 27-32 have an MIC ≤4 µg/mL against H.
influenzae ATCC 49247 and M. catarrhalis ATCC 23246.
Examples 1-4,6,7,9-15 and 18-32 have an MIC ≤1 µg/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:

WE CLAIM:
1. A macrolide compound of formula (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-0(CH2)dXR11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C1-4alkyl, or C3_6alkenyl optionally substituted by 9 to 10 membered
fused bicyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic
heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or -0(CH2)eNR7R12
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(R13)- and -CH
(SR13)-;
R8 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or -C(O)
R14, or

R8 and R9 together form =CH(CR14R15)faryl, =CH(CR14R15)fheterocyclyl, =CR14R15
or =C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally
substituted by up to three groups independently selected from R16;
R10 is -OR17, C1_6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)iOR7,
wherein each R10 group is optionally substituted by up to three groups independently
selected from R16;
R11 is a heterocyclic group having the following structure:

R12
is hydrogen or C1-6galkyl;
R13 is hydrogen or C1-4alkyl 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;
R14
and R15 are each independently hydrogen or C1-6alkyl;
R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R21, -C(O)OR21, -OC(O)R21,
-OC(O)OR21, -NR22C(O)R23, -C(O)NR22R23, -NR22R23, hydroxy, C1-6alkyl, -S(O)
kC1-6alkyl, C1-6alkoxy, -(CH2)maryl or -(CH2)mheteroaryl, wherein the alkoxy group is
optionally substituted by up to three groups independently selected from -NR14R15,
halogen and -OR14, and the aryl and heteroaryl groups are optionally substituted by up to
five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C
(O)R24, -C(O)OR24, -OC(O)OR24, -NR25C(O)R26, -0(O)NR25R26, -NR25R26,
hydroxy, C1-6alkyl and C1-6alkoxy;
R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl 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, -OR27, -S(O)nR27, -NR27R28, -CONR27R28, halogen and cyano;
R18 is hydrogen, -C(O)OR29, -C(O)NHR29, -C(O)CH2NO2 or -C(O)CH2S02R7;

R19 iS hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3-
7cycloalkyl, or optionally substituted phenyl or benzyl;
R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1-
4alkyl)2;
R21 is hydrogen, C1-10alkyl, -(CH2)paryl or -(CH2)pheteroaryl;
R22 and R23 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or -(CH2)
qheterocyclyl;
R24
is hydrogen, C1-10alkyl, -(CH2)raryl or -(CH2)rheteroaryl;
R25 and R26 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or -(CH2)
sheterocyclyl;
R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
R29
is hydrogen,
C1-6alkyl optionally substituted by up to three groups independently selected from
halogen, cyano, C1-4alkoxy optionally substituted by phenyl or C1-4alkoxy, -C(O)
C1-6alkyl, -C(O)OC1-6alkyl, -OC(O)C1-6alkyl, -OC(O)OC1-6alkyl, -C(O)
NR32R33 -NR32R3 phenyl optionally substituted by nitro or -C(O)OC1-
6alkyl,
-(CH2)wC3-7cycloalkyl,
-(CH2)wheterocyclyl,
-(CH2)wheteroaryl,
-(CH2)waryl,
C3-6alkenyl, or
C3-6alkynyl;
R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl
or benzoyl;

R31 is hydrogen or R20 or R31 and R19 are linked to form the bivalent radical -O(CH2)
2- or -(CH2)t-;
R32 and R33 are each independently hydrogen or C1-6alkyl optionally substituted by
phenyl or -C(O)OC1-6alkyl, or

R32 and R33, 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;
X is -U(CH2)VB-, -U(CH2)V- or a group selected from:

U and B are independently a divalent radical selected from -N(R30)-, -0-, -S(O)z-, -N
(R30)C(O)-, -C(O)N(R30)- and -N[C(O)R30]-;
W is -C(R31)- or a nitrogen atom;
d is an integer from 2 to 6;
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.
2. A compound as claimed in claim 1 wherein A is -C(O)- or -N(R7)-CH2-
3. A compound as claimed in claim 1 or claim 2 wherein X is -U(CH2)VB- or -U(CH2)
V'
4. A compound as claimed in any one of the preceding claims wherein d is 2 or 3.
5. A compound as claimed in any one of the preceding claims wherein R11 is a
heterocyclic group of the following formula:

wherein the heterocyclic is linked in the 6 or 7 position and j, R18, R19 and R20 are as
defined in claim 1;
a heterocyclic group of the following formula:

wherein the heterocylic is linked in the (ii) or (iii) position, W is -C(R31)- and R31 and R19
are linked to form the bivalent radical -(CH2)t- as defined in claim 1, and j, R18, R19 and
R20 are as defined in claim 1; or
a heterocyclic group of the following formula:

wherein the heterocyclic is linked in the 7 or 8 position and j, R18, R19 and R20 are as
defined in claim 1.
6. A compound as claimed in claim 1 as defined in any one of Examples 1 to 42, or a
pharmaceutically acceptable derivative thereof.
7. A compound selected from:
4"-0-(2-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-
methylamino}-ethyl)-6-0-methyl-erythromycin A 11,12-carbonate;
4"-0-(3-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)ethyl]-
methylamino}-propyl)-6-0-methyl-erythromycin A 11,12-carbonate;
4"-0-{3-[2-(2-carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-(ij]quinoline-9-yloxy)-
ethylamino]-propyl}-6- O-methyl-erythromycin A 11,12-carbonate;

4"-0-(3-{[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino}-
propyl)-6-O-methyl-erythromycin A 11,12-carbonate;
4"-0-(3-{[2-(3-carboxy-1 -ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)
ethyl]-methylamino}-propyl)-6-O-methyl-erythromycin A 11,12-carbonate;
4"-0-{2-[2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)
ethyl]-methylamino}-ethyl }-6-O-methyl-erythromycin A;
4"-O-{3-[[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamino]-
propyl}-6-0-methyl-11 -desoxy-11 -(R)-amino-erythromycin A 11,12-carbamate;
4"-0-{3-[[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethyl]-
methylamino]-propyl}-6-O-methyt-11-desoxy-11-(R)-amino-erythromycin A 11,12-
carbamate;
4"-0-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-
ethylcarbamoyl]-propyl}-azithromycin;
4"-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-
ethylamino]-ethyl}-azithromycin 11,12-cyclic carbonate;
4"-0-{2-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinotin-6-ylamino)-
ethylamino]-ethyl}-azithromycin; and
4"-0-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-
ethylamino]-ethyl}-azithromycin;
or a pharmaceutically acceptable derivative thereof.
8. A process for the preparation of a macrolide compound as claimed in claim 1
which comprises:
a) reacting a compound of formula (II)

with a suitable amine (IlIa) or (IIIb), wherein Ba and R11a are B and R11 as defined in
claim 1 or groups convertible to B and R11;
b) reacting a compound of formula (V)

(V)
with a compound of formula XaR11a (IV), wherein R11a is R11 as defined in claim 1 or a
group convertible to R11 and Xa is -U(CH2)V- or -U(CH2)VB-, or a group convertible to
-U(CH2)V- or -U(CH2)VB-, in which U is a group selected from -N(R30)- and -S-, and L is
suitable leaving group, to produce a compound of formula (I) wherein U is a group
selected from -N(R30)- and -S-;
a) converting one compound of formula (I) into another compound of formula (I);
d) where U is -O-, reacting a compound of formula (VII)

with a suitable compound of formula XaR11a in the presence of a catalyst; or
e) where U is -C(O)N(R30)-, reacting a compound of formula (VIII)

with a suitable amine compound,
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 XaR11 a to XR11,
iii) conversion of BaR11a to R11,
iv) conversion of R11a to R11,
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. A compound as claimed in any one of claims 1 to 7 for use in the manufacture of
a medicament capable of being used in the treatment or prophylaxis of systemic or
topical microbial infections in a human or animal body.
11. A compound as claimed in any one of claims 1 to 7 for the treatment or
prophylaxis of systemic or topical microbial infections in a human or animal body.
12. 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.
13. A pharmaceutical composition as claimed in claim 12 for the treatment of the
human or non-human animal body to combat microbial infection.
14. A compound of formula (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-0(CH2)dXR11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered
fused bicyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic
heteroaryl, or C1-6alkoxy optionally substituted by C1-6galkoxy or -O(CH2)eNR7R12.

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(R13)- and -CH
(SR13)-;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, -C(=NR10)NR14R15 or -C(O)
R14 or
R8 and R9 together form =CH(CR14R15)faryl, =CH(CR14R15)fheterocyclyl, =CR14R15
or =C(R-14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally
substituted by up to three groups independently selected from R16;
R10 is -OR17, C1-6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)jOR7,
wherein each R10 group is optionally substituted by up to three groups independently
selected from R16
R11 is a heterocyclic group having the following structure:
or
R12
is hydrogen or C1-6alkyl;
R13 is hydrogen or C1-4alkyl 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;
R14 and R15 are each independently hydrogen or C1-6alkyl;

R16 is halogen, cyano, nitro, trifluoromethyl, azido, -C(O)R21, -C(O)OR21, -OC(O)R21,
-OC(O)OR21, -NR22C(O)R23, -C(O)NR22R23, -NR22R23, hydroxy, C1_6alkyl, -S(O)
kC1-6alkyl, C1-6alkoxy, -(CH2)maryl or -(CH2)mheteroaryl, wherein the alkoxy group is
optionally substituted by up to three groups independently selected from -NR14R15,
halogen and -OR14, and the aryl and heteroaryl groups are optionally substituted by up to
five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C
(O)R24, -C(O)OR24, -OC(O)OR24, -NR25C(O)R26, -C(O)NR25R26, -NR25R26,
hydroxy, C1-6alkyl and C1-6alkoxy;
R17 is hydrogen, C1-6alkyl, C3-7cycloaikyl, C3-6alkenyl 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, -OR27, -S(O)nR27, -NR27R28, -CONR27R28, halogen and cyano;
R18 is hydrogen, -C(O)OR29, -C(O)NHR29 or -C(O)CH2NO2;
R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-6alkoxy, C3-
7cycloalkyl, or optionally substituted phenyl or benzyl;
R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or -N(C1-
4alkyl)2;
R21 is hydrogen, C1-10alkyl, -(CH2)paryl or -(CH2)pheteroaryl;
R22 and R23 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)qaryl or -(CH2)
qheterocyclyl;
R24 is hydrogen, C1-10alkyl, -(CH2)raryl or-(CH2)rheteroaryl;
R25 and R26 are each independently hydrogen, -OR14, C1-6alkyl, -(CH2)saryl or -(CH2)
sheterocyclyl;
R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
R29 is hydrogen or C1-6alkyl optionally substituted by up to three groups independently
selected from halogen, C1-4alkoxy, -OC(O)C1-6alkyl and -OC(O)OC1-6alkyl;
R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl
or benzoyl;
R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical -O(CH2)
2-or-(CH2)t-;
X is -U(CH2)VB-, -U(CH2)V- or a group selected from;

U and B are independently a divalent radical selected from -N(R30)-, -O-, -S(O)z-, -N
(R30)C(O)-, -C(O)N(R30)- and -N[C(O)R30]-;
W is -C(R31)- or a nitrogen atom;
d is an integer from 2 to 6;
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.

The present invention relates to 14- or 15-membered macrolides substituted at the 4" 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.

Documents:

2197-kolnp-2005-granted-abstract.pdf

2197-kolnp-2005-granted-assignment.pdf

2197-kolnp-2005-granted-claims.pdf

2197-kolnp-2005-granted-correspondence.pdf

2197-kolnp-2005-granted-description (complete).pdf

2197-kolnp-2005-granted-examination report.pdf

2197-kolnp-2005-granted-form 1.pdf

2197-kolnp-2005-granted-form 18.pdf

2197-kolnp-2005-granted-form 3.pdf

2197-kolnp-2005-granted-form 5.pdf

2197-kolnp-2005-granted-gpa.pdf

2197-kolnp-2005-granted-reply to examination report.pdf

2197-kolnp-2005-granted-specification.pdf

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Patent Number

231395

Indian Patent Application Number

2197/KOLNP/2005

PG Journal Number

10/2009

Publication Date

06-Mar-2009

Grant Date

04-Mar-2009

Date of Filing

07-Nov-2005

Name of Patentee

PLIVA-ISTRAZIVACKI INSTITUT D.O.C.

Applicant Address

PRILAZ BARUNA FILIPOVICA 29, 10000 ZAGREB

Inventors:

#	Inventor's Name	Inventor's Address
1	FORREST ANDREW KEITH	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX, CM19 5AW
2	ALIOHODZIC SULEJMAN	PLIVA-ISTRAZIVACKI INSTITUT D.O.C. PRILAZ BARUNA FILIPOVICA 29, 10000 ZAGREB
3	JARVEST RICHARD LEWIS	GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE SG1 2NY
4	LAZAREVSKI GORJANA	PLIVA-ISTRAZIVACKI INSTITUT D.O.C. PRILAZ BARUNA FILIPOVICA 29, 10000 ZAGREB
5	PAVLOVIC DRAZEN	PLIVA-ISTRAZIVACKI INSTITUT D.O.C. PRILAZ BARUNA FILIPOVICA 29, 10000 ZAGREB

PCT International Classification Number

h01 2d

PCT International Application Number

PCT/EP2004/5082

PCT International Filing date

2004-05-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0310986.5	2003-05-13	U.K.