NOVEL 14 AND 15 MEMBERED-RING COMPOUNDS The present invention relates to novel semi-synthetic macrolides having antimicrobial activity, in particular antibacterial activity. More particularly, the invention relates to 14- and 15-membered macrolides substituted at the 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-resistant 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 macrolides substituted at the 4"position which also have antimicrobial activity.

Thus, the present invention provides compounds of general formula (t) (l) 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)-; Rl is-OC (O) (CH2) dXR1 1 ; 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-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) Rl4 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 Rl 6 ; R10 is -OR17, C1-6alkyl, - (CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)iOR7, wherein each RIO group is optionally substituted by up to three groups independently selected from R16 ; Rl 1 is a heterocyclic group having the following structure:

wherein said heterocyclic is linked to X in position (i) or position (ii); R12 is hydrogen or C1-6alkyl ; R13 is hydrogen or Chalky) 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 Rl 5 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 -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; Rl8 is hydrogen, -C (O) OR29,-C (O) NHR29, -C (O) CH2NO2 or-C (O) CH2SO2R7 ; 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 (Cbz 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,-NR32R33 and phenyl optionally substituted by nitro or-C (O) OC 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 R1 9 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- or X is a group selected from: U and B are independently a divalent radical selected from-N (R30)-,-0-,-S (0) z-,- N(R30)C(O)-, -C(O)N(R30)- and -N [C (O) R30]- ; W is-C (R31)- or a nitrogen atom; d is 0 or an integer from 1 to 5; e is an integer from 2 to 4; f, g, h, m, p, q, r, s and w are each independently integers from 0 to 4; i is an integer from 1 to 6; j, k, n and z are each independently integers from 0 to 2; t is 2 or 3 ; v is an integer from 1 to 8 ;. and pharmaceutically acceptable derivatives thereof.

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

wherein A is a bivalent radical selected from-C (0)-,-C (O) NH-, -NHC (O)-,-N (R7)-CH2-,-CH2- N (R7)-,-CH (NR8R9)- and -C(=NR10)-; R1 is -OC (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 bicyclic heteroaryl ; R4 is hydroxy, C3 galkenyloxy 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 Chalky) ; 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 RIO group is optionally substituted by up to three groups independently selected from R16 ; Rl 1 is a heterocyclic group having the following structure:

wherein said heterocyclic is linked to X in position (i) or position (ii); 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 Rl 5 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, Cl-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, C3-7cycloalkyl, 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 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, C1-4thioalkyl, C1-4alkoxy, -NH2, -NH(C1-4alkyl) or-N (Cbz 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 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- or X is 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 0 or an integer from 1 to 5; e is an integer from 2 to 4; f, g, h, m, p, q, r and s are each independently integers from 0 to 4; i is an integer from 1 to 6; j, k, n and z are each independently integers from 0 to 2; t is 2 or 3 ; v is an integer from 2 to 8; and pharmaceutically acceptable derivatives thereof.

The term"pharmaceutically acceptable"as used herein means a compound which is suitable for pharmaceutical use. Salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non- pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.

The term"pharmaceutically acceptable derivative"as used herein means any pharmaceutically acceptable salt, solvate or prodrug, e. g. ester, of a compound of the invention, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof. Such derivatives are recognizable to those skilled in the art, without undue experimentation.

Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5t Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives. Preferred pharmaceutically acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters.

Particularly preferred pharmaceutically acceptable derivatives are salts, solvates and esters. Most preferred pharmaceutically acceptable derivatives are salts and esters, in particular salts.

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

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

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

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and

tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.

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

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

The term"prodrug"as used herein means a compound which is converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects.

Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems", Vol. 14 of the A. C. S. Symposium Series, Edward B. Roche, ed.,"Bioreversible Carriers in Drug Design", American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which are incorporated herein by reference.

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

References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable derivatives.

With regard to stereoisomers, the compounds of structure (I) have more than one asymmetric carbon atom. In the general formula (I) as drawn, the solid wedge shaped bond indicates that the bond is above the plane of the paper. The broken bond indicates that the bond is below the plane of the paper.

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

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

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

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

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

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

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

Rl 1 is a heterocyclic group having the following structure:

wherein said heterocyclic is linked to X in position (i) or position (ii). It will be appreciated that when W is a nitrogen atom or-C (R31)- wherein R31 is R20 or R31 and R19 are linked to form the bivalent radical-O (CH2) 2- or- (CH2) t-, the R11 group may only be linked in position (i).

For example, when R11 is a heterocyclic group having the following structure: said heterocyclic is linked in the 5 or 8 position to the X group as above defined. 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 8 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-O (CH2) 2- or -(CH2)t-, said heterocyclic is linked in the (i) position to the X group as above defined.

When Rl 1 is a heterocyclic group having the following structure:

said heterocyclic is linked in the 5 position to the X group as above defined.

When R11 is a heterocyclic group having the following structure: said heterocyclic is linked in the 6 or 9 position to the X group as above defined.

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-O (CH2) 2- or- (CH2) t-, said heterocyclic is linked in the (i) position to the X group as above defined.

When R11 is a heterocyclic group having the following structure:

said heterocyclic is linked in the 4 position to the X group as above defined.

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, <BR> <BR> <BR> methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl, hexyl, heptyl, 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"group as used herein refers to a non-aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term"alkoxy"as used herein refers to a straight or branched chain alkoxy group containing the specified number of carbon atoms. For example, 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-enyl. It will be appreciated that in groups of the form-O-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"Cgaikenyf"means a straight or branched alkynyl containing at least 3, and at most 6, carbon atoms containing at least one triple bond. Examples of"alkynyl"as used herein include, but are not limited to, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 3-methyl-1-butynyl.

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

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

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

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

The term"heterocyclyl"as used herein, unless otherwise defined, refers to a monocyclic or bicyclic three-to ten-membered saturated or non-aromatic, unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur.

Preferably, the heterocyclyl ring has five or six ring atoms. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl and thiomorpholino.

The term"5 or 6 membered heterocyclic group"as used herein as a group or part of a group refers to a monocyclic 5 or 6 membered saturated hydrocarbon ring containing at

least one heteroatom independently selected from oxygen, nitrogen and sulfur. Examples of such heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl and thiomorpholino.

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

The terms"optionally substituted phenyl","optionally substituted phenyl or benzyl", "optionally substituted 5 or 6 membered heteroaryl","optionally substituted 9 to 10 membered fused bicyclic heteroaryl"or"optionally substituted 5 or 6 membered heterocyclic group"as used herein refer to a group which is substituted by 1 to 3 groups selected from halogen, C1 4alkyl, C1 4alkoxy, hydroxy, nitro, cyano, amino, C 4alkylamino 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-,-CH2-N (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-N (R7)-CH2-.

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 hydrogen.

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 the bivalent radical-0-.

A representative example of R6 is hydrogen.

A representative example of R7 is C1 6alkyl, for example C1 4alkyl, in particular methyl.

In one embodiment, RI 1 includes heterocyclic groups having the following structure:

wherein the heterocyclic is linked in the 5 or 8 position to the X group as above defined, and heterocyclic groups having the following structure: wherein W is-C (R31)- where R31 and R19 are linked to form the bivalent radical- O (CH2) 2- or- (CH2) t-, in particular- (CH2) t-, and said heterocyclic is linked in the (i) position to the X group as above defined.

Representative examples of R11 include heterocyclic groups having the following structure: wherein the heterocyclic is linked in the 5 or 8 position to the X group as above defined.

In particular, the heterocyclic is linked in the 5 position.

Further representative examples of R11 include heterocyclic groups having the following structure:

wherein W is-C (R31)- where R31 and R19 are linked to form the bivalent radical- O (CH2) 2- or- (CH2) t-, in particular- (CH2) t-, and said heterocyclic is linked in the (i) 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 bicyclic heteroaryl.

In one embodiment, R18 is hydrogen,-C (O) OR29, -C (O) NHR29 or-C (O) CH2NO2. In a further embodiment, Rl8 is-C (O) OR29, -C (O) NHR29 or-C (O) CH2N02. A representative example of Rl 8 is-C (O) OR29, wherein R29 is hydrogen.

A representative example of R19 is C-14alkyl, in particular ethyl.

A representative example of R20 is halogen, in particular fluorine.

In one embodiment, R29 is 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.

In one embodiment, R30 is hydrogen or C1-4alkyl. A representative example of R30 is hydrogen.

In one embodiment, R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical- (CH2) t-. Representative examples of R31 include hydrogen and R20.

In one embodiment, X is-U (CH2) vB-,-U (CH2) v- or a group selected from: A representative example of X is-U (CH2) vB-.

Representative examples of U and B include the divalent radicals-N (R30)-,-O-and- S (O) z-. In particular, U is the divalent radical-N (R30)-and B is selected from the divalent radicals-N (R30)-,-O-and-S (O) Z-, especially-S (O) Z-. Alternatively, U is the divalent radical-O-and B is the divalent radical-N (R30)-.

A representative example of Y is the bivalent radical-0-.

A representative example of d is 1 to 3, for example 2.

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

In one embodiment, v is an integer from 2 to 8. A representative example of v is 2 to 4, for example 2.

A representative example of z is 0.

It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove. It is also to be understood that the present invention encompasses compounds of formula (I) in which a particular group or parameter, for example R7, R14, R15, R16, R20, R21, R22, R23, R24, R25, R26, R27, p28 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.

In one embodiment, when A is-N (R7)-CH2-, d is 2, X is-NH (CH2) 2S-and R11 is a heterocyclic group of the following formula: wherein the heterocyclic is linked in the 5 or 8 position to the X group, j is 1, R18 is carboxy, R1 9 is ethyl and R20 is fluorine.

A particularly preferred compound of the invention is 4"-O- 3- [2- (3-carboxy-1, 4-dihydro-1- ethyl-8-fluoro-4-oxo-quinolin-5-ylsulfanyl) ethylamino] propionyl}-azithromycin-11, 12- carbonate, or a pharmaceutical acceptable derivative thereof.

Compounds according to the invention also exhibit a broad spectrum of antimicrobial activity, in particular antibacterial activity, against a wide range of clinical pathogenic

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

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

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

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

According to a yet further aspect of the invention we provide a method of treatment of the human or non-human animal body to combat microbial infections comprising administration to a body in need of such treatment of an effective amount of a compound of formula (I) or a pharmaceutical 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 pharmaceutical 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 therapeutical 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 pharmaceutical acceptable derivative thereof, together with a pharmaceutical acceptable excipient, diluent and/or carrier.

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

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

For some embodiments, the agents of the present invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-

inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e. g. as a carrier, diluent or solubiliser.

Alpha-, beta-and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148.

The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example see International Patent Application No. WO 02/00196 (SmithKline Beecham).

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

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

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

Where appropriate, the pharmaceutical compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the

compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. it is to be understood that not all of the compounds need be administered by the same 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 genito-urinary use.

For some applications, the agents of the present invention are delivered systemically (such as orally, buccally, sublingually), more preferably orally. Hence, preferably the agent is in a form that is suitable for oral delivery.

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

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

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

The compounds of the invention can be administered (e. g. orally or topically) in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain

flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

The compounds of the invention may also be presented for human or veterinary use in a form suitable for oral or buccal administration, for example in the form of solutions, gels, syrups, mouth washes or suspensions, or a dry powder for constitution with water or other suitable vehicle before use, optionally with flavouring and colouring agents. Solid compositions such as tablets, capsules, lozenges, pastilles, pills, bouses, 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 pharmaceutical acceptable carriers and excipients which may be in solid or liquid form.

The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), 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 excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

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

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

The compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders),

pessaries, tampons, sprays, dips, aerosols, drops (e. g. eye ear or nose drops) or pour- ons.

For application topically to the skin, the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.

Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

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

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

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

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

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

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

When a compound of the invention or a pharmaceutical 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 group XaRl 1 a is XR1 I as defined for formula (I) or a group convertible to XR11.

Similarly, the group BaRl 1 a is BR1 1 as defined for formula (I) or a group convertible to BR11. Conversion of a group XaR11a or gaR11 a to a XR1 1 or BR1 1 group typically arises if a protecting group is needed during the reactions described below. A comprehensive discussion of the ways in which such groups may be protected and methods for cleaving the resulting protected derivatives is given by for example T. W.

Greene and P. G. M Wuts in Protective Groups in Organic Synthesis 2nd ed. , John Wiley & Son, Inc 1991 and by P. J. Kocienski in Protecting Groups, Georg Thieme Verlag 1994 which are incorporated herein by reference. Examples of suitable amino protecting groups include acyl type protecting groups (e. g. formyl, trifluoroacetyl and acetyl), aromatic urethane type protecting groups (e. g. benzyloxycarbonyl (Cbz) and substituted Cbz, and 9-fluorenylmethoxycarbonyl (Fmoc) ), aliphatic urethane protecting groups (e. g. t- butyloxycarbonyl (Boc), isopropyloxycarbonyl and cyclohexyloxycarbonyl) and alkyl type protecting groups (e. g. benzyl, trityl and chlorotrityl). Examples of suitable oxygen protecting groups may include for example alkyl silyl groups, such as trimethylsilyl or tert- butyidimethylsilyl ; alkyl ethers such as tetrahydropyranyl or ter-butyl ; or esters such as acetate. Hydroxy groups may be protected by reaction of for example acetic anhydride, benzoic anhydride or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, N, N-dimethylformamide, dimethylsulfoxid6, tetrahydrofuran and the like.

Compounds of formula (I) wherein d is an integer from 1 to 5, may be prepared by reaction of a 4"hydroxy compound of formula (II) wherein R2 is a hydroxy protecting group with a suitable activated and protected derivative of the carboxylic acid (III), followed where necessary by subsequent removal of the hydroxyl protecting group R2 and conversion of the XaR1 1 a group to XR1 1.

Suitable activated derivatives of the carboxyl group include the corresponding acyl halide, mixed anhydride or activated ester such as a thioester. The reaction is preferably carried out in a suitable aprotic solvent such as a halohydrocarbon (e. g. dichloromethane) or N, N- dimethylformamide optionally in the presence of a tertiary organic base such as dimethylaminopyridine or triethylamine or in the presence of inorganic base (eg sodium hydroxide) and at a temperature within the range of 0° to 120°C. The compounds of formula (II) and (II1) may also be reacted in the presence of a carbodiimide such as dicyclohexylcarbodiimide (DCC).

Compounds of formula (I) wherein d is 0, U is a group selected from-N (R30)-,-O-and- S (O) z-wherein z is 0, may be prepared by reaction of compounds of formula (II), in which the 4"hydroxy is suitably activated, with a compound of formula XaRl 1 a (IV) followed where necessary by subsequent removal of the hydroxyl protecting group R2 and conversion of the XaR1 1 a group to XR1 1. Suitable activated derivatives of the 4"hydroxy group include for example carbonyl imidazolide. The reaction is preferably carried out in a suitable aprotic solvent such as a halohydrocarbon (e. g. dichloromethane) or N, N- dimethylformamide optionally in the presence of a tertiary base such as 1,8- diazabicyclo [5.4. 0] undec-7-ene (DBU), dimethylaminopyridine or triethylamine and at a temperature within the range of 0° to 120°C.

Compounds of formula (I) wherein d is 0 and U is-N (R30) C (O)-, may be prepared by reaction of compounds of formula (V),

with a compound of formula HOC (O) (CH2) vBaR11a (VI) followed where necessary by subsequent removal of the hydroxyl protecting group R2 and conversion of the BaR11a group to BR11. The reaction is preferably carried out in a suitable aprotic solvent such as a halohydrocarbon (e. g. dichloromethane) or N, N-dimethylformamide optionally in the presence of a tertiary base such as dimethylaminopyridine or triethylamine and at a temperature within the range of 0° to 120°C.

Compounds of formula (V) may be prepared by treatment of compounds of formula (II), in which the 4"hydroxy is suitable activated, with amine NR30 (Vlla). Suitable activated derivatives of the 4"hydroxy group include for example carbonyl imidazole.

Compounds of formula (I) wherein d is 0 and U is-C (O) N (R30)-may be prepared by reaction of 4"hydroxy of formula (II) with a suitable activated derivative of the carboxylic acid HOC (O) C (O) N (R30) (CH2) vBaR11a (Vllb) followed where necessary by subsequent removal of the hydroxyl protecting group R2 and conversion of the BaR11a group to Bd1 1.

In a further embodiment of the invention, compounds of formula (I) wherein d is an integer from 1 to 5 and U is a group selected from-N (R30)- and-S-, may be prepared by reaction of compounds of formula (VIII),

(voll) wherein d is an integer from 1 to 5 and L is a suitable leaving group, with XaRl 1 a (IV) 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, dimethylsulfoxide, N, N-dimethylformamide or 1-methyl-pyrrolidone and in the presence of a base, followed, if desired, by removal of the hydroxyl protecting group R2 and conversion of the XaR11a group to XR1 1. Examples of the bases which may be used include organic bases such as diisopropylethylamine, triethylamine and 1,8- diazabicyclo [5.4. 0] undec-7-ene, and inorganic bases such as potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride and the like. Suitable leaving groups for this reaction include halide (e. g. chloride, bromide or iodide) or a sulfonyloxy group (e. g. tosyloxy or methanesulfonyloxy).

Compounds of formula (VIII) may be prepared by reaction of a compound of formula (II), wherein R2 is a hydroxyl protecting group, with a suitable activated derivative of the carboxylic acid HOC (O) (CH2) dL (IX), wherein L is a suitable leaving group as above defined. Suitable activated derivatives of the carboxyl group are those defined above for carboxylic acid (III). The reaction is carried out using the conditions described above for the reaction of a compound of formula (II) with carboxylic acid (III).

In a preferred embodiment of the invention, compounds of formula (I) wherein d is 2 and U is a group selected from-N (R30)- and-S-, may be prepared by Michael reaction of a compound of formula (X) wherein R2 is optionally a hydroxyl protecting group

with a compound of formula XaR11a (IV). The reaction is suitably carried out in a solvent such as dimethylsulfoxide, N, N-dimethylformamide, 1-methyl-pyrrolidone, a halohydrocarbon (e. g. dichloromethane), an ether (e. g. tetrahydrofuran or dimethoxyethane), acetonitrile or alcohol (e. g methanol or isopropanol) and the like, and in the presence of a base, followed, if desired, by removal of hydroxyl protecting group R2 and conversion of the XaR11 a group to XR11.

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 alkylation.

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 bicyclic 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 6alkenyl optionally substituted by 9 to 10 membered fused bicyclic 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 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 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 Cl-4 alkyl may be prepared by decarboxylation of a compound of formula (XI), wherein R34 is hydroxy protecting group followed, if required, by removal of the protecting group R2 or R34.

(Xi) The decarboxylation may be carried out in the presence of a lithium salt such as lithium chloride, preferably in an organic solvent such as dimethylsulfoxide.

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 Cl-4 alkyl may be prepared according to the procedures described in WO 02/50091 and WO 02/50092.

Compounds of formula (III) wherein X is-U (CH2) vN (R30)-, in which U is-N (R30)-,-O-or- S-or X is a group selected from: may be prepared by reaction of XaR11a(IV), wherein X has the meaning defined above with R350C (O) (CH2) dL (XII) wherein R35 is carboxyl protecting group and L is a suitable leaving group, followed by removal of R35. Suitable R35 carboxyl protecting group include t-butyl, allyl or benzyl.

Compounds of formula (IV) wherein X is-U (CH2) vB- in which B is-N (R30)-, -O- or -S- or X is a group selected from: may be prepared by reaction of a compound of formula R11aL (XIII), wherein L is a suitable leaving group such as chlorine, fluorine or bromine, with a compound of formula- U (CH2) VB (XIV) in which B is-N (R30)-,-O-or-S-, or with piperazine or with 1H- pyrrolo [3,4-b] pyridine, octahydro.

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, BOC for t-butoxycarbonyl, DBU for 1, 8-diazabicyclo [5.4. 0] undec-7-ene, DCM for dichloromethane, DMAP for 4- dimethylaminopyridine, DMF for N, N-dimethylformamide, DMSO for dimethyl sulfoxide, EDACxHCL for 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, MeOH for methanol, TEA for triethylamine and THF for tetrahydrofuran.

Examples 2'-O-Acetyl-6-O-methyl-erythromycin A may be prepared by the procedure described by W. R. Baker et a/. in J. Org. Chem. 1988,53, 2340, and 2'-O-acetyl-azithromycin and 2'- O-acetyl-azithromycin-11, 12-carbonate may be prepared by the procedure described by S. Djokic et a/. in J. Chem. Res. (S) 1988,152.

Nomenclature In the Examples, compounds of formula (I) in which Rl 1 is a tricyclic heterocyclic group are referred to using the numbering system below : 1-oxo-6, 7-dihydro-1H, 5H-pyrido [3,2, 1-ij] quinoline Intermediate 1: 8-(2-Aminoethvisulfanvl)-1, 4-dihvdro-1-ethvl-6-fluoro-4-oxo- quinoline-3-carboxvlic acid sodium salt a) 6, 8-Difluoro-1, 4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ethyl ester.

6, 8-Difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (4.945 g, 19.5 mmol) in dry DMF (60 mL) was treated with potassium carbonate (3.0 g, 21.5 mmol) and iodoethane (7 mL, 88 mmol). The mixture was heated at 60°C, with vigorous stirring, for 162 h. During this time further portions of iodoethane (5 x 5 mL) were added. The mixture was reduced in volume, diluted with water then extracted with ethyl acetate (x 3). The combined organic extracts were washed with aqueous sodium thiosulfate and brine, dried, and evaporated to give the crude product. This material was pre-absorbed onto silica gel (10 g) then chromatographed on silica gel (100 g), eluting with 2-4% ethanol in dichloromethane, to give the title compound as a white solid ; ESMS m/z 282 [M+H] +. b) 8-(2-t-Butoxycarbonylaminoethylsulfanyl)-1, 4-dihydro-1-ethyl-6-fluoro-4-oxo- quinoline-3-carboxylic acid ethyl ester.

A suspension of Intermediate 1a (0.843 g, 3 mmol) in dry DMSO (5 mL) was treated sequentially with potassium carbonate (0.828 g, 6 mmol) then N-Boc-cysteinamine (0.56 mL, 3.3 mmol). The mixture was stirred vigorously under argon at 60°C for 1.5 h. The cooled mixture was diluted with water and extracted with ethyl acetate (x 3). The combined organic extracts were washed with brine, dried, and evaporated to give the

crude product. This material was chromatographed on silica gel (100 g), eluting with 0-4% ethanol in dichloromethane, to give the title compound as a white solid ; ESMS m/z 439 [M+H] +. <BR> <BR> <BR> <BR> <BR> <BR> <BR> c) 8-(2-Aminoethylsulfanyl)-1, 4-dihydro-1-ethyl-6-fluoro-4-oxo-quinoline-3- carboxylic acid ethyl ester.

Intermediate 1b (1.2 g, 2.74 mmol) was dissolved in DCM (20 mL) then trifluoroacetic acid (4 mL) was added. After 2 h the solution was evaporated to dryness and the residue was applied to a Varian Bond Elut SCX cartridge. Flushing with MeOH and subsequent elution with 0.04 M NH3 in MeOH up to 2.0 M NH3 in MeOH provided the title compound as a pale yellow solid ; ESMS m/z 339 [M+H] +. d) 8-(2-Aminoethylsulfanyl)-1, 4-dihydro-1-ethyl-6-fluoro-4-oxo-quinoline-3- carboxylic acid sodium salt.

Intermediate 1c (0.92 g, 2.72 mmol) was dissolved in 1,4-dioxane (25 mL) and treated with 0.2 N aqueous sodium hydroxide (13.6 mL, 2.72 mmol). The solution was stirred for 63 h then evaporated to dryness to give the title compound as a yellow solid ; ESMS m/z 311 [M+H] +.

Intermediate 2: 5- (2-Aminoethvlsulfanvl)-1, 4-dihvdro-1-ethvl-8-fluoro-4-oxo- quinoline-3-carboxvlic acid sodium salt a) 5, 8-Difluoro-1, 4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ethyl ester.

Using a similar procedure described for the preparation of Intermediate 1a, 5, 8-difluoro-4- oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.00 g, 4.0 mmol) was converted to the title compound with iodoethane and potassium carbonate; ESMS m/z 282 [M+H] +. b) 5- (2-t-Butoxycarbonylaminoethylsulfanyl)-1, 4-dihydro-1-ethyl-8-fluoro-4-oxo- quinoline-3-carboxylic acid ethyl ester.

Using a method similar to that described for the preparation of Intermediate 1b, Intermediate 2a (0.281 g, 1 mmol) gave, after purification by preparative reverse phase HPLC, the title compound as a white solid ; ESMS m/z 439 [M+H] +. <BR> <BR> <BR> <BR> <BR> <BR> <BR> c) 5- (2-Aminoethylsulfanyl)-1, 4-dihydro-1-ethyl-8-fluoro-4-oxo-quinoline-3- carboxylic acid ethyl ester.

Using a method similar to that described for the preparation of Intermediate 1c, Intermediate 2b (0.23 g, 0.53 mmol) was deprotected with trifluoroacetic acid (2. 5 mL).

Chromatography on silica gel (9 g), eluting with 0-10%'2 M NH3 in methanol'in dichloromethane, gave the title compound; ESMS m/z 339 [M+H] +. d) 5- (2-Aminoethylsulfanyl)-1, 4-dihydro-1-ethyl-8-fluoro-4-oxo-quinoline-3- carboxylic acid sodium salt.

Using a method similar to that described for the preparation of Intermediate 1d, Intermediate 2c (0.15 g, 0.43 mmol) was converted to the title compound; ESMS m/z 311 [M+H] +.

Intermediate 3: 5- (2-Aminoethylamino)-1, 4-dihvdro-1-ethvl-8-fluoro-4-oxo-quinoline -3-carboxviic acid trifluoroacetate salt a) 5- (2-t-Butoxycarbonylaminoethylamino)-1, 4-dihydro-1-ethyi-8-fluoro-4-oxo- quinoline-3-carboxylic acid ethyl ester.

Intermediate 2a (0.333 g, 1.19 mmol) was dissolved in dry THF (10 mL), then triethylamine (0.5 mL, 3.6 mmol) was added followed by 2-t- butoxycarbonylaminoethylamine (0.21 g, 1.31 mmol). The solution was then refluxed for 67 h, and during this time further portions of 2-t-butoxycarbonylaminoethylamine (2 x 0.16 g) and triethylamine (2 x 0.5 mL) were added. The reaction mixture was then evaporated to dryness and chromatographed on silica gel (40 g), eluting with 40-75% ethyl acetate in petroleum ether, to give the title compound as a yellow solid ; ESMS m/z 422 [M+H] +. b) 5-(2-t-Butoxycarbonylaminoethylamino)-1, 4-dihydro-1-ethyl-8-fluoro-4-oxo- quinoline-3-carboxylic acid.

Intermediate 3a (0.175 g, 0.416 mmol) was dissolved in THF, 0.2 N aqueous sodium hydroxide (2.5 mL, 0.5 mmol) added, and the solution stirred at room temperature for 17.5 h. Solid carbon dioxide was then added, and the mixture reduced to a small volume. The solid was filtered off, washing with cold water, and dried in vacuo to give the title compound as a yellow powder; ESMS m/z 394 [M+H] +. c) 5-(2-Aminoethylamino)-1, 4-dihydro-1-ethyl-8-fluoro-4-oxo-quinoline-3-carboxylic acid trifluoroacetate salt.

Intermediate 3b (0.154 g, 0.392 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2.5 mL) added, and the solution stirred for 1 h. The reaction mixture was evaporated to dryness, and again from dichloromethane (x2). The residue was then triturated with dichloromethane to give the title compound as a yellow powder; ESMS m/z 294 [M+H] +.

Intermediate 4: 8-(2-Aminoethoxv)-1, 4-dihvdro-1-ethvl-4-oxo-quinoline-3-carboxviic acid hydrochloride salt a) 8-Benzyloxy-1, 4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ethyl ester.

Using a similar procedure described for the preparation of Intermediate 1a, 8-benzyloxy- 1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (C. Wang, et al., J. Med. Chem., 1995, 38, 950; 1.5 g, 5.08 mmol) gave the title compound as a cream solid ; ESMS m/z 352 [M+H] +.

b) 1, 4-Dihydro-1-ethyl-8-hydroxy-4-oxo-quinoline-3-carboxylic acid ethyl ester.

A mixture of Intermediate 4a and 10% palladium on charcoal in methanol was hydrogenated at atmospheric pressure and room temperature. After 14 h the mixture was filtered and the solvent evaporated to yield the title compound as a bright yellow solid ; 1 H NMR 6 (DgDMSO) 1.28 (3H, t, J = 7.1 Hz), 1.36 (3H, t, J = 6.9 Hz), 4.21 (2H, q, J = 7.1 Hz), 4.67 (2H, q, J = 6.9 Hz), 7.17-7. 30, (2H, m), 7.75 (1H, dd, J = 2.5 & 7.7 Hz), 8.49 (1H, s); 10.68-10. 90 (1 H, brd. s). c) 8- (2-Dibenzylaminoethoxy)-1, 4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ethyl ester.

A mixture of Intermediate 4b (1.00 g, 3.83 mmol), dibenzyl- (2-chloroethyl) amine (1.11 g, 3. 83 mmol) and potassium carbonate (0.60 g, 4.32 mmol) in dry DMF (10 mL) was stirred at 70°C. After 14 h the mixture was cooled, the DMF evaporated and the residue partitioned between diethyl ether (40 mL) and water (25 mL). The organic phase was separated, dried and evaporated to yield the title compound as a dark brown gum; ESMS m/z 485 [M+H] +. d) 8- (2-Dibenzylaminoethoxy)-1, 4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylic acid hydrochloride salt.

Using a similar procedure described for the preparation of Intermediate 1d, Intermediate 4c (1.7 g, 3.5 mmol) gave the title compound after conversion to the hydrochloride salt with 1 M hydrogen chloride in methanol ; 1H NMR 8 (DgDMSO) 1.16 (3H, t, J = 6.8 Hz), 2.91 (2H, t, J = 5.6 Hz), 3.66 (4H, s), 4.33 (2H, t, J = 5.6 Hz), 4.74 (2H, q, J = 7.2 Hz), 7.20-7. 52 (12H, m), 7.96 (1H, dd, J = 2.0 & 7.2 Hz), 8.85 (1H, s), 15.21 (1H, brd. s). e) 8- (2-Aminoethoxy)-1, 4-dihydro-1-ethyl-4-oxo-quinoline-3-carboxylic acid hydrochloride salt.

A mixture of Intermediate 4d (1.4 g, 3.07 mmol) and 10% palladium on charcoal (0.5 g) in methanol (70 mL) was hydrogenated at 50 psi and room temperature. After 48 h the mixture was filtered and the solvent evaporated to yield the crude product. Crystallisation from methanol gave the title compound as a buff-coloured solid ; 1 H NMR 8 (D6DMSO+D2O) 1.41 (3H, t, J = 6.8 Hz), 3.37 (2H, t, J = 4.4 Hz), 4.47 (2H, t, J = 4. 4 Hz), 4.84 (2H, q, J = 7.2 Hz), 7.62-7. 64 (2H, m), 8.06 (1 H, dd, J = 4 & 5.6 Hz), 8.92 (1 H, s).

Intermediate 5 : 2'-O-Acetvl-4"-O-propenovl-azithromvcin-11, 12-carbonate A solution of 2'-O-acetyl-azithromycin-11, 12-carbonate (10.9 g) in toluene (300 mL) was stirred at room temperature under argon atmosphere. To this solution TEA (12.66 mL) and 3-chloro-propionyl chloride (1.94 mL) were added in two portions over a period of 10 minutes. After 20 minutes the solution was diluted with a saturated aqueous solution of NaHCO3 (300 mL) and extracted with toluene (4x80 mL). The collected organic phase

was dried, filtered and concentrated under reduced pressure affording the title compound (11. 0 g).

MS; m/z (ES): 872 [MH] +.

Intermediate 6: 4"-O-Propenovl-azithromvcin-11, 12-carbonate A solution of Intermediate 5 (11.0 g) in MeOH (200 mL) was stirred at room temperature for 48 h. The solvent was evaporated under reduced pressure affording the title compound (9.81 g).

MS; m/z (ES): 829.1 [MH] +.

'H-NMR (500 MHz,) 8 : 6.45 (d, 1H), 6.17 (dd, 1H), 5.87 (d, 1H), 5.11 (d, 1H), 4.88 (dd, 1 H), 4.77 (d, 1 H), 4.53 (d, 1 H), 4.47-4. 40 (m, 3H), 3.72 (m, 1 H), 3.60 (d, 1 H), 3.33 (s, 3H), 3.25 (dd, 1H), 2.87-2. 85 (m, 2H), 2.58 (m, 1H), 2.44-2. 38 (m, 2H), 2.32 (s, 6H), 2.21 (s, 3H), 2.06 (m, 1H), 2.00 (m, 1H), 1.92 (m, 1H), 1.84 (m, 1H), 170-1.56 (m, 4H), 1.45 (s, 3H), 1.40 (dd, 1H), 1.29 (s, 3H), 1.25 (m, 1H), 1.22 (d, 3H), 1.18 (d, 6H), 1.12 (s, 3H), 108- 1.06 (2d, 6H), 0.93 (m, 6H).

Intermediate 7: 2'-O-Acetvl-4"-O-propenovl-6-O-methvl-erythromvcin A To a solution of 2'-O-acetyl-6-O-methyl-erythromycin A (1.1 g) in DCM (20 mL) pyridine (1.7 mL) and acryloyl chloride (1.1 mL) were added at 0°C. After 2 h a further addition of pyridine (1.7 mL) and of acryloyl chloride (1.1 mL) was performed. The reaction mixture was quenched with a saturated solution of NH4CI (10 mL) and extracted with DCM (3x20 mL). The organic phase was washed with a saturated solution of NaHCO3 (10 mL), water (10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash-chromatography (DCM/MeOH/NH3 95/5/0. 5) affording the title compound (470 mg); ESMS m/z 844 [M+H] +.

Intermediate 8: 4"-O-Propenovl-6-O-methvlervthromvcin A Intermediate 7 (1. 82 g) was dissolved in MeOH (100 mL) and stirred at 60°C for 4 h, then at room temperature for 16 h. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (eluent : MeOH/DCM/NH40H 5/90/0) affording the title compound (1.4 g).

MS; m/z (ES): 802 [MH] +.

'H-NMR (500 MHz) 8 : 6.44 (d, 1H), 6.13 (dd, 1H), 5. 89 (d, 1H), 5.07 (d, 1H), 5.00 (d, 1H), 4.75 (d, 1 H), 4.60 (d, 1 H), 4.38 (m, 1 H), 3.97 (s, 1 H), 3.80-3. 73 (m, 2H), 3.66 (d, 1 H), 3.46 (s, 1H), 3.32 (s, 3H), 3.21-3. 18 (m, 2H), 3.04 (s, 3 H), 3.00 (m, 1H), 2.92 (m, 1H), 2.56 (m, 2H), 2.43 (d, 1H), 2.31 (s, 6H).

13C-NMR (75 MHz) 8 : 221.0 ; 175.7 ; 165.8 ; 131.5 ; 128.0 ; 102.1 ; 96.0 ; 80.5, 78.8, 78.3 ; 78.0 ; 76.6 ; 74.3, 72.7 ; 71.1 ; 69.1 ; 67.8 ; 65.3 ; 63.2 : 50.7 ; 49.5 ; 45.3 ; 44.9 ; 40.3 ; 39.2 ; 38.8 ; 37.2 ; 35.2 ; 28.9 ; 21.7, 21.1 ; 19.7, 18.3, 18.0, 15.9 ; 12.3 ; 10.6 ; 9.1.

Intermediate 9: Diethyl 2-((3, 4-dihydro-2H-quinolin-1-vl) methvlene) malonate A mixture of tetrahydroquinoline (13. 32g, 100mmol) and diethyl ethoxymethylenemalonate (21.62g, 100mol) was 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+).

Intermediate 10: Ethyl 1-oXo-6. 7-dihvdro-1H, 5H-pvridof3. 2, 1-iilctuinoline-2- carboxylate Intermediate 9 (2.5g, 8. 24mmol) was dissolved in polyphosphoric acid and the viscous mixture stirred for 4 hours at 110°C. The reaction mixture was cooled down before adding ice. The resulting precipitate was filtered off, washed with water then dried in a dessicator in the presence of phosphorous pentoxide to give the title compound as a beige solid.

ESMS mlz 258 (MH+). I H NMR (DMSO-d6) 8 8.55 (s, 1 H), 8.05 (dd, 1H), 7.54 (dd, 1 H), 7.36 (dd, 1H), 4.27 (q, 2H), 4.22 (q, 2H), 3.00 (t, 2H), 2.10 (tt, 2H), 1.28 (t, 3H).

Intermediate 11: 10-Nitro-1-oxo-6. 7-dihvdro-1 H, 5H-pvridof3, 2, 1-iilauinoline-2- carboxylic acid ethyl ester Intermediate 10 (500 mg) was placed in a round bottom flask. A mixture of H2SO4 : HN03 (1: 1) was added and the resulting mixture was stirred at 0°C for 3 h. The reaction mixture was poured onto ice and the precipitate was filtered affording 400 mg of the title compound. MS (ES) m/z: [MH] + 305.31. 13C NMR (125 MHz, CDCI3) # ppm: 187.0, 165.0, 153.7, 146.0, 145.3, 135.7, 113.1, 109.6, 107.2, 104.1, 59.6, 58.2, 34.4, 29.3, 13.7.

Intermediate 12: 10-Amino-1-oxo-6. 7-dihvdro-1H, 5H-pvridof3, 2, 1-iilauinoline-2- carboxylic acid ethyl ester Intermediate 11 (400 mg) was dissolved in dilute in hydrochloric acid (20 mL) and to this mixture Fe powder (112 mg) was added. The reaction mixture was stirred at room temperature for 15 h and then filtered to remove the catalyst. The pH of the reaction mixture was adjusted to pH=5 during which product precipitated affording 350 mg of the title compound. MS (ES) m/z: [MH] + 273. 4. 13C NMR (125 MHz, CDCl3) J ppm: 187.2, 165.3, 154.2, 147.7, 145.5, 135.9, 129.2, 115.7, 112.6, 110.1, 60.3, 58. 3,34. 5,29. 3,13. 9.

Intermediate 13: 10- (2-Benzvloxv-ethvlamino)-1-oxo-6, 7-dihvdro-1H, 5H- pvridof3, 2, 1-iilcquinoline-2-carboxvlic acid ethvl ester Intermediate 12 (350 mg) was dissolved in methanol (30 mL). Benzyloxyacetaldehyde (0.542 mL), sodium cyanoborohydride (242.5 mg) and acetic acid (0.004 mL) were

added to the solution and the reaction mixture was stirred at room temperature for 3h.

The reaction mixture was concentrated in vacuo and ethylacetate (150 mL) was added.

The mixture was washed with water (2x100 mL) and the organic layers were washed with brine. The mixture was then concentrated in vacuo affording 330 mg of the title compound. MS (ES) m/z: [MH] +407. 49.

Intermediate 14: 10- (2-Hvdroxv-ethvlamino)-1-oxo-6, 7-dihvdro-1 H, 5H-Pvridor3, 2, 1- ilauinoline-2-carboxvlic acid ethyl ester Intermediate 13 (330 mg) was dissolved in ethanol (30 mL). Cyclohexene (27 mL) and 10% Pd/C (0.515 g) were added to the solution and the reaction mixture was stirred at 75°C overnight. The reaction mixture was filtered to remove the catalyst and the ethanol was removed in vacuo affording 320 mg of the title compound. MS (ES) m/z: [MH] + 317.36.

Intermediate 15 : 10-r2- (2-Cvano-ethoxv)-ethvlaminol-1-oxo-6, 7-dihvdro-1 H, 5H- pvridof3. 2, 1-ilquinoline-2-carboxvlic acid ethyl ester Intermediate 14 (320 mg) was dissolved in acrylonitrile (32 mL) and DBU (0.32 mL) was added. The reaction mixture was stirred at 80°C for 24 h and then concentrated in vacuo.

The residue was dissolved in DCM, the pH was adjusted to pH=3 and the residue was then washed with H20 (3x20 mL). The DCM was removed in vacuo affording 300mg of the title compound. MS (ES) m/z: [MH]+307. 42.

Intermediate 16: 10-r2- (2-Carboxv-ethoxv)-ethvlaminol-1-oxo-6, 7-dihvdro-1H, 5H- pvridof3, 2, 1-iilquinoline-2-carboxylic acid Intermediate 15 (300 mg) was dissolved in H2O : H2SO4 (1: 1) (40 mL) and stirred for 24 h at 75°C. The pH of the reaction mixture was adjusted to pH=3 during which a precitipate was obtained. The precipitate was filtered and dried affording 200 mg of the title compound. MS (ES) m/z: [MHr361. 37.

Example 1: 4"-O-3-r2- (3-Carboxv-1, 4-dihvdro-1-ethvl-6-fluoro-4-oxo-quinolin-8- visulfanvl) ethvlaminolpropionvl-6-O-methvlervthromvcin A monoformate salt

A mixture of Intermediate 8 (0.096g, 0.12 mmol) and Intermediate 1d (0.044 g, 0.13 mmol) in DMSO (0.5 mL), water (1 drop) and triethylamine (0.056 mL, 0.4 mmol) were heated at 80°C. After 41 h the mixture was cooled, filtered, and purified by preparative reverse phase HPLC to give the title compound as an off-white powder; ESMS m/z 1112 [M+H] +.

Example 2: 4"-O-3-r2- (3-Carboxv-1, 4-dihvdro-1-ethvl-6-fluoro-4-oxo-quinolin-8- vlsulfanvl) ethylaminolpropionvlT-azithromvoin-11. 12-carbonate monoformate salt A mixture of Intermediate 6 (0.100 g, 0.12 mmol) and Intermediate 1d (0.044 g, 0.13 mmol) in DMSO (0.5 mL), water (1 drop) and triethylamine (0.056 mL, 0.4 mmol) were heated at 80°C. After 120 h the mixture was cooled, filtered, and purified by preparative reverse phase HPLC to give impure material. This was further purified by chromatography on silica gel (0.8 g), eluting with 0-30%'2 M NH3 in methanol'in dichloromethane, to give the title compound as an off-white foam; ESMS m/z 1139 [M+H] +.

Example 3: 4"-O-{3-[2-(3-Carboxy-1,4-dihydro-1-ethyl-8-fluoro-4-oxoquin olin-5- ylsulfanvl) ethvlaminolpropionvlT-6-O-methvlervthromvoin A diformate salt

A mixture of Intermediate 8 (0.096g, 0.12 mmol) and Intermediate 2d (0.056 g,-80% pure, 0.13 mmol) in DMSO (0.5 mL), water (1 drop) and triethylamine (0.056 mL, 0.4 mmol) were heated at 80°C. After 235 h the mixture was cooled, filtered, and purified by preparative reverse phase HPLC to give the title compound as an off-white powder; ESMS m/z 1112 [M+H] +.

Example 4: 4"-O-{3-[2-(3-Carboxy-1,4-dihydro-1-ethyl-8-fluoro-4-oxoquin olin-5- visulfanvl) ethvlaminolPropionvlT-azithromvcin-11, 12-carbonate monoformate salt A mixture of Intermediate 6 (0.100 g, 0.12 mmol) and Intermediate 2d (0.056 g, #80% pure, 0.13 mmol) in DMSO (0.5 mL), water (1 drop) and triethylamine (0.056 mL, 0.4 mmol) were heated at 80°C. After 235 h the mixture was cooled, filtered, and purified by preparative reverse phase HPLC to give impure material. This was further purified by chromatography on silica gel (0.5 g), eluting with 0-33%'2 M NH3 in methanol'in dichloromethane, to give the title compound as an off-white powder; ESMS m/z 1139 [M+H] + ; 1 H NMR 8 (CDCI3) (inter alia) 3.32 (3H, s), 4.71 (1 H, d), 5.3 (1 H, d), 7.3 (1 H, dd), 7.48 (1 H, dd), 8.62 (1 H, s).

Example 5: 4"-O-{3-[2-(3-Carboxy-1,4-dihydro-1-ethyl-8-fluoro-4-oxoquin olin-5- vlamino) ethvlaminolpropionvlT-6-O-methvlervthromvoin A monoformate salt

A mixture of Intermediate 8 (0.096g, 0.12 mmol) and Intermediate 3c (0.053 g, 0.13 mmol) in DMSO (0.5 mL), water (1 drop) and triethylamine (0.042 mL, 0.3 mmol) were heated at 80°C. After 240 h the mixture was cooled, filtered, and purified by preparative reverse phase HPLC to give the title compound as a yellow powder; ESMS m/z 1095 [M+H] +.

Example 6: 4"-O-{3-[2-(3-Carboxy-1,4-dihydro-1-ethyl-8-fluoro-4-oxoquin olin-5- vlamino) ethvlaminolpropionvl-azithromvcin-11, 12-carbonate A mixture of Intermediate 6 (0.100 g, 0.12 mmol) and Intermediate 3c (0.053 g, 0.13 mmol) in DMSO (0.5 mL), water (1 drop) and triethylamine (0.042 mL, 0.3 mmol) were heated at 80°C. After 312 h the mixture was cooled, filtered, and purified by preparative reverse phase HPLC to give impure material. This was further purified by chromatography on silica gel (0.6 g), eluting with 0-35%'2 M NH3 in methanol'in dichloromethane, to give the title compound as an yellow powder; ESMS m/z 1122 [M+H] +. <BR> <BR> <P>Example 7 : 4"-O- (3-f2- (3-Carboxv-1. 4-dihvdro-1-ethvl-4-oxo-quinolin-8- <BR> vioxv) ethvlaminolpropionvl-6-O-methvlervthromvcin A

Using a method similar to that described for the preparation of Example 1, Intermediate 8 (0.14 g, 0.16 mmol) and Intermediate 4e (0.10 g, 0.32 mmol) gave the title compound after chromatography over silica gel eluting with dichloromethane/methanol/ammonia ; ESMS m/z 1078 [M+H] +.

Example 8 : 4"-O- (3- 2- (3-Carboxv-1, 4-dihvdro-1-ethvl-4-oxo-quinolin-8- yloxy) ethvlaminolpropionvl-azithromvcin-11, 12-carbonate tris (trifluoroacetate)

Using a method similar to that described for the preparation of Example 2, Intermediate 6 (0.2 g, 0.24 mmol) and Intermediate 4e (0.075 g, 0.24 mmol) gave the title compound after purification by reverse phase chromatography; ESMS m/z 1104 [M+H]-.

Example 9: 4"-O-{3-[2-(6-Carboxy-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-i j]quinolin- 8-vlamino)-ethoxvl-propionvl-azithromvcin

Intermediate 16 (150 mg) was dissolved in DMF (dried over 4A molecular sieves, 15 mL) and the solution was cooled to 0°C under an N2 atmosphere. EDACxHCI (160 mg) was added and the reaction mixture stirred for 5 min. 2'OAc-Azithromycin (660 mg) diluted with DCM (dried over 4A molecular sieves, 5 mL) and DMAP (154 mg) were added and the reaction mixture stirred for 24 h. EtOAc (30 mL) was then added and the mixture was extracted with H20 (3x20 mL). The organic layers were washed with brine and the solvent was concentrated in vacuo affording 280 mg of product which was dissolved in MeOH (50 mL) and stirred at 50°C for 24 h. The MeOH was then concentrated in vacuo.

Column chromatography in 90: 5: 0.5 (DCM: MeOH: NH3) yielded 120 mg of the title compound. MS (ES) m/z: [MH] + 1092.36.

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 (/jg/mL) of test compounds against various organisms was determined including: S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565, E. faecalis ATCC 29212, H. influenzae ATCC 49247, M. catarrhalis ATCC 23246.

Examples 1,3, 4 and 7 have an MIC <1, ug/mL against S. aureus Smith ATCC 13709, S. pneumoniae SP030, S. pyogenes 3565 and E. faecalis ATCC 29212.

Examples 2, 4 and 7 have an MIC <2 jug/mL against H. influenzae ATCC 49247 and M. catarrhalis ATCC 23246. Examples 3,4 and 6 have an MIC <1, ug/mL against erythromycin resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes.

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