WO1991009856A1 - Pharmaceutically active oxazole compounds - Google Patents

Abstract

Compounds of formula (I), in which R1 represents an optionally substituted pyridyl group are of use in anti-bacterial and anti-mycoplasmal therapy. Pharmaceutical and veterinary compositions comprising such compounds, processes for the preparation thereof and intermediates for use in the preparation of such compounds are also described.

Description

Pharmaceutically active oxazole compounds.

The present invention relates to a class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine and also to intermediates for use in the preparation of such compounds.

Compounds of the general formula (A):

in which the group R° represents an optionally substituted 5-membered heteroaryl ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur,

have been previously disclosed in EP-A-0 087 953 (Beecham Group pic) and EP-A-0 123 378 (Beecham Group pic) and will be recognised as derivatives of monic acid A in which the carboxylic acid group thereof has been replaced by the group

Rº . Such compounds were shown to have antibacterial and antimycoplasmal activity.

Amongst the compounds of formula (A) described in EP-A-0 087 953 are examples in which the group R° is oxazolyl, substituted with a range of groups including substituted phenyl, substituted alkyl and thienyl.

In addition EP-A-0 399 645 (Beecham Group pic) (published after the priority date claimed for the present application) discloses compounds of formula (A) in which R° is a 5-furyloxazol-2-yl or a 5-isoxazolyloxazol-2-yl moiety.

Surprisingly, it has now been found that biological activity may be enhanced in other types of substituted oxazolyl derivatives compared with those described in EP-A-0 087 953 and EP-A-0 399 645.

Accordingly, the present invention provides a compound of formula (I):

in which R¹ represents a pyridyl group which is bonded via a carbon atom thereof to the oxazolyl moiety, which pyridyl group may be unsubstituted or substituted by up to five, preferably up to three, substituents which may be the same or different.

Suitable substituents for the pyridyl group of R¹ include, for example:

(i) halogen, cyano, azido, nitro, formyl, carboxy, carboxylate salts, sulpho, or sulphonate salts,

(ii) amino, ureido, carbamoyl, or sulphonamido, in each of which groups a nitrogen atom may be further optionally substituted by one or two groups (which may be the same or different) selected from the groups listed in sub-paragraphs (iv), (v) and (vi); (iii) hydroxy, or mercapto, in each of which groups hydrogen may be replaced by one of the groups listed in subparagraphs (iv), (v) and (vi);

(iv) a group R^p wherein R^p denotes aryl or heterocyclyl;

(v) a group R^q wherein R^q denotes (C_1-6)alkyl,

(C_{3 - 7})cycloalkyl, (C_2-6)alkenyl, (C_3-8)cycloalkenyl or (C_2-6)alkynyl, each of which may be optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in sub-paragraphs (i), (ii), (iii), (iv) and (vi);

(vi) a group R^pCO-, R^pOCO-, R^qCO-, R^qOCO-, R^pSO-, R^pSO₂-, R^qSO-, or R^qSO₂- wherein R^p and R^q are as defined in subparagraphs (iv) and (v) respectively; and

(vii) a divalent group Y° which together with two carbon atoms of the pyridyl group to which it is bonded form a heterocyclic or carbocyclic ring.

Preferably the divalent group Y° is bonded to two carbon atoms which are in a 1,2-relationship.

Typically, the divalent group Y° may be formed by the removal of a hydrogen atom from one of the substituents hereinbefore listed in sub-paragraphs (ii) to (vi) or by the linking together of two substituents hereinbefore listed in sub-paragraphs (ii) to (vi), by the removal of a hydrogen atom from each.

It will be appreciated that in compounds of formula (I) in which one of the pyridyl substituents is a hydroxy group located α- or γ- to the pyridyl nitrogen atom, giving an α- or γ-pyridone, respectively, then one of the other pyridyl substituents may be located on the nitrogen atom. Examples for groups suited to being located at the nitrogen atom of the pyridyl ring include those listed hereinbefore at sub-paragraphs (iv), (v) and (vi) and also amino optionally substituted by groups listed hereinbefore in subparagraphs (iv), (v) and (vi), in respect of substituents for the pyridyl group.

Specific substituents for the pyridyl group include, for example, hydroxy, halogen, cyano, nitro, optionally substituted (C_1-6)alkyl, aryl, heterocyclyl, (C_1-6)alkoxy, carboxy and salts thereof, (C_1-6)alkoxycarbonyl, acyl, amino, mono- or di-(C_1-6)alkylamino, carbamoyl, mono- or di-(C_1-6)alkylcarbamoyl, carbamoyloxy, mono- or di-

(C_1-6)alkylcarbamoyl, acylamino, (C_1-6)alkoxycarbonylamino, (C_1-6) alkylthio, arylthio, (C_1-6)alkylsulphinyl, arylsulphinyl, (C_1-6)alkylsulphonyl, arylsulphonyl, sulphamoyl, mono- or di-(C_1-6)alkylsulphamoyl.

More specific examples of substituents for the pyridyl group include, for instance, hydroxy; halogen, for instance fluoro, chloro and bromo; (C_1-6)alkyl, for instance methyl; (C_1-6)alkoxy, for instance methoxy, ethoxy; (C_1-6)alkylthio, for instance thiomethyl; (C_1-6)alkylsulphinyl, for instance methylsulphinyl; (C_1-6)alkylsulphonyl, for instance methylsulphonyl; di(C_1-6)alkylamino, for instance, dimethylamino; and di(C_1-6)alkylcarbamoyloxy, for instance N, N diethylcarbamoyloxy.

When used herein, the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.

Suitably in R¹, the pyridyl group has a single substituent which is preferably located on a carbon atom α- or β- to the pyridyl nitrogen atom.

When used herein, the term 'heterocyclyl' includes, unless otherwise defined, aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents. Suitably the heterocyclic ring comprises from 4 to 7, preferably 5 to 6 atoms.

When used herein, the term 'halogen' refers to fluorine, chlorine, bromine and iodine.

Substituents for groups hereinbefore defined as being optionally substituted, for instance alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or heterocyclyl, include:

(a) halogen, cyano, azido, nitro, phthalimido, formyl, carboxy, carboxylate salts, sulpho, sulphonate salts, or oxo;

(b) amino, imino, hydrazino, hydrazono, ureido, guanidino, carbamoyl, or sulphonamido, in each of which groups a nitrogen may be further optionally substituted by one or two groups (which may be the same or different) selected from the groups listed in sub-paragraphs (d), (e) and (f);

(c) hydroxy, oxyimino, hydroximoyl, benzohydroximoyl, or mercapto, in each of which groups hydrogen may be replaced by one of the groups listed in subparagraphs (d), (e) and (f);

(d) a group R^p wherein R^p denotes aryl or heterocyclyl; (e) a group R^q wherein R^q denotes (C_1-6)alkyl,

(C_3-7) cycloalkyl, (C_2-6) alkenyl, (C_3-8)cycloalkenyl, or (C_2-6) alkynyl, each of which may be optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in sub-paragraphs (a), (b), (c), (d) and (f); and

(f) a group R^pCO-, R^pOCO-, R^qCO-, R^qOCO-, R^pSO-, R^pSO₂-, R^qSO-, or R^qSO₂- wherein R^p and R^q are as defined in subparagraphs (d) and (e) respectively.

Suitable substituents for an alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group include, for example, halogen, cyano, azido, nitro, hydroxy, oxo, carboxy, (C_1-6) alkoxycarbonyl, carbamoyl, mono- or di-(C_1-6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C_1-6)alkylsulphamoyl, amino, mono- or di-(C_1-6)alkylamino, acylamino, ureido, (C_1-6)alkoxycarbonylamino, 2,2,2-trichloro- ethoxycarbonylamino, aryl, heterocyclyl, (C_1-6)alkoxy, acyloxy, 2-thenoyl, (C_1-6)alkylthio, (C_1-6)alkanesulphinyl, (C_1-6)alkanesulphonyl, hydroxyimino, (C_1-6)alkoxyimino, hydrazino, hydrazono, benzohydroximoyl, guanidino, amidino, or iminoalkylamino.

Suitable substituents for an aryl group include, for example, halogen, cyano, (C_1-6) alkyl, phenyl, (C_1-6)alkoxy, halo(C_1-()alkyl, hydroxy, amino, mono- or di-(C_1-6)alkylamino, acylamino, nitro, carboxy, (C_1-6)alkanoyl, (C_1-6)alkoxycarbonyl,

(C_2-6)alkoxycarbonyl (C_1-6)alkyl, (C_1-6)alkylcarbonyloxy, (C_1-6)alkylthio, (C_2-6)alkylsulphinyl, (C_1-6)-alkylsulphonyl, sulphamoyl, mono- or di-(C_1-6)alkylsulphamoyl, carbamoyl, and mono- or di-(C_1-6)alkylcarbamoyl. Suitable substituents for a heterocyclyl group include, for example, halogen, (C_1-6) alkyl, (C_1-6) alkoxy, halo (C_1-6) alkyl, hydroxy, amino, mono- or di-(C_1-6)alkylamino, carboxy, (C_1-6)alkoxycarbonyl, (C_1-6)alkoxycarbonyl (C_1-6)alkyl, aryl or oxo.

It will be appreciated that in compounds of formula (I), the pyridyl of group R¹ may be bonded to the oxazole ring via a carbon atom which is α-, β-, or γ- to the pyridyl nitrogen atom. Preferably, in compounds of formula (I), the pyridyl group of R¹ is bonded to the oxazole ring by a carbon atom which is β- to the pyridyl nitrogen atom.

Compounds of formula (I) may conveniently be named as '(1-normon-2-yl)oxazoles'. Normonyl is the trivial name for the 3-[(2S,3R,4R,5S)-5-[(2S,4S,5S)-2,3- epoxy-5-hydroxy-4-methylhexyl]-3,4-dihydroxy- tetrahydropyran-2-yl]-2-methylprop-1 (E)-enyl radical, as shown in formula (II):

(II)

It will be appreciated that in compounds of formula (I), the chiral centres of the radical of formula (II) will have the same absolute configuration as the corresponding radical in monic acid A. It will be further appreciated that in compounds of formula (I), in R¹, substituents of the pydridyl group may contain one or more chiral centres. The present invention encompasses all such resultant isomeric possibilities.

Since the compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.

When some of the compounds of this invention are allowed to crystallise, or are recrystallised, from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Examples of compounds within this invention include the following:

2-(1-Normon-2-yl)-5-(2-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(3-pyridyl)oxazole; 2-(1-Normon-2-yl)-5-(4-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(2-methyl-5-pyridyl)oxazole; 2-(1-Normon-2-yl)-5-(1,2-dihydro-2-oxo-5-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(2-methoxy-5-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(1,2-dihydro-1-methyl-2-oxo-5-pyridyl)oxazole;

5-(2-Methoxy-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Chloro-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2,3-Dichloro-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Methylthio-5-pyridyl)-2-(1-normon-2-yl)oxazole; 5-(2-Methylsulphinyl-5-pyridyl)-2-(1-normon-2-yl)oxazole; 5-(2-Methylsulphonyl-5-pyridyl)-2-(1-normon-2-yl)oxazole; 5-[2-(N,N-Diethylcarbamoyloxy)-5-pyridyl]-2-(1-normon-2-yl)oxazole; 5-(2-Bromo-5-pyridyl)-2-(1-normon-2-yl)oxazole; 5-(2-Fluoro-5-pyridyl)-2-(1-normon-2-yl)oxazole; 5-(2-Ethoxy-5-pyridyl)-2-(1-normon-2-yl)oxazole; 5- (3-Bromo-5-pyridyl ) -2- (1-normon-2-yl) oxazole;

5-(2-Dimethylamino-5-pyridyl)-2-(1-normon-2-yl)oxazole; and

5-(2-Fluoro-3-pyridyl)-2-(1-normon-2-yl)oxazole.

Compounds of formula (I) can be prepared by analogy with the methods described in EP-A-0 087 953 and EP-A-0 123 378.

In particular, the present invention provides a process for the preparation of a compound of formula (I) which process comprises cyclising a compound of formula (III):

m which R¹ is as hereinbefore defined, and Z¹, Z² and Z³ are the same or different and each is hydrogen or a hydroxyl-protecting group;

to form a compound of formula (I) and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Compounds of formula (III) may be cyclised using a carboxylic anhydride or mixed anhydride or an acid chloride, such as trifluoroacetic anhydride or trichloroacetic anhydride or trichloroacetyl chloride, which latter is preferably used in the presence of pyridine and 4-dimethylaminopyridine. In this reaction the hydroxyl groups of the 1-normon-2-yl radical become acylated and must subsequently be deprotected. Trihaloacetyl groups formed during cyclisation may be removed using potassium carbonate in solvents such as water, alkanols or admixtures thereof. Appropriate deprotecting conditions for removing other acyl residues will be readily apparent to the skilled person. Alternatively the hydroxyl groups of the 1-normon-2-yl radical may be protected, prior to cyclising with a carboxylic anhydride, and deprotected by conventional methods such as described below.

The cyclisation of a compound of formula (III) may also be suitably effected using a chlorinating agent such as phosphorus oxychloride, phosgene, thionyl chloride or phosphorus pentachloride in the presence of a tertiary amine, such as triethylamine or pyridine. Such a reaction is conveniently effected in an organic solvent, for instance dichloromethane or tetrahydrofuran, at from reduced to elevated temperature, for instance -80° to 100°C, over a period of several hours to a few days. Preferably phosgene or phosphorus oxychloride is used, at a temperature of from 0° to 20°C.

Alternatively, cyclisation may be effected using triphenylphosphine and carbon tetrachloride as the chlorinating reagent, in the presence of a tertiary amine, for instance triethylamine, in an inert solvent such as acetonitrile or acetonitrile-pyridine. This type of process is described by H. Vorbruggen and K. Krolikiewicz in Tetrahedron Lett., 1981, 4471; it is particularly advantageous in that the formation of compounds of formula (III) and cyclisation of these to compounds of formula (I) may be conducted In situ.

Compounds of formula (III) as defined above are novel and useful as chemical intermediates in the aforementioned rocess. Accordingly, the present invention also provides a compound of formula (III), as hereinbefore defined.

Example of compounds within formula (III) include the following:

N-[2-oxo-2-(2-pyridyl)ethyl]monamide;

N-[2-oxo-2-(3-pyridyl)ethyl]monamide;

N-[2-oxo-2-(4-pyridyl)ethyl]monamide;

N-[2-oxo-2-(2-methyl-5-pyridyl)ethyl]monamide;

N-[2-oxo-2-(1,2-dihydro-2-oxo-5-pyridyl)ethyl]monamide;

N-[2-(2-methoxy-5-pyridyl)-2-oxoethyl]monamide;

N-[2-(2-chloro-5-pyridyl)-2-oxoethyl]monamide;

N-[2-(2,3-dichloro-5-pyridyl)-2-oxoethyl]monamide;

N-[2-(2-methylthio-5-pyridyl)-2-oxoethyl]monamide;

N-[2-(2-Bromo-5-pyridyl)-2-oxoethyl]monamide;

N-[2-Oxo-2(2-fluoro-5-pyridyl)ethyl]oxymonamide;

N-[2-Oxo-2(2-ethoxy-5-pyridyl)ethyl]monamide;

N-[2-(3-Bromo-5-pyridyl)-2-oxoethyl]monamide; N-[2-(2-Dimethylamino-5-pyridyl)-2-oxoethyl]monamide; and

N-[2-(2-Fluoro-2-pyridyl)-2-oxoethyl]monamide.

Compounds of formula (III) may be produced from monic acid A by analogy with the reaction sequence previously described in EP-A-0 087 953 (Beecham Group pic).

Suitably monic acid A is initially converted to an activated derivative, for instance a mixed anhydride such as that formed by reaction with iso-butylchlorformate in the presence of a suitable base such as triethylamine; followed by reaction of this intermediate with an amine hydrochloride salt of the formula (IV):

R¹COCH₂NH₃ ⁺Cl- (IV)

wherein R ¹ is as hereinbefore defined; in the presence of a suitable base such as triethylamine.

It will be appreciated that the compounds of formula (IV), as hereinbefore defined, are pyridines with β-aminoketones side chains and these may be obtained from starting materials which are either well known or readily available or produced by conventional processes, for instance, by analogy with the methodology described in Organic Synthesis, Coll. Vol. V, 909.

The present invention also provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (V): (V)

in which Z¹, Z² and Z³ are the same or different and each is hydrogen or a hydroxyl-protecting group;

with a compound of formula (VI):

(VI)

in which R¹ is as hereinbefore defined;

M⁺ is a metal cation, preferably an alkali metal cation, most preferably a lithium or sodium cation; and

R² is an anion-stabilismg group which will spontaneously eliminate with a β-hydroxyl group to produce an olefin, preferably a trialkylsilyl or a dialkylphosphonate group, most preferably trimethylsilyl or diethylphosphonate;

and, thereafter and if necessary, removing any hydroxyl-protecting groups. The reaction of a compound of formula (V) with a compound of formula (VI) may conveniently be effected in an organic solvent, such as tetrahydrofuran, diethyl ether or dimethyl sulphoxide, at from reduced to elevated temperature, such as from -80° to 100°C.

The compound of formula (V) in which each of Z¹, Z² and Z³ is hydrogen, and processes for its production, are described in GB 1 587 060. Derivatives thereof wherein Z¹, Z² and Z³ are hydroxyl protecting groups may be produced by conventional methods such as those mentioned below. When this compound is produced with hydroxyl protecting groups already in place it may be used directly or even in situ in the above reaction or it may be optionally deprotected and/or isolated.

The compounds of formula (VI) may be prepared by conventional processes, by analogy with those as described in EP-A-0 123 378 (Beecham Group pic.). For instance, a compound of formula (VII):

(VII)

wherein W is hydrogen or halogen and R¹ is as hereinbefore defined, may be converted into a compound of formula (VI) in which M is lithium and R² is trimethylsilyl, according to the methodology of W.S. Wadsworth Jr, Organic Reactions, 1977, 25, 73; and by E.J. Corey and D.L. Boger, Tet. Letters, 1978, 5; T.H. Chan,, Acc. Chem. Res. 1977, 10, 442. Alternatively, a compound formula (VII) may be converted to a compound of formula (VI) in which M is an alkali metal and R² is diethylphosphonate, by anology with Hungate, J. Org. Chem., 1981, 46, 1410;

It will be appreciated that compounds of formula (VII), as hereinbefore defined, are 2-substituted-5-pyridyloxazoles and are either well known and readily available or may be produced by conventional processes. The synthesis of oxazoles is reviewed in 'Comprehensive Heterocyclic Chemistry', ed. Katritzky and Rees, 6, Chapter 4.18. By way of illustration only, a convenient synthetic strategy uses as its starting point a pyridyl derivative, for instance a compound of formula (IV), as hereinbefore defined, which may then be converted to a compound of formula (VII), by the analogy with the methodology described by J.L. La Mattina J. Org. Chem., 1980, 45, 2261.

The present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula (VIII):

in which:

Z¹, Z², and Z³ are the same or different and each is hydrogen or a hydroxyl-protecting group, R¹ is as hereinbefore defined, and Y is a leaving group;

with a strong base, and thereafter and if necessary removing any hydroxyl-protecting groups, by analogy with the process described in EP-A-0 399 645 (Beecham Group pic).

Suitable values for Y include, for instance, aryl sulphonyl, for example p-toluenesulphonyl, alkylsulphonyl, alkyl or aryl sulphinyl, quaternary ammonium, for example trialkylammonium, and dialkoxy phosphine oxide.

Suitable strong bases include for example 1,8-diazo- bicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazobicyclo[4.3.0]non-5-ene (DBN).

Suitably the reaction is effected in a solvent such as acetonitrile, and at a temperature in the range from -20 to +80°C.

Compounds of formula (VIII) as hereinbefore defined are novel and useful as intermediates in the aforementioned processs.

Accordingly, the present invention also provides a compound of formula (VIII), as hereinbefore defined.

Compounds of formula (VIII) may be prepared by the treatment of a compound of formula (IX):

in which Z¹, Z², and Z³ are the same or different and each is hydrogen or a hydroxyl-protecting group, and Y is as hereinbefore defined,

with a compound of formula (X):

R¹-CHO (X)

in which R¹ is as hereinbefore defined,

or a corresponding analogue thereof in which the aldehyde functionality of the compound formula (X) is masked, under dehydrating conditions.

Suitable dehydrating conditions are similar to those hereinbefore described in respect of the cyclisation of a compound of formula (III) to give a compound of formula (I).

Particularly suitable conditions include the use of triphenylphosphine in combination with carbon tetrachloride or hexachloroethane, in the presence of triethylamine.

The preparation of compounds of formula (IX) is described in EP-A-0 399 645 (the Beecham Group pic).

Compounds of formula (X) are recognisable as aldehyde derivatives of pyridine and are either available commercially or well known or prepared from readily available starting materials by the adaptation of standard methodology.

The present invention also provides a process for preparing a compound of formula (I) which process comprises isomerising the carbon-carbon double bond of a compound of formula (XI) :

(XI) in which R¹, Z¹, Z² and Z³ are as hereinbefore defined; by methods known for the isomerisation of a carbon-carbon double bond.

Suitable isomerisation methods are described by Sonnet in Tetrahedron, 1980, 36, 557 and include photo- chemical and addition-elimination methods.

A compound of formula (XI) may be obtained by treating a compound of formula (V) with a compound of formula (VI), as hereinbefore described. This reaction is lacking stereoselectivity and may lead to the formation of compounds of formulae (I) and (XI), which may then be separated by conventional procedures such as chromatography.

The present invention also provides for the conversion of one compound of formula (I) to another compound of formula (I), which may be effected by conventional methods. Thus, for instance, all or any one of the substituents of the pyridyl group of R¹ may be modified or converted. Included within this is salification and esterification of a carboxy substituent, trans- and de-esterification of an ester-containing substituent, reduction of an alkoxycarbonyl substituent and formation of the free carboxy group from a carboxylate salt. Another example of such conversion is the formation of alkanesulphinyl and alkanesulphonyl compounds from the corresponding alkylthio compound of formula (I). This latter conversion may be achieved using conventional oxidising agents such as percarboxylic acids, for instance m-chloroperbenzoic acid, in a suitable solvent.

When used herein, the term 'hydroxyl-protecting group' refers to any such group known in the art which may be removed without disruption of the remainder of the molecule. Suitable hydroxyl-protecting groups are described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981.

The hydroxyl groups of monic acid A, and compounds of formulae (III), (V), (VIII), (IX) and (XI) may be protected at any stage of the above processes, using conventional methods. The hydroxyl-protecting group may be removed by methods known in the art, including enzymatic methods.

Particularly suitable hydroxyl-protecting groups are silyl groups since these are readily removed under mild conditions. Such groups are introduced using conventional silylating agents, including halosilanes and silazanes, for example those of the formulae below:

L₃SiX L₃SiO-C=NSiL₃ L₂SiX₂

L₃SiNL₂ L₃SiNHSiL₃ Me₃Si L₃SiNHCOL

L₃SiNHCONHSiL₃ ^tBuMe₂Si- LNHCONHSiL₃

tBuMe₂Si-O-SO₂-CF₃

in which Me denotes methyl, t-Bu denotes t-butyl, X is halogen and each group L is independently selected from hydrogen, (C_1-6)alkyl, (C_1-6)alkoxy, aryl or aryl(C_{1- 4})alkyl. A preferred silyating agent is trimethylsilyl chloride. Particularly suitable hydroxyl-protecting groups are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred hydroxyl-protecting groups are trimethylsilyl groups because of their ease of removal.

The glycol function of monic acid A and of the compounds of formulae (III), (V), (VIII), (IX) and (XI) may be protected by forming a cyclic derivative using a compound of formula (XII):

(XII)

wherein R³ is hydrogen or (C_1-6) alkyl and each of R⁴, R⁵ and

R⁶ is (C_{1- 6}) alkyl. In the cyclic derivative, Z¹ and Z² together are a moiety:

wherein R⁷ is (C_1-6) alkyl.

Suitably R³ is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen. The groups R⁴, R⁵ and R⁶ are suitably methyl, ethyl, n- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.

Similarly the hydroxyl groups of a compound of formula (I) may be protected prior to conversion to a further compound of formula (I) as described above.

In each case the protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K. Luk and N.H. Rogers, in 'Chemistry of Pseudomonic Acid, Part II', J.C.S. Perkin Trans. I, 1979, 308.

The compounds of this invention are useful for the treatment of bacterial and mycoplasma-induced infections in animals, including humans, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in man, mastitis in cattle, and respiratory infections in animals such as pigs and cattle.

The compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus, for instance H.influenzae Ql; Branhamella, for instance B.Catarrhalis 1502; Streptococci, for instance S.pyogenes CN10 and S.pneumonia PU7; and Staphylococci, for instance S.aureus Oxford; and against mycoplasma. In addition, compounds of this invention are active against Staphylococci organisms such as S. aureus and S. epidermis which are resistant (including multiply-resistant) to other antibacterial agents, for instance, β-lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides and lincosamides.

This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.

The compositions may be formulated for administration by any route, and would depend on the disease being treated. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For topical application to the skin the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as 'Harry's Cosmeticology' published by George Godwin, London, and the British Pharmacopoeia.

Suppositories will contain conventional suppository bases, e.g. cocoa-butters or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle. The drug, depending on the vehicle and concentration used, can be suspended in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability the composition can be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial. The drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug. For topical application to the ear, the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.

For topical application to the eye, the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

The dosage employed for compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg of the drug.

Veterinary compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis, will generally contain a suspension of the drug in an oily vehicle.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the drug, depending on the method of administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg, of the drug. The dosage as employed for adult human treatment (average weight about 70 kg) will preferably range from 100 mg to 3 g per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.

Alternatively, the drug may be administered as part of the total dietary intake of a non-human animal. In this case the amount of drug employed may be less than 1% by weight of the diet and in preferably no more than 0.5% by weight. The diet for animals may consist of normal foodstuffs to which the drug may be added or the drug may be included in a premix for admixture with the foodstuff. A suitable method of administration of the drug to animals is to add it to the non-human animal's drinking water. In this case a concentration of the drug in the drinking water of about 5-500 μg/ml, for example 5-200 μg/ml, is suitable.

The present invention provides a compound of formula (I) as hereinbefore defined for use in therapy.

The present invention further provides a method of treating the bacterial and/or mycoplasmal infection in human or non-human animal, which method comprises administering a therapeutically effective amount of a compound of formula (I) as hereinbefore defined, to a human or non-human animal in need of such therapy.

Alternatively, a pharmaceutical composition as hereinbefore described may be employed in the treatment.

In particular aspects of the treatment there are provided methods for treating bacterial or mycoplasma-induced infections of human or non-human animals, especially respiratory infections in human and in non-human animals.

The present invention further provides for the use of a compound of formula (I) as hereinbefore defined in the manufacture of a medicament for use in anti-bacterial and/or anti-mycoplasma therapy.

The following Examples illustrate the invention, but are not intended to limit the scope in any way. The following abbreviations have been used in the Examples:

DMF N,N-Dimethylformamide

DMSO Dimethyl sulphoxide THF Tetrahydrofuran

MgSO₄ Anhydrous magnesium sulphate

Chromatography was carried out using silica gel as the adsorbent.

Monic acid A was obtained from pseudomonic acid according to the process described in GB 1 587 058 (to Beecham Group Ltd.).

General method of preparation of monamides

To a solution of monic acid A in dry THF (5ml/mmol) at 0ºC were added triethylamine (1.1 equiv.) and isobutyl chloroformate (1 equiv.). After 0.5h at 0°C the appropriate ammonium salt (1 equiv.) and triethylamine (1 equiv.) were added and the reaction mixture stirred at 0°C for 3h. Ethyl acetate was added and the solution washed with aqueous sodium hydrogen carbonate and brine, then dried (MgSO₄) and evaporated under reduced pressure. The resulting residue was purified by chromatography (silica gel, eluting with 0-20% methanol in dichloromethane) to yield pure amide.

General method of preparation of oxazoles via monamides

Trichloroacetyl chloride (9 equiv.) was added to a solution of the monamide, 4-dimethylaminopyridine (few crystals/mmol) and pyridine (20 equiv.) in dichloromethane (10ml/mmol), cooled in an ice bath. After 0.5h the solution was washed with aqueous sodium hydrogen carbonate solution and then evaporated under reduced pressure. The resulting residue evaporated under reduced pressure. The resulting residue was dissolved in methanol (5ml/mmol) and the solution cooled to 0°C before addition of potassium carbonate (3 equiv.). After 15min at 0°C brine and ethyl acetate were added and the organic layer separated. The aqueous layer was further extracted with ethyl acetate and the combined extracts washed with brine, dried (MgSO₄) then evaporated under reduced pressure. The resulting residue was chromatographed on silica (0-20% methanol in dichloromethane) to give pure oxazole.

Example 1

2-(1-Normon-2-yl)-5-(2-pyridyl)oxazole

a) 2-Amino-1-(2-pyridyl)ethanone dihydrochloride

A solution of 2,2-diethoxy-2-(2-pyridyl)ethylamine dihydrochloride (2.6g, 9.19mmol) in 5M deuterium chloride (16ml) was heated at 80°C under a stream of argon and the reaction followed by ¹H n.m.r. After 2½h the reaction mixture was evaporated, ethanol added and then re-evaporated. The residue treated with acetone and the title compound was collected by filtration (1.8g, 92%); v_max (KBr) 1723cm-¹; δ_H (D₂O) 7.95-8.91 (m).

b) N-[2-Oxo-2-(2-ρyridyl)ethyl]monamide

The title monamide was prepared according to the general method from the amine dihydrochloride from (la) (1.8g, 8.6mmol) in THF:water (1:1, 12ml) and triethylamine (2.4ml, 17.2mmol) and isolated after column chromatography as an amorphous solid (963mg, 24%); v_max (CH₂Cl₂) 3400-3100, 1720, 1665, 1640cm-¹; λ_max (EtOH) 226 (ε_m 20,586), 260nm (sh) (5300); δ_H (CDCl₃) inter alia 0.93 (3H, d, J 7.1Hz, 17-H₃), 1.22 (3H, d, J 6.2Hz, 14-H₃), 2.21 (3H, s, 15-H₃), 5.04 (2H, d, J 4.9Hz, 1'-H₂), 5.83 (1H, s, 2-H), 6.54 (1H, E, J 4.9Hz, N-H), 7.52 (1H, ddd, J 1.1, 4.6, 7.6Hz, 5"-H), 7.86 (1H, dt, J 1.6, 7.8Hz, 4"-H), 8.05 (1H, dd, J 0.9, 7.8Hz, 3"-H), 8.70 (1H, dd, J 1.0, 6.0Hz, 6" -H); δ_C (CDCI₃) 12.7 (C-17), 18.9 (C-15), 20.8 (C-14), 31.7 (C-9), 39.6 (C-8), 42.7 (C-4), 42.7 (C-12), 46.5 (C-1'), 55.7 (C-10), 61.2 (C-11), 65.4 (C-16), 68.9 (C-6), 70.4 (C-7), 71.1 (C-13), 75.0 (C-5), 119.8 (C-2), 122.0 (C-3"), 128.0 (C"-5"), 137.1 (C-4"), 149.3 (C-6''), 151.9 (C-2"), 157.9 (C~3), 167.6 (C-1), 196.4 (C-2'2; m/z 462 (M⁺, 22%) and 136 (100%) . c) 2- (1-Normon-2-yl ) -5- (2-pyridyl ) oxazole

The monamide from (1b) (200mg) was cyclised according to the general procedure to give the title oxazole as an amorphous solid (60mg, 31%); v_max (CH₂Cl₂) 3600-3100, 1720, 1650, 1605, 1580cm-¹; λ_max (EtOH) 223 (ε_m 9,990), 312nm (18,470); δ_H (CDCl₃) inter alia 0.93 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.3Hz, 14-H₃), 2.35 (3H, d, J 0.7Hz, 15-H₃), 6.33 (1H, bs, J 3.7Hz, 2-H), 7.21 (1H, ddd, J 1.0, 4.9, 7.6Hz, 5"-H), 7.63 (1H, dd, J 0.9, 9.0Hz, 3"-H), 7.72 (s, 4'-H) overlaying 7.68-7.78 (m, 4"-H) (together 2H), 8.61 (1H, dd, J 0.9, 4.6Hz, 6"-H); δ_C (CDCI₃) 12.7 (C-17), 19.7 (C-15), 20.8 (C-14), 31.7 (C-9), 39.6 (C-8), 42.7 (C-12), 42.9 (C-4), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.8 (C-6), 70.4 (C-7), 171.1 (C-13), 75.2 (C-5) , 112.9 (C-2), 119.2 (C-3"), 122.7 (C-5"), 126.2 (C-4'), 137.0 (C-4 ' ' ) , 197.3 (C-5'), 148.3 (C-6" ) , 149.2 (C-3), 149.8 (C-2"), 162.0 (C-2'); m/z 444 (M⁺, 10%), 200 (100%).

Example 2

2-(1-Normon-2-yl)-5-(3-pyridyl)oxazole

a) 2-Amino-1-(3-pyridyl)ethanone dihydrochloride

A solution of 2,2-diethoxy-2-(3-pyridyl)ethylamine (2.5g) in 5M hydrochloric acid (20ml) was heated at 80°C for 16h. The reaction mixture was evaporated, then ethanol was added and the mixture evaporated. Acetone was added and the title compound (89a) was collected by filtration (1.7g, 92%). v_max (KBr) 1709cm-¹; δ (D₂O) 4.75 (2H, s, CH₂), 8.22 (1H, dd, J 6, 8Hz, 5'-H), 8.95-9.15 (2H, 4'- and 6'-H), 9.33 (1H, d, J 2Hz, 2'-H). b) N-[2-Oxo-2-(3-pyridyl)ethyl]monamide

The title monamide was prepared according to the general method from the amine dihydrochloride from (2b) (418mg, 2mmol) in THF:water (1:1, 10ml) and triethylamine (0.6ml, 4mmol) and isolated after column chromatography as an amorphous solid (230mg, 25%); λ_max (CHCl₃) 3600-3100, 1690, 1655, 1635cm-¹; δ (CDCI₃) inter alia 0.93 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.3Hz, 14-H₃), 2.21 (3H, s, 15-H₃), 4.82 (2H, d, J 4.5Hz, 1'-H₂), 5.89 (1H, s, 2-H), 7.22 (1H, bs, NH), 7.48 (1H, dd, J 4.8, 8.0Hz, 5"-H), 8.28 (1H, dd, J 1.6, 8.0Hz, 4"-H), 8.84 (1H, d, J 6.5Hz, 6"-H), 9.22 (1H, bs, 2"-H); δ_C (CDCI₃) 194.1 (C-2'), 167.5 (C-1), 154.0 (C-2"), 152.7 (C-3), 149.2 (C-6"), 135.7 (C-4"), 130.3 (C-3"), 124.0 (C-5"), 119.4 (C-2), 75.0 (C-5), 71.1 (C-13), 70.4 (C-7), 68.9 (C-6), 65.3 (C-16), 61.1 (C-11), 55.6 (C-10), 4.5 (C-1'), 42.8 (C-12), 42.7 (C-4), 39.7 (C-8), 31.7 (C-9), 20.8 (C-14), 18.9 (C-15), 12.7 (C-17); (Found: M⁺, 462.2388. C₂₄H₃₄N₂O₇ requires 462.2366).

c) 2-(1-Normon-2-yl)-5-(3-pyridyl)oxazole

The monamide from (2b) (150mg) was cyclised according to the general procedure to give the title oxazole as an amorphous solid (92mg, 65%); λ_max (EtOH) 305 (ε_m 24,230), 221nm (10,260); v_max (KBr) 3399, 1648, 1525cm-¹; δ [(CD₃)₂CO] inter alia 0.93 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.3Hz, 14-H₃), 2.33 (3H, s, 15-H₃), 6.30 (1H, bs, 2-H), 7.36 (1H, dd, J 4.8, 8.0, 5"-H), 7.45 (1H, s, 4'-H), 7.90 (1H, dt, J 1.3, 8.0Hz, 4"-H), 8.53 (1H, dd, J 1.1, 4.8Hz, 6"-H), 8.90 (1H, d, J 1.4Hz, 2"-H); δ_C (CDCI₃) 161.6 (C-1), 148.8 (C-2"), 148.0 (C-3), 146.8 (C-5'), 145.2 (C-6"), 124.5 (C-3"), 124.1 (C-4'), 123.8 (C-5'"), 112.8 (C-2), 75.2 (C-5), 71.5 (C-7), 70.4 (C-13), 68.9 (C-6), 65.6 (C-16), 61.3 (C-11), 55.6 (C-10), 43.0 (C-4)- 42.9 (C-12), 39.7 (C-8), 31.7 (C-9), 20.8 (C-14), 19.7 (C-15), 12.71 (C-17); (Found: M⁺. 444.2265. C₂₄H₃₂N₂O₆ requires 444.2260).

Example 3

2-(1-Normon-2-yl)-5-(4-pyridyl)oxazole

a) 2-Amino-1-(4-pyridyl)ethanone dihydrochloride

A solution of 2,2-diethoxy-2-(4-pyridyl)ethylamine (7.3g) in 5M hydrochloric acid (50ml) was heated at 80°C for 16h. The reaction mixture was evaporated, ethanol added and then re-evaporated. Residue treated with acetone and the resulting red/brown solid was collected by filtration and dried (4.7g, 87%). The 'H n.m.r. spectrum indicated that in D₂O a 1:1 mixture between the title compound and its hydrate* existed; δ (D₂O) 3.1* (1H, s, CH₂), 4.9 (1H, s, CH₂), 8.0* (1H, d, J 8Hz, 3'- and 5'-H), 8.3 (1H, d, J 8Hz, 3'- and 5'-H) 8.7* (1H, d, J 8Hz, 2'- and 6'-H), 8.9 (1H, d, J 8Hz, 2'- and 6'-H).

b) N-[2-Oxo-2-(4-pyridyl)ethyl]monamide

The title monamide was prepared according to the general method from the amine dihydrochloride from (3a) (1.56g, 7.5mmol) in THF, water (1:1), (15ml), and isolated after column chromatography as an amorphous solid (190mg). The 'H n.m.r. spectrum showed that this material contained at least 20% impurities but the material was progressed through to the next sequence. v_max (KBr) 3393, 1710, 1654, 1635, 1527cm-¹; δ (CDCI₃) 0.93 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, s, J 6.3Hz, 14-H₃), 2.20 (3H, s, 15-H₃), 7.79 (2H, dd, J 1.6, 4.5Hz, 3",5"-H₂), 8.85 (2H, dd, J 1.6, 4.5Hz, 2",6"-H₂); (Found: M⁺ 462.2351. C₂₄H₃₄N₂O₇ requires 462.2366). c) 2- ( 1-Normon-2-yl ) -5- (4-pyridyl ) oxazole

The crude monamide from (3b) (135mg) was cyclized according to the general procedure to give the oxazole as an amorphous solid (41mg, 32%). λ_max (EtOH) 312 (ε_m 23,470), 223nm (12,110); v_max (KBr) 3393, 1647, 1610, 1582, 1520cm-¹; δ (CDCl₃), inter alia 0.94 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.3Hz), 13-H₃), 2.34 (3H, 15-H₃), 6.3 (1H, s, 2-H), 7.49 (2H, d, J 5.9Hz, 3",5"-H₂), 7.56 (1H, s, 4'-H), 8.62 (2H, d, J 5.9Hz, 2",6"-H₂); δ_C (CDCI₃) 161.6 (C-1), 150.2 (2 x C-2") 149.1 (C-3), 147.1 (C-5'), 135.2 (C-4"), 126.5 (C-4'), 117.9 (2 x C-3 " ) , 112.8 (C-2), 75.2 (C-5), 71.2 (C-13), 70.4 (C-7), 68.9 (C- 6) , 65.6 (C-16), 61.3 (C-11), 55.6 (C-10), 43.1 (C-4), 42.8 (C-12), 39.7 (C-8), 31.7 (C-9), 20.8 (C-14), 19.7 (C-15), 12.7 (C-17); (Found: M, 444.2261. C₂₄H₃₂N₂O₆ requires 444.226).

Example 4

2-(1-Normon-2-yl)-5-(2-methyl-5-pyridyl)oxazole

a) Ethyl 5-(2-methyl-5-pyridyl)oxazole-4-carboxylate

A solution of 6-methylnicotinic acid (912mg, 6mmol) in dimethylformamide (8ml) under argon at -15°C was sequentially treated with diethyl cyanophosphonate (0.9ml, 6.5mmol) and triethylamine (0.83ml, 6mmol). After 20min a solution of ethyl isocyanoacetate (0.56ml, 5mmol) and triethylamine (2.09ml, 15mmol) in dimethylformamide (6ml) was added dropwise. After 2h at -15°C the reaction mixture was warmed to room temperature over 2h. The reaction mixture was diluted with ethyl acetate and toluene and then washed with saturated sodium hydrogen carbonate, water and brine then dried and evaporated. Chromatography on silica eluting with dichloromethane/methanol mixtures gave impure title compound which was rechromatographed eluting with ethyl acetate/hexane mixtures to give the title compound (507mg, 46%); δ_H (CDCI₃) 1.41 (3H, t, J 7.5Hz, CO₂CH₂CH₃),

2.62 (3H, s, Ar-Me), 4.43 (2H, q, J 7.5Hz, CO₂CH₂CH₃), 7.25 (1H, d, J 8Hz, 3'-H), 7.95 (1H, s, 2-H), 8.36 (1H, dd, J 2.8Hz, 4'-H), 9.05 (1H, d, J 2Hz, 6'-H).

b) 2-Amino-1-(2-methyl-5-pyridyl)ethanone dihydrochloride

A solution of the oxazole from (4a) (507mg, 2.3mmol) in 6N hydrochloric acid was heated at 100°C for 5h. The reaction mixture was diluted with water, evaporated, ethanol added and then re-evaporated to give the title compound as an off-white solid (507mg, 99%); δ_H (D₂O) 2.90 (3H, s, Ar-Me), 4.84 (2H, s, COCH₂NH₂), 8.15 (1H, d, J 8Hz, 3'-H), 9.02 (1H, dd, J 2,8Hz, 4'-H), 9.32 (1H, d, J 2Hz, 6'-H).

c) N-[2-Oxo-2-(2-methyl-5-pyridyl)ethyl]monamide

The title monamide was prepared according to the general method from the amine dihydrochloride from (4b) (507mg, 2.27mmol) in THF:water (1:1, 10ml) and triethylamine (0.63ml, 4.54mmol) and isolated after column chromatography as an amorphous solid (400mg, 38%); v_max (CHCI₃) 3600-3100, 1690, 1660, 1640, 1595cm-¹; λ_max (EtOH) 231 (ε_m 19,390), 270nm (5,920); δ_H (CDCI₃) inter alia 0.93 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.2Hz, 14-H₃), 2.20 (3H, s, 15-H₃), 2.65 (3H, s, 2"-H₃), 4.79 (2H, d, J 4.4HZ, 1'-Hz), 5.83 (1H, s, 2-H), 6.75 (1H, t, J 4.4Hz, NH), 7.31 (1H, d, J 8.2Hz, 3"-H), 8.16 (1H, dd, J 2.1, 8.2Hz, 4"-H), 9.09 (1H, d, J 1.4Hz, 6"-H); δ_C (CDCI₃) 12.5 (C-17), 18.8 (C-15),

20.5 (C-14), 24.5 (C-Me), 31.8 (C-9), 39.8 (C-8), 42.7 (C-12), 42.8 (C-4), 46.2 (C-1'), 55.8 (C-10), 61.1 (C-11),

65.6 (C-16), 68.7 (C-6), 70.3 (C-13), 75.0 (C-5), 119.6 (C-2), 123.9 (C-3"), 128.0 (C-5"), 136.2 (C-4"), 148.8

(C-6"), 152.4 (C-3), 164.1 (C-2"), 167.8 (C-1), 193.8 (C-2'); m/z 476 (M⁺, 10%), 120 (100%); (Found: M⁺ 476.2526. C₂₅H₃₆N₂O₇ requires M⁺, 476.2523).

d) 2-(1-Normon-2-yl)-5-(2-methyl-5-pyridyl)oxazole

The monamide from (4c) (337mg) was cyclised according to the general procedure to give the title oxazole as an amorphous solid (220mg, 67%); v_max (CH₂Cl₂) 3700-3000, 1650cm-¹; λ_max (EtOH) 224 (ε_m 10,575), 302nm (24,380); δ_H (CDCl₃) inter alia 0.93 (3H, d, J 7.1Hz, 17-H₃); 1.21 (3H, d, J 6.3Hz,

14-H₃), 2.32 (3H, s, 15-H₃), 2.59 (3H, s, 2" -Me), 6.29 (1H, s, 2-H), 7.21 (1H, d, J 8.1Hz, 3"-H), 7.39 (1H, s, 4'-H), 7.79 (1H, dd, J 2.1, 8.1Hz, 4"-H), 8.77 (1H, d, J 2.1Hz, 6"-H); δ_C (CDCI₃) 12.6 (C-17), 19.6 (C-15), 20.8 (C-14), 24.2 (C-Me), 31.8 (C-9), 42.8 (C-12), 43.0 (C-4), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.8 (C-6), 70.4 (C-7), 71.1 (C-13), 75.3 (C-5), 112.9 (C-2), 121.7 (C-5"), 123.3 (C-4'), 123.5 (C-3"), 131.7 (C-4"), 144.6 (C-6"), 147.2 (C-5'), 147.7 (C-3), 158.0 (C-2"), 161.6 (C-1); m/z 458 (M⁺, 15%), 214 (100%); (Found: M⁺, 458.2401. C₂₅H₃₄N₂O₆ requires 458.2416).

Example 5

2-(1-Normon-2-yl)-5-(1,2-dihydro-2-oxo-5-pyridyl)oxazole

a) Ethyl (2-chloro-5-ρyridyl)oxazole-4-carboxylate

A solution of 6-chloronicotinic acid (945mg, 6mmol) in DMF (8ml) under argon at -15°C was sequentially treated with diethyl cyanophosphonate (0.99ml, 6.5mmol) and triethylamine (0.83ml, 6mmol). After 20min. a solution of ethyl isocyanoacetate (0.56ml, 5mmol) and triethylamine (2.09ml, 15mmol) in DMF (6ml) was added dropwise. After 2h at -15°C the reaction mixture was warmed to room temperature over 2h. The reaction mixture was diluted with ethyl acetate and toluene and then washed with saturated sodium hydrogen carbonate, water and brine then dried and evaporated. Chromatography on silica eluting with dichloromethane/methanol mixtures gave the title compound (570mg, 43%). δ_H (CDCI₃) 1.33 (3H, t, J 7.0Hz, CH₃CH₂CO₂-), 4.44 (2H, q, J 7.0Hz, CH₃CH₂CO₂-), 7.45 (1H, d, J 9.0Hz, 3'-H), 8.02 (1H, s, 2-H), 8.50 (1H, dd, J 2.0, 9.0Hz, 4'-H), 8.99 (1H, d, J 2.0Hz, 6'-H).

b) 2-Amino-1-(1,2-dihydro-2-oxo-5-pyridyl)ethanone dihydrochloride

A solution of the oxazole from (5a) (501mg) in 6N hydrochloric acid (10ml) was heated at 95-100°C for 4h. The reaction mixture was diluted with water, evaporated, ethanol added and re-evaporated to give the title compound as an off-white solid (400mg, 85%), δ_H (D₂O) 4.38 (2H, s, 2-H₂), 6.46 (1H, d, J 9.0Hz, 3'-H), 7.82 (1H, dd, J 2.0, 9.0Hz, 4'-H), 8.42 (1H, d, J 2.0Hz, 6'-H).

c) N-[2-Oxo-2-(1,2-dihydro-2-oxo-5-pyridyl)ethyl] monamide

The title monamide was prepared according to the general method from the amine dihydrochloride from (5b) (400mg) in THF/water (1:1, 6ml) and triethylamine (0.46ml). On work-up the aqueous residues were evaporated, digested with methanol and the solution filtered through flash silica eluting with methanol. Silica was added and after evaporation the material was applied to a silica column and eluted with dichloromethane/methanol mixtures to give the title compound (350mg, 44%); v_max (KBr) 3373, 1653, 1527, 1429cm-¹; λ_max (EtOH) 211 (ε_m 17,365), 276nm (14,370); δ_H (d₄-MeOH) inter alia 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.23 (3H, d, J 6.2Hz, 14-H₃), 2.16 (3H, s, 15-H₃), 4.53 (2H, s, 1'-H₂), 4.58 (1H, s, 2-H), 6.54 (2H, d, J 9.7Hz, 3"-H), 8.07 (1H, dd, J 2.7, 9.6Hz, 4"-H), 8.31 (1H, d, J 2.4Hz, 6"-H) (Material contaminated with ca.5% NEt₃.HCl); δ_C (CD₃OD) 12.3 (C-17), 18.0 (C-15), 19.4 (C-14), 33.0 (C-9), 41.7 (C-8), 43.8 (C-4), 43.8 (C-12), 46.1 (C-1'), 57.0 (C-10), 61.1 (C-11), 66.3 (C-16), 70.0 (C-6), 70.7 (C-13), 71.7 (C-7), 76.3 (C-5), 117.7 (C-5"), 120.7 (C-2), 120.8 (C-3"), 140.6 (C-4"), 141.2 (C-6"), 153.2 (C-3), 165.5 (C-2"), 169.8 (C-1), 192.3 (C-2'); m/z 501 (MNa⁺, 37%), 176 (100).

d) 2-(1-Normon-2-yl)-5-(1,2-dihydro-2-oxo-5-pyridyl) oxazole

The monamide from (5c) (100mg) was cyclised according to the general procedure to give the title oxazole as an amorphous solid (60mg, 62%); v_max (KBr) 3385, 1661, 1623, 1565cm-¹; λ_max (EtOH) 256 (ε_m 8,220), 302nm (16,505); δ_H (d₄-MeOH) inter alia 0.95 (3H, d, J 7.1Hz, 17-H₃), 1.20 (3H, d, J 6.4Hz, 14-H₃), 2.26 (3H, s, 15-H₃), 6.22 (1H, s, 2-H), 6.64 (1H, d, J

9.2Hz, 3"-H), 7.35 (1H, s, 4'-H), 7.78 (1H, d, J 2.5Hz, 6"-H), 7.91 (1H, dd, J 2.5, 9.2Hz, 4"-H); δ_C (d₄-MeOH), 12.2 (C-17), 19.7 (C-15), 20.3 (C-14), 32.9 (C-9), 41.6 (C-8), 43.6 (C-12), 43.8 (C-4), 56.8 (C-10), 61.2 (C-11), 66.3 (C-16), 69.9 (C-6), 70.6 (C-13), 71.6 (C-7), 76.3 (C-5), 110.6 (C-5"), 112.3 (C-2), 121.6 (C-3"), 122.5 (C-4'), 131.7 (C-4"), 139.6 (C-6"), 147.7 (C-5'), 149.3 (C-3), 162.2 (C-2"), 164.6 (C-2'); m/z 461 (MH⁺, 7%) , 123 (100) . Example 6

2-(1-Normon-2-yl)-5-(2-methoxy-5-pyridyl)oxazole and

Example 7 2-(1-Normon-2-yl)-5-(1,2-dihydro-1-methyl-2-oxo-5pyridyl) oxazole

A solution of the oxazole from (5d) (100mg) in methanol (3ml) at 0°C under argon was treated with excess ethereal diazomethane. After 24h at 5-10°C argon was bubbled into the reaction mixture then the mixture evaporated and chromatographed on silica eluting with dichloromethane/methanol mixtures to give two separable components. The less polar material was identified as the methoxypyridine (example 6) and was isolated as a gum (15mg, 14%); v_max (CH₂Cl₂) 3600, 1670, 1620, 1485cm-¹; δ_H (CDCI₃ + 2 drops d₄-MeOH) inter alia (material contains ca.10-15% of a monic impurity) 0.93 (3H, d, J 7.1Hz, 17-H₃), 1.22 (3H, d, J 6.3Hz, 14-H₃), 2.30 (3H, s, 15-H₃), 3.98 (3H, s, Ar-OMe), 6.26 (1H, s, 2-H), 6.82 (1H, d, J 8.8Hz, 3"-H), 7.27 (1H, s, 4'-H), 7.81 (1H, dd, J 2.2, 8.7Hz, 4"-H), 8.46 (1H, d, J 2.2Hz, 6"-H); m/z 474 (M⁺, 7%), 30(100%); (Found: M 474.2371. C₂₅H₃₄N₂O₇ requires 474.2366). The more polar material, the N-methylpyridine (example 7) was isolated as an amorphous solid (60mg, 48%); v_max (KBr) 3416, 1664, 1612, 1565, 1541cm-¹; δ_H (CDCI₃ + 3 drops d₅-MeOH) inter alia 0.93 (3H, d, J 7.1Hz, 17-H₃), 1.23 (3H, d, J 6.3Hz, 14-H3), 2.26 (3H, s, 15-H3), 3.64 (3H, s, Ar-N-Me), 6.19 (1H, s, 2-H), 6.69 (1H, d, J 9.4Hz, 3"-H), 7.13 (1H, s, 4'-H), 7.60 (1H, dd, J 2.4, 9.3Hz,4"-H), 7.66 (1H, d, J 2.3Hz, 6"-H); m/z 474 (M⁺, 8%), 34 (100); (Found: M⁺, 474.2371. C₂₅H₃₄N₂O₇ requires M, 474.2366). Example 8

5-(2-Methoxy-5-ρyridyl)-2-(1-normon-2-yl)oxazole

a) 5-Chloroacetyl-2-methoxypyridine

6-Methoxynicotinic acid (3.79g, 24.8mmol) in dichloromethane (60ml) and DMF (a few drops) was treated with oxalyl chloride (2.6ml, 29.8mmol). After ca.2½ hours all material was in solution; reaction mixture then added dropwise to excess diazomethane in ether. After 2 hours argon passed through the reaction mixture, then evaporated and chromatographed on silica eluting with dichloromethane/ethyl acetate mixtures. The less polar fractions afforded the title compound (430mg) and from the more polar fractions, the diazoketone was isolated (1.34g). This material was dissolved in dichloromethane (100ml) and HCl gas was bubbled in for 40 min. Then argon was passed through the solution. The reaction mixture was washed with sodium hydrogen carbonate and brine then dried and evaporated to give the title compound (1.4g); v_max (CH₂Cl₂) 1785, 1720, 1700cm-¹; δ_H (CDCl₃) 3.98 (3H, s, OMe), 4.58 (2H, s, COCH₂Cl), 6.80 (1H, d, J 9Hz, 3-H), 8.12 (1H, dd, J 2,9Hz, 4-H), 8.78 (1H, d, J 2Hz, 6-H).

b) 5-Azidoacetyl-2-methoxypyridine

A solution of the chloroketone from (8a) (1.4g, 7.55mmol) in dichloromethane (70ml) was treated with tetramethylguanidinium azide (1.43g, 9.06mmol). After 1 hour reaction mixture evaporated and chromatographed on silica eluting with ethyl acetate/hexane mixtures to give the title compound (1.29g, 89%); v_max (CH₂Cl₂) 2200, 1695, 1605cm-¹; δ_H (CDCI₃), 3.98 (3H, s, OMe), 4.45 (2H, s, COCH₂N₃), 6.87 (1H, d, J 9Hz, 3-H), 8.07 (1H, dd, J 2,9Hz, 4-H), 8.69 (1H, d, J 2Hz, 6-H). c) 2-Amino-1-(2-methoxy-5-pyridyl)ethan-1-one dihydrochloride

A solution of the azide from (8b) (1.29g, 6.72mmol) in THF (40ml), water (30ml) and 5M HCl (3.35ml, 16.8mmol) was hydrogenated with over 10% Pd/C (250mg) for 5 minutes. The mixture was filtered through Kieselguhr and evaporated to dryness. Ethanol added and re-evaporated, residue triturated with acetone to give the title compound (1.54g, 96%); v_max (KBr) 1690, 1637, 1613cm-¹; δ_H (d₆-DMSO) 3.95 (3H, s, OMe), 4.56 (2H,m, collapses to, s, on D₂O exch., COCH₂), 4.95 (2H, bs, exch.), 7.02 (1H, d, J 9Hz, 3-H), 8.25 (1H, dd, J 2.9Hz, 4-H), 8.45 (2H, bs, exch.), 8.90 (1H, d, J 2Hz, 6-H).

d) N-[2-(2-Methoxy-5-pyridyl)-2-oxoethyl]monamide

The title monamide was prepared according to the general method from the amine salt from (8c) (1.94g, 8.12mmol) in THF/water (1:1, 20ml) and triethylamine (2.26ml, 16.23mmol) and isolated after column chromatography as an amorphous solid, (2.3g, 58%); λ_max (EtOH) 274 (ε_m 12,235), 253nm (14,780); δ_H (CDCl₃), inter alia 0.93 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.1Hz, 14-H₃), 2.21 (3H, s, 15-H₃), 4.02 (3H, s, ArOMe), 4.75 (2H, d, J 4.4Hz, 1'-H₂), 5.83 (1H, s, 2-H), 6.70 (1H, t, J 4.4Hz, N-H), 6.82 (1H, d, J 8.8Hz, 3"-H), 8.14 (1H, dd, J 2.3, 8.8Hz, 4"-H), 8.83 (1H, d, J 2.3Hz, 6"-H); δ_C (CDCI₃) 12.7 (C-17), 19.0 (C-15), 20.8 (C-14), 31.7 (C-9), 39.6 (C-8), 42.7 (C-4), 42.8 (C-12), 46.0 (C-1'), 54.3 (C-OMe), 55.6 (C-10), 61.2 (C-11), 65.4 (C-16), 68.9 (C-6), 70.5 (C-13), 71.2 (C-7), 75.0 (C-5), 111.5 (C-3"), 119.6 (C-2), 124.6 (C-5"), 137.9 (C-4"), 149.1 (C-6"), 152.3 (C-3), 167.4 (C-2" + C-1), 192.7 (C-2'); m/z 492 (M⁺, 5%), 136 (100); (Found: M⁺, 492.2465. C₂₅H₃₆N₂O₈ requires M, 492.2472) . e) 5- (2-Methoxy-5-pyridyl ) -2- ( 1-normon-2-yl ) oxazole

The monamide from (8d) (2.2g) was cyclised according to the general method to give the title oxazole (1.74g, 82%); λ_max (EtOH) 302 (ε_m 25,880), 232nm (10,630); δ_C (CDCl₃) 12.7 (C-17), 19.6 (C-15), 20.8 (C-14), 341.7 (C-9), 39.6 (C-8), 42.8 (C-12), 42.9 (C-4), 53.7 (C-OMe), 55.6 (C-10), 61.3 (C-11), 65.5 (C-16), 68.9 (C-6), 70.4 (C-13), 71.2 (C-7), 75.3 (C-5), 111.2 (C-3"), 113.0 (C-2), 118.0 (C-5"), 121.8 (C-4), 134.5 (C-4"), 142.9 (C-6"), 147.0 (C-3), 147.6 (C-5'), 161.1 (C-2"), 163.9 (C-2').

Example 9

5-(2-Chloro-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 5-Chloroacetyl-2-chloropyridine

A suspension of 6-chloronicotinic acid (1.58g, 10mmol) in dichloromethane (50ml) and DMF (4 drops) was treated with oxalyl chloride (1.05ml, 12mmol). After 2½h the solution was added to a solution of excess diazomethane in ether. After 2 hours argon was passed through the solution then HCl gas was passed through for 10 minutes. Argon was passed through the mixture then washed with sodium hydrogen carbonate and brine then dried and evaporated. Chromatography on silica eluting with dichloromethane gave the title compound (1.82g, 96%); v_max (CH₂Cl₂) 1643, 1530cm-¹; δ_H (CDCl₃) 4.65 (2H, s, COCH₂Cl) 7.46 (1H, d, J 8Hz, 3-H), 8.20 (1H, dd, J 2,8Hz, 4-H), 8.91 (1H, d, J 2Hz, 6-H). b) 5-Azidoacetyl-2-chloropyridine

A solution of the chloroketone from (9a) (455mg, 2.4mmol) in dichloromethane (10ml) was treated with tetramethylguanidinium azide (436mg, 2.76mmol). After 1½ hours the reaction mixture was evaporated and chromatographed eluting with dichloromethane to give the title compound (260mg, 55%) (Evidence of instability to silica); v_max (CH₂Cl₂) 2100, 1705, 1580cm-¹; δ_H (CDCl₃) 4.58 (2H, s, COCH₂N₃), 7.49 (1H, d, J 8Hz, 3-H), 8.18 (1H, dd, J 2,8Hz, 4-H), 8.86 (1H, d, J 2Hz, 6-H).

c) 2-Amino-1-(2-chloro-5-pyridyl)ethan-1-one dihydrochloride

A solution of the azide from (9b) (247mg, 1.26mmol) in THF (9ml), water (6ml) and 5M HCl (0.63ml, 3.15mmol) was hydrogenated with 10% Pd/C (50mg) for 5 min. The mixture was filtered through Kieselguhr and the filtrate evaporated to dryness. Ethanol was added to the residue and the solution re-evaporated to give the title compound (250mg,

82%); v_max (KBr) 3105-2800, 1695, 1583, 1560cm-¹; δ_H (d₆-DMSO) 4.63 (2H, d, J 5.3Hz, collapsed to s on D₂O exch.

COCH₂NH₂), 7.78 (1H, d, J 8.4Hz, 3-H), 8.41 (1H, dd, J 2.3, 8.4Hz, 4-H), 8.49 (4H, bs, exch.), 9.04 (1H, d, J 2.3Hz,

6-H).

d) N-[2-(2-Chloro-5-pyridyl)-2-oxoethyl]monamide

The title monamide was prepared according to the general method from the amine salt from (9c) (243.5mg, lmmol) in THF/water (1:1, 6ml) and triethylamine (0.3ml, 2mmol) and isolated after chromatography as an amorphous solid (104mg, 21%); v_max (KBr) 3394, 1704, 1661, 1630, 1583cm-¹; δ_H (CDCI₃) inter alia 0.93 (3H, d, J 6.7Hz, 17-H₃), 1.22 (3H, d, J 6.3Hz, 14-H₃), 2.20 (3H, s, 15-H₃), 4.78 (2H, d, J 5.4Hz, 1'-H₂), 5.82 (1H, s, 2-H), 6.66 (1H, t, J 4.5Hz, NH), 7.50 (1H, d, J 8.3Hz, 3"-H), 8.23 (1H, dd, J 2.2; 8.3Hz, 4"-H), 8.99 (1H, d, J 2.2Hz, 6"-H); m/z (FAB, thioglycerol) 497 (MH⁺).

e) 5-(2-Chloro-5-pyridyl)-2-(1-normon-2-yl)oxazole

The monamide from (9d) (94mg) was cyclised according to the general method to give the title oxazole (48mg, 52%); δ_H (CDCl₃) inter alia 0.94 (3H, d, J 6.7Hz, 17-H₃), 1.22 (3H, d, J 6.3Hz, 14-H₃), 2.32 (3H, s , 15-H₃), 6.29 (1H, s, 2-H), 7.58 (1H, d, J 8.3Hz, 3"-H), 7.44 (1H, s, 4'-H), 7.85 (1H, dd, J 2.2Hz, 8.3Hz, 4"-H), 8.67 (1H, d, J 1.8Hz, 6"-H); δ_C (CDCI₃) 13.0 (C-17), 20.0 (C-15), 21.1 (C-14), 32.0 (C- 9 ) , 39.9 (C-8), 43.1 (C-12) 43.2 (C-4), 55.9 (C-10), 61.6 (C-11), 65.8 (C-16), 69.2 (C-6) , 70.6 (C-13), 71.5 (C-7), 75.5 (C-5), 113.0 (C-2), 123.6 (C-5"), 124.8 (C-4'), 124.8 (C-3"), 134.0 (C-4"), 145.3 (C- 6" ) , 146.2 (C-3), 148.9 (C-5'), 150.7 (C-2"), 162.4 (C-2'); m/z 478 (M⁺, 12%), 234 (100); (Found: M⁺, 478.1863. C₂₄H₃₁N₂O₆ Cl requires M, 478.1871).

Example 10

5-(2,3-Dichloro-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 5-Chloroacetyl-2,3-dichloroρyridine

A suspension of 5,6-dichloronicotinic acid (1.92g, 10mmol) in dichloromethane (50ml) and DMF (4 drops) was treated with oxalyl chloride (1.05ml, 12mmol). After 2½ h the solution was added to a solution of excess diazomethane in ether. After 2 hours argon was passed through the solution then a solution of HCl in ether (5M, 2 x 28ml) was added. The mixture was diluted with dichloromethane then washed with sodium hydrogen carbonate and brine then dried and evaporated. Chromatography on silica eluting with dichloromethane gave the title compound (1.7g, 75%); δ (CDCl₃) 4.62 (2H, s, COCH₂Cl), 8.30 (1H, d, J 2Hz, 4-H), 8.80 (1H, d, J 2Hz, 6-H).

b) 5-Azidoacetyl-2,3-dichloropyridine

A solution of the chloroketone from (10a) (800mg, 3.56mmol) in dichloromethane (20ml) was treated with tetramethylguanidinium azide (619mg, 3.92mmol). After 1 h the reaction mixture was evaporated and chromatographed on silica eluting with dichloromethane to give the title compound (313mg, 38%); v_max (CH₂Cl₂) 2105, 1710cm-¹; δ_H (CDCI₃) 4.55 (2H, s, COCH₂N₃), 8.26 (1H, d, J 2Hz, 4-H), 8.73 (1H, d, J 2Hz, 6-H).

c) 2-Amino-1- (2 , 3-dichloro-5-pyridyl) ethan-1-one hydrochloride

A solution of the azide from (10b) (300mg, 1.3mmol) in THF (10ml), water (8ml) and 5M HCl (0.65ml, 3.25mmol) was hydrogenated with 10% Pd/C (60mg) for 10 min. The mixture was filtered through Kieselguhr washing the pad well with water. The filtrate was washed with ethyl acetate and the aqueous phase evaporated to dryness. Ethanol added and re-evaporated to give the title compound (250mg, 80%); v_max (KBr) 3250-2800, 1711, 1701cm-¹; δ_H (d₆-DMSO) 4.64 (2H, d, J 4.5Hz, COCH₂NH₂), 8.44 (2H, bs, NH₂), 8.70 (1H, d, J 2Hz, 4-H), 8.98 (1H, d, J 2Hz, 6-H).

d) N-[2-(2,3-Dichloro-5-pyridyl)-2-oxoethyl]monamide

The title monaoide was prepared according to the general method from the amine salt from (10c) (520mg, 2.15mmol) in THF/water (1:1, 12ml) and triethylamine (0.6ml, 4.30mmol) and isolated after chromatography as an amorphous solid (290mg, 25%); v_max (KBr) 3200, 1707, 1659, 1630, 1533, 1412cm-¹; δ_H (d₄-MeOH) inter alia 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.15 (3H, s, 15-H₃), 4.68 (2H, s, 1'-H₂), 5.88 (1H, s, 2-H), 8.51 (1H, d, J 2.0Hz, 4"-H), 8.91 (1H, d, J 2.0Hz, 6"-H); m/z (FAB, Matrix 3-NOBA/Na) 553 (MNa⁺, 70%), 422 (100%).

e) 5-(2,3-Dichloro-5-pyridyl)-2-(1-normon-2-yl)oxazole

The monamide from (10d) (250mg, 0.47mmol) was cyclised according to the general method to give the title oxazole (123mg, 51%); v_max (KBr) 3405, 1649, 1605cm-¹; λ_max (EtOH) 314nm )ε_m 22,746), 229 (11,423); δ_H (d₄-MeOH) inter alia 0.95 (3H, d, J 7.1Hz, 17-H₃), 1.20 (3H, d, J 6.4Hz, 14-H₃), 2.31 (3H, s, 15-H₃), 6.28 (1H, s, 2-H), 7.74 (1H, s, 4'-H), 8.28 (1H, d, J 2.1Hz, 4"-H), 8.66 (1H, d, J 2.1Hz, 6"-H); δ_C (CDCl₃ + d₄-MeOH) 12.3 (C-17), 19.7 (C-15), 20.4 (C-14), 31.9 (C-9), 39.9 (C-8), 42.7 (C-12), 43.2 (C-4), 55.9 (C-10), 61.1 (C-11), 65.7 (C-16), 65.7 (C-6), 70.3 (C-13), 70.6 (C-7), 75.2 (C-5), 112.5 (C-2), 124.7 (C-3"), 125.5 (C-4'), 131.3 (C-5"), 133.7 (C-4"), 142.5 (C-2"), 144.6 (C-6"), 147.9 (C-3'), 149.6 (C-5'), 162.8 (C-2') .

Example 11

5-(2-Methylthio-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 5-Chloroacetyl-2-methylthiopyridine

A suspension of 6-methylthionicotinic acid (1.69g, 10.0mM) in dichloromethane (50ml) and DMF (4 drops) was treated with oxalyl chloride (1.05ml, 12.0mM). After 2h the solution was added to a solution of diazomethane (ca.40mM) in ether (100ml) at 5°C and the mixture stirred 1.5h to ambient. A solution of hydrogen chloride in ether (ca.0.8N, 25ml) was then added and the reaction stirred for a further 20mins. The mixture was partitioned between dichloromethane (100ml) and water (100ml) and sodium carbonate added to pH 8.0. The organic phase was washed with brine, dried (MgSO₄) and evaporated to give a crude product (2g) which was chromatographed (40g silica, eluent: hexane:ethyl acetate 2:1) to give the title pyridine (1.49, 70%) ;v_max (CHCl₃) 1680 and 1580cm-¹; δ_H (CDCI₃) inter alia 2.60 (3H, s, -SCH₃), 4.60 (2H, s, -CH₂Cl), 7.24 (1H, d, J 8.5Hz, 3-H), 8.00 (1H, dd, J 8.5 and 2.0Hz, 4-H) and 8.95 (1H, d, J 2.0Hz, 6-H).

b) 5-Azidoacetyl-2-methylthiopyridine

Tetramethylguanidinium azide (0.47g, 2.9mM) was added to an ice-cooled solution of 5-chloroacetyl-2-methylthiopyridine (0.41g, 2.0mM) in dichloromethane (25ml) under argon. The mixture was stirred 0.75h, reduced in volume and applied to a silica column (10g) eluting with dichloromethane to give the title compound (0.36g, 85%); v_max (CHCI₃) 2100, 1695 and 1585cm-¹; δ_H (CDCI₃) inter alia 2.60 (3H, s, -SCH₃), 4.48 (2H, s, -CH₂N₃), 7.27 (1H, d, J 8.5H, 3-H), 7.95 (1H, dd, J 8.5 and 2.0Hz, 4-H) and 8.90 (1H, d, J 2.0Hz, 6-H); m/z 208 (M⁺, 62%) and 152 (100).

c) 5-Aminoacetyl-2-methylthiopyridine dihydrochloride

5-Azidoacetyl-2-methylthiopyridine (0.35g, 1.6mM) was dissolved in THF (12ml) and to this solution water (8ml) and 5N hydrochloric acid (0.84ml, 4.2mM) were added. The mixture was hydrogenated over 10% palladium on charcoal (0.19g) for 13 minutes, filtered through a celite pad and the filtrate washed (x2) with ethyl acetate and evaporated to give the required product (0.2g) as a yellow solid (47%); v_max (KBr) 3400, 1700 and 1615cm-¹; δ_H (D₂O) 2.67 (3H, s, -SCH₃), 4.67 (2H, s, -CH₂-), 7.66 (1H, d, J 8.8Hz, 3-H), 8.38 (1H, dd, J 8.8 and 2.0Hz, 4-H) and 8.97 (1H, d, J 2.0Hz, 6-H) .

d) N-[2-(2-Methylthio-5-pyridyl)-2-oxoethyl]monamide

The monamide was prepared according to the general method from the amine salt (0.20g, 0.78mM) and isolatedas an amorphous solid (0.10g, 25%); v_max (KBr) 3420, 1695, 1660, 1630 and 1580cm-¹; λ_max (EtOH) 223nm (ε_m 19,390) and 311nm (19,050); δ_H (CD₃OD) inter alia 0.96 (3H, d, J 7.0Hz,

17-H₃), 1.21 (3H, d, J 6.5Hz, 14-H₃), 2.17 (3H, s, 15-H₃), 2.61 (3H, s, -SCH₃), 4.69 (2H, s, 1'-H₂), 5.90 (1H, s, 2-H), 7.39 (1H, d, J 8.5Hz, 3"-H), 8.13 (1H, dd, J 8.5 and 2.0Hz, 5"-H) and 9.00 (1H, d, J 2.0Hz, 6"-H); δ_C (CD₃OD) 12.3 (C-17), 13.4 (-SCH₃), 19.1 (C-15), 20.4 (C-14) 33.0 (C-9), 41.7 (C-8), 43.8 (C-4 and C-12), 47.0 (C-1'), 56.9 (C-10), 61.3 (C-11), 66.4 (C-16), 70.1 (C-6), 70.7 (C-7), 71.7 (C-13), 76.3 (C-5), 120.7 (C-2), 122.0 (C-3"), 127.9 (C-5"), 136.2 (C-4"), 150.3 (C-6"), 153.4 (C-3), 168.1 (C-2"), 169.8 (C-1) and 195.0 (C-2'); m/z (FAB, thiioglycerol) 509 (MH⁺) .

e) 5-(2-Methylthio-5-pyridyl)-2-(1-normon-2-yl)oxazole

The monamide (0.30g, 0.59mM) was cyclised according to the general method to give the title oxazole (0.16g, 53%); v_max

(KBr) 3400 and 1650cm-¹; λ_max (EtOH) 328nm ₍ε_m 29,940); _δH (CD₃OD) inter alia 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.19 (3H, d, J 6.5Hz, 14-H₃), 2.30 (3H, s, 15-H₃), 2.58 (3H, s, -SCH₃), 6.27 (1H, s, 2-H), 7.33 (1H, d, J 8.5Hz, 3"-H), 7.57 (1H, s, 4'-H), 7.90 (1H, dd, J 8.5 and 2.0Hz, 4"-H) and 8.72 (1H, d, J 2.0Hz, 6"-H); δ_C (CD₃OD) 12.3 (C-17), 13.5 (-SCH₃), 19.9 (C-15), 20.4 (C-14), 33.1 (C-9), 41.7 (C-8), 43.8 (C-12), 44.0 (C-4), 56.9 (C-10), 61.3 (C-11), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.7 (C-13), 76.4 (C-5), 113.5 (C-2), 121.3 (C-5"), 122.3 (C-3"), 124.1 (C-4), 132.7 (C-4"), 145.7 (C-6"), 148.6 (C-3), 149.8 (C-5'), 161.7 (C-2") and 163.0 (C-2'); m/z 490 (M⁺, 23%) and 246 (100). (Found: M⁺, 490.2144. C₂₅H₃₄N₂O₆S requires 490.2138).

Example 12

5-(2-Methylsulphinyl-5-pyridyl)-2-(1-normon-2-yl)oxazole

A solution of the oxazole from (lie) (0.124g, 0.25mM) in dichloromethane (9ml) was chilled to 5°C under argon and treated with a solution of m-chloroperbenzoic acid (0.052g, 0.30mM) in dichloromethane (1ml). After 0.5h ethyl acetate (10ml) followed by sodium hydrogen carbonate solution (0.5ml) were added with thorough mixing. The organic phase was separated, washed with brine, dried (MgSO₄), evaporated and subjected to a silica column (3g, eluent: 5-10% methanol in dichloromethane) to give the title oxazole (0.09g, 70%); v_max (KBr) 3400, 1650, 1600 and 1550cm-¹; λ_max (EtOH) 324nm (ε_m 21,058); δ_H (CD₃OD) inter alia 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.33 (3H, s, 15-H₃), 2.92 (3H, s, -SOCH₃), 6.31 (1H, s, 2-H), 7.79 (1H, s, 4'-H), 18.01 (1H, d, J 8.5Hz, 3"-H), 8.36 (1H, dd, J 8.5 and 2.0Hz, 4"-H) and 9.02 (1H, d, J 2.0Hz, 6"-H); δ_C (CD₃OD) 12.3 (C-17), 20.0 (C-15), 20.3 (C-14), 33.1 (C-9), 41.2 (-SOCH₃), 41.8 (C-8), 43.8 (C-12), 44.1 (C-4), 56.9 (C-10), 61.3 (C-11), 66.4 (C-16), 70.1 (C-6), 70.7 (C-7), 71.7 (C-13), 76.4 (C-5), 133.3 (C-2), 120.8 (C-4'), 126.8 (C-3"), 127.1 (C-5"), 134.3 (C-4"), 146.4 (C-6"), 147.5 (C-3), 151.2 (C-5'), 163.9 (C-2') and 164.7 (C-2"); m/z (FAB, thioglycerol) 507 (MH⁺) and 529 (MNa⁺). Example 13

5-(2-Methylsulphonyl-5-pyridyl)-2-(1-normon-2yl)oxazole

A solution of the oxazole from example 12 (0.067g, 0.128mM) in dichloromethane (5ml) at 5°C under argon was treated with a solution of m-chloroperbenzoic acid (0.026g, 0.15mM) in dichloromethane (1ml). After 2h, ethyl acetate (5ml) and sodium hydrogen carbonate solution (0.2ml) were added with thorough mixing. The organic phase was washed with brine, dried (MgSO₄), evaporated and the residue subjected to a small silica column (2g, eluent: 5-10% methanol in dichloromethane) to give the title oxazole (0.048g, 72%); v_max (KBr) 3440, 1710, 1650 and 1600cm-¹; λ_max (EtOH) 327nm 'ε_m 23,000); δ_H (CD₃OD) inter alia 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.34 (3H, s, 15-H₃), 3.27 (3H, s, -SO₂CH₃), 6.30 (1H, s, 2-H), 7.77 (1H, s, 4'-H), 8.13 (1H, d, J 8.5Hz, 3"-H), 8.35 (1H, dd, J 8.5 and 2.0Hz, 4"-H) and 9.08 (1H, d, J 2.0Hz, 6"-H); δ_C (CD₃OD) 12.3 (C-17), 20.0 (C-15), 20.4 (C-14), 33.1 (C-9), 40.6 (SO₂CH₃), 41.8 (C-8), 43.8 (C-12), 4.1 (C-4), 57.0 (C-10), 61.3 (C-11), 66.5 (C-16), 70.1 (C-6), 70.8 (C-7), 71.7 (C-13), OS76.4 (C-5), 113.3 (C-2), 122.7 (C-4'), 128.0 (C-3"), 129.2 (C-5"), 134.1 (C-4"), 146.5 (C-6"), 147.1 (C-3), 151.8 (C-5'), 157.8 (C-2") and 164.4 (C-2'); m/z (FAB, thioglycerol) 523 (MH⁺).

Example 14

5-[2-(N,N-Diethylcarbamoyloxy)-5-pyridyl]-2-(1-normon- 2-yl)oxazole

a) 2-(1-Normon-2-yl)-5-(1,2-dihydro-2-oxo-5-pyridyl) oxazole 6,7,13-tristrimethylsilyl ether

A solution of the oxazole from (5d) (230mg, 0.5mmol) in THF (10ml) was sequentially treated with DMAP (cat.), triethylamine (0.56ml, 4mmol) and trimethylsilyl chloride (0.38ml, 3mmol). After lh, the mixture was evaporated, dissolved with ethyl acetate and washed with water and brine, then dried and evaporated. Chromatography on silica eluting dichloromethane/ methanol mixtures gave the title compound (245mg, 73%); v_max (CH₂Cl₂) 1680, 1660, 1635cm-¹; δ_H (CDCl₃) inter alia -0.04-0.20 (9H, m, (TMS)₃), 0.89 (3H, d, J 7.1Hz, 17-H₃), 1.19 (3H, d, J 6.3Hz, 14-H₃), 2.26 (3H, s, 15-H₃), 6.21 (1H,s, 2-H), 6.68 (1H, d, J 10.2Hz, 3"-H), 7.14 (1H, s, 4'-H), 7.65-7.77 (2H, m, 4" and 6"-H₂).

b) 5-[2-(N,N-Diethylcarbamoyloxy)-5-pyridyl]-2-(1- normon-2-yl)oxazole 6,7,13-tristrimethylsilyl ether

A solution of the oxazole from (14a) (240mg, 0.36mmol) in benzene (7ml) was treated with triethylamine (74μl, 0.53mmol) and diethylcarbamoyl chloride (45μl, 0.36mmol). After 18h at reflux temperature, the reaction mixture was chromatographed on silica eluting with dichloromethane/methanol mixtures to give the crude title compound (130mg). Further chromatography using 30% ethyl acetate/hexane as eluent gve the title compound (100mg, 36%); δ_H (CDCI₃) inter alia 0.89 (3H, d, J 7.0Hz, 17-H₃), 1.19 (d, J 6.3Hz, 14-H₃), 1.22 (t, J, 1 . 3Hz , Et), 1.28 (t, J 7.3Hz, Et) , (all together 9H) , 2.30 (3H, s, 15-H₃), 6.27 (1H, s, 2-H), 7.17 (1H, d, J 8.4Hz, 3"-H), 7.38 (1H, s, 4'-H) , 7.95 (1H, dd, J 2.3, 8.4Hz, 4"-H) , 8.64 (1H, d, J 2.3Hz, 6''-H) .

c) 5-[2-(N,N-Diethylcarbamoyloxy-5-pyridyl]-2-(1- normon-2-yl)oxazole

A solution of the oxazole from (14b) (100mg, 0.13mmol) in methanol (3ml) was treated with DMAP.2HCl (Img). After 40 minute, the reaction mixture wa.s diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, then dried and evaporated. Chromatography on silica eluting with dichloromethane/ methanol mixtures gave the title oxazole (44mg, 61%); v_max (KBr) 3421, 1718, 1652cm-¹; λ_max (EtOH) 303nm (ε_m 27,415); δ_H (CDCl₃) inter alia 0.92 (3H, d, J 7.0Hz, 17-H₃), 1.21 (d, J 6.4Hz, 14-H₃), 1.26 and 1.29 (both t, J 7.1Hz, 2 x Et) (together 9H), 2.31 (3H, s, 15-H₃), 6.29 (1H, s, 2-H), 7.18 (1H, d, J 8.4Hz, 3"-H), 7.39 (1H, s, 4'-H), 7.96 (1H, dd, J 2.3, 8.4Hz, 4"-H), 8.64 (1H, d, J 2.3Hz, 6" -H); δ_C (CDCI₃)

12.6 (C-17), 13.2 and 14.1 (1 x CH₂Me), 19.5 (C-15), 20.7 (C-14), 31.6 (C-9), 39.5 (C-8), 42.1 and 42.2 (2 x CH₂Me),

42.7 (C-12), 42.9 (C-4), 55.5 (C-10), 61.2 (C-11), 65.4 (C-16), 68.8 (C-6), 70.3 (C-13), 71.1 (C-7), 76.7 (C-5),

112.8 (C-2), 116.5 (C-3"), 122.3 (C-5"), 123.6 (C-4'), 134.6 (C-4"), 143.7 (C-6"), 146.4 (C-5"), 147.8 (C-3), 153.2 (C-2"), 158.0 (CO), 161.7 (C-2'); m/z M⁺, 559 (5%), 100 (100%); (Found: M⁺ 559.2886. C₂₉H₄₁N₃O₃ requires M 559.2894). Example 15

5-(2-Bromo-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 5-Diazoacetyl-2-bromopyridine

A suspension of 6-bromonicotinic acid (1.60g, 8mmol) in dichloromethane (40ml) at 5°C was treated with triethylamine (1.22ml, 8.8mmol) followed by isobutylchloroformate (1.04ml, 8mmol). After 0.75 hours the solution was added to a solution of excess diazomethane in ether at 5°C. After 4 hours at 5°C folowed by 1.5 hours at ambient argon was passed through the mixture which was then evaporated and chromatographed (20g silica, eluent:hexane:ethyl acetate 1:1) to give the title pyridine (0.48g, 26%); v_max (CHCI₃) 2100, 1620 and 1575cm-¹; δ_H (CDCI₃) 6.08 (1H, s, -COCHN₂), 7.75 (1H, d, J 9.0Hz, 3-H), 8.15 (1H, dd, J 9.0 and 3.0Hz, 4-H) and 8.84 (1H, d, J 3.0Hz, 6-H).

b) 5-Bromoacetyl-2-bromopyridine

A solution of 5-diazoacetyl-2-bromopyridine (0.48g, 2.1mmole) in diethyl ether (100ml) at 5°C was treated with excess IN hydrogen bromide in diethyl ether and after 0.75 hours the mixture was washed with sodium hydrogen carbonate and brine then dried and evaporated to give the title compound (0.54g, 100%); v_max (CHCI₃) 1690 and 1575cm-¹; δ_H (CDCI₃) 4.47 (2H, s, -COCH₂Br), 7.78 (1H, d, J 9.0Hz, 3-H), 8.28 (1H, dd, J 9.0 and k3.0Hz, 4-H) and 9.10 (1H, d, J 3.0Hz, 6-H).

c) 5-Azidoacetyl-2-bromopyridine

A solution of the bromoketone from (15b) (0.54g, 2.1mmol) in dichloromethane (30ml) at 5°C was treated with tetramethylguanidinium azide (0.37g, 2.3mmol). After 0.5 hours at 5°C followed by 0.25 hours to ambient the reaction mixture was evaporated and chromatographed (15g silica, eluent: 10% ethyl acetate in dichloromethane) to give the title pyridine (0.38g, 84%); v_max (CHCl₃) 2100, 1705 and 1575cm-¹; δ_H (CDCI₃) 4.64 (2H, s, COCH₂N₃), 7.82 (1H, d, J 9.0Hz, 3-H), 8.26 (1H, dd, J 9.0 and 3.0Hz, 4-H) and 9.02 (1H, d, J 3.0Hz, 6-H).

d) 2-Amino-1-(2-bromo-5-pyridyl)ethane-1-one dihydrochloride

A solution of the azide from (15c) (365mgs, 2.1mmol) in THF (15ml), water (10ml) and 5M HCl (0.90ml, 4.5mmol) was hydrogenated with 10% Pd/C (200mgs) for 10min. The mixture was filtered through celite and the filtrate evaporated to dryness. Ethanol was added to the residue and the solution re-evaporated to give material which contained the title compound (350mgs, 60% wt. yield); v_max (KBr) 3600-2000 (b), 1700 and 1500cm-¹; δ_H (D₂O) inter alia 4.65 (2H, s,

-COCH₂NH₂), 7.82 (1H, d, J 8.5Hz, 3-H), 8.22 (1H, dd, J 8.5 and 2.5Hz, 4-H) and 8.87 (1H, d, J 2.5Hz, 6-H).

e) N-[2-(2-Bromo-5-pyridyl)-2-oxoethyl]monamide

The title monamide was prepared according to the general method from the amine salt from (15d) (340mgs, 1.3mmol) in THF/water (1:1, 4ml) and triethylamine (360μl, 2.6mmol) and isolated after chromatography as a white foam (210mgs, 30% yierld); λ _max (EtOH) 239nm (ε_m 19,700); δ_H (CD₃OD) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.17 (3H, s, 15-H₃), 4.68 (2H, s, 1'-H₂), 5.88 (1H, s, 2-H), 7.78 (1H, d, J 8.5Hz, 3"-H), 8.23 (1H, dd, J 8.5 and 2.5Hz, 4"-H) and 8.96 (1H, d, J 2.5Hz, 6"-H); δ_C (CD₃OD) 12.2 (C-17), 18.9 (C-15), 20.2 (C-14), 41.6 (C-8), 43.7 (C-12 and C-4), 47.2 (C-1'), 56.8 (C-10), 61.2 (C-11), 66.2 (C-16), 70.0 (C-6), 70.6 (C-7), 71.5 (C-13), 76.1 (C-5), 120.4 (C-2), 129.7 (C-3"), 131.5 (C-5"), 139.2 (C-4 " ) , 147.6 (C-3), 150.6 (C-6"), 153.7 (C-2"), 169.8 (C-1) and 195.0 (C-2'); m/z (FAB, 3-NOBA/Na) 565 (MNa⁺, 2%) and 176 (100).

f) 5-(2-Bromo-5-pyridyl)-2-(1-normon-2-yl)oxazole

The monamide from (15e) (0.2g) was cyclised according to the general method to give the title oxazole (0.07g, 40%); λ_max (EtOH) 313nm (ε_m 25,050); δ_H (CD₃OD) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.5Hz, 14-H₃), 2.31 (3H, s, 15-H₃), 6.28 (1H, s, 2-H), 7.66-7.71 (2H, m, 4' -H and 3" -H), 8.0 (1H, dd, J 8.5 and 2.5Hz, 4"-H) and 8.71 (1H, d, J 2.5Hz, 6"-H); δ_C (CD₃OD) 12.3 (C-17), 19.9 (C-15), 20.3 (C-14), 33.0 (C-9), 41.7 (C-8), 43.8 (C-12), 44.0 (C-4), 56.9 (C-10), 61.3 (C-11), 66.4 (C-16), 70.1 (C-6) , 70.7 (C-7), 71.7 (C-13), 76.4 (C-5), 113.3 (C-2), 125.3 (C-5"), 125.9 (C-4'), 129.8 (C-3"), 135.3 (C-4"), 141.8 (C-3), 146.4 (C-6"), 147.5 (C-5'), 150.8 (C-2") and 163.7 (C-2'); m/z 522 (M⁺, 10%) and 278 (100); (Found: M⁺, 522.1353. C₂₄H₃₁N₂O₆Br requires M, 522.1365).

Example 16

5-(2-Fluoro-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 5-Chloroacetyl-2-fluoroρyridine

A suspension of 2-fluoronicotinic acid (0.565g, 4mmol) in dichloromethane (10ml) and DMF (0.2ml) was treated with oxalyl chloride (0.45ml, 4.8mmol) and allowed to react over 1 hour. The resulting solution was then added to a solution of excess diazomethane in ether. After 2 hours IN hydrogen chloride in diethyl ether (20ml, 20mmol) was added and the reaction left 1 hour, then washed with sodium bicarbonate, brine, dried (MgSO₄) and evaporated. Column chromatography, eluting with 2:1 hexane: ethyl acetate, gave the title compound (0.44g, 65%); v_max (DCM) 1700 and 1595cm-¹; δ_H (CDCl₃) 4.64 (2H, s, -COCH₂Cl), 7.10 (1H, dd, J 8.5 and 2.5Hz, 3-H), 8.25-8.52 (1H, m, 4-H) and 8.83 (1H, d, J 2.5Hz, 6-H).

b) 5-Azidoacetyl-2-fluoropyridine

A solution of the chloroketone from (16a) (1.0g, 6mmol) in dichloromethane (50ml) at 5°C was treated with tetramethylguanidinium azide (1.0g, 6.5mmol). After 0.75 hours at 5°C followed by 0.5 hours to ambient temperature the reaction mixture was concentrated and applied to a silica column (30g) eluting with dichloromethane to 10% ethyl acetate/dichloromethane to give the title azide (0.5g, 50%); v_max (CHCI₃) 2100, 1700 and 1590cm-¹; δ_H (CDCI₃) 4.53 (2H, s, -COCH₂N₃), 7.08 (1H, dd, J 8.5 and 2.5Hz, 3-H), 8.20-8.45 (1H, m, 4-H) and 8.74 (1H, d, J 2.5Hz, 6-H).

c) 2-Amino-1-(2-fluoro-5-pyridyl)ethan-1-one

A solution of the azide from (16b) (0.29g, 1.6mmol) in THF (15ml), water (9ml) and 5N HCl (0.75ml) was hydrogenated in the presence of 10% Pd/C (75mgs, 35mgs) for 2 x 5 minutes. The mixture was filtered through a celite pad and evaporated to afford material which contained about 10% of the title compound; δ_H (D₂O) inter alia 7.25 (1H, d, J 8.5Hz), 8.44-8.56 (1H, m) and 8.82 (1H, bs). d) N-[2-Oxo-2(2-fluoro-5-pyridyl)ethyl]monamide

The monamide was prepared according to the general method from the amine salt from (16c) and isolated, after chromatography, as a white foam (0.06g, <10%) ; δ_H (CDCI₃) inter alia 0.94 (3H, d, J 7.0Hz, 17-H₃), 1.23 (3H, d, J 6.5Hz, 14-H₃), 2.22 (3H, s, 15-H₃), 4.82 (2H, d, J 4.0Hz, 1'-H₂), 5.86 (1H, s, 2-H), 6.75 (1H, t, -NH), 7.10 (1H, dd, J 8.5 and 2.3Hz, 3"-H), 8.42 (1H, t, J 8.5Hz, 4"-H) and 8.92 (1H, s, 6"-H).

e) N-[2-Oxo-2(2-fluoro-5-pyridyl)ethyl]6,7,13-tris- trimethylsilyloxymonamide

A solution of the monamide from (16d) (0.15g, 0.3mmol) in dry THF (8ml) at 5°C under argon was treated sequentially with DMAP (catalytic amount), triethylamine (0.34ml, 2.44mmol) and trimethylsilyl chloride (0.23ml, 1.8mmol) and the reaction stirred for 2 hours. The mixture was then filtered, the filtrate evaporated and the residue chromatographed (7g silica, eluent: 40% ethyl acetate/hexane) to give the title compound (0.19g, 89%); δ_H (CDCI₃) 0.06-0.28 (27H, m, 3 x (CH₃)₃Si-), 0.92 (3H, d, J 7.0Hz, 17-H₃), 1.22 (3H, d, J 6.5Hz, 14-H₃), 2.23 (3H, s, 15-H₃), 4.80 (2H, d, J 4.5Hz, 1'-H₂), 6.38 (1H, t, -NH), 7.08 (1H, dd, J 8.5 and 2.5Hz, 3"-H), 8.40 (1H, t, J 8.5Hz) and 8.98 (1H, s, 6''-H).

f) 5-(2-Fluoro-5-pyridyl)-2-(1-nor-6,7,13-tristri- methylsilyloxy-mon-2-yl)oxazole

A solution of the monamide from (16e) (0.19g, 0.27mmol) in dichloromethane at 5°C under argon was treated sequentially with DMAP (catalytic amount), pyridine (65μl, 0.81mmol) and trichloroacetyl chloride (60μl, 0.54mmol) and the reaction stirred 1 hour. The mixture was then diluted with dichloromethane and washed with sodium bicarbonate soluuion, brine, dried (MgSO₄), evaporated and chromatographed (6g silica, eluent: hexane:ethyl acetate 3:1) to give the title oxazole (34mg, 18%) as a foam; δ_H (CDCl₃) inter alia 0.05-0.24 (27H, m, 3 x (CH₃)₃Si-), 0.90 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.32 (3H, s, 15-H₃), 6.27 (1H, s, 2-H), 7.01 (1H, dd, J 8.0 and 3.0Hz, 3"-H), 7.40 (1H, s, 4'-H), 8.01 (1H, dt, J 8.0 and 2.5Hz, 3"-H) and 8.53 (1H, s, 6"-H).

g) 5-(2-Fluoro-5-pyridyl)-2-(1-normon-2-yl)oxazole

A solution of the oxazole from (16f) (34mg, 0.049mmol) in dry THF (1.7ml) was treated with 0.4N hydrochloric acid (0.33ml) for 2 minutes at ambient temperature with stirring. The solution was then neutralised with saturated sodium bicarbonate solution (1.5ml) and partitioned between ethyl acetate and brine. The organic phase was concentrated and applied to a silica column (800mgs silica, eluent: 7.5% methanol/dichloromethane) to give the title oxazole (16mg, 70%); δ_H(CDCl₃) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.23 (3H, d, J 6.5Hz, 14-H₃), 2.34 (3H, s, 15-H₃), 6.30 (1H, s, 2-H), 7.02 (1H, dd, J 8.5 and 2.8Hz, 3"-H), 7.40 (1H, s, 4'-H), 8.02 (1H, t, J 8.5Hz, 4"-H) and 8.53 (1H, s, 6"-H); m/z 462 (M⁺, 15%) and 218 (100); (Found: M⁺, 462.2184. C₂₄H₃₁N₂O₆F requires M, 462.2166).

Example 17

5-(2-Ethoxy-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 2-Amino-1-(2-ethoxy-5-pyridyl)ethan-1-one hydrochloride

A solution of azide from (16b) (0.2g, 1.2mmole) in THF (10ml), water (6ml) and 5N HCl (0.5ml) was hydrogenated in the presence of 10% Pd/C (50mgs, 50mgs) for 2 x 5 minutes. The mixture was filtered through a celite pad and evaporated to dryness. Ethanol was added to the residue and the solution re-evaported to give material (0.25g) containing ca.35% of the title compound; δ_H (D₂O) inter alia 1.41 (3H, t, J 7.0Hz), 4.47 (2H, q, J 7.0Hz), 4.63 (2H, s), 7.23 (1H, d, J 9.0Hz), 8.50 (1HH dd, J 9.0 and 2.0Hz) and 8.80 (1H, d, J 2.0Hz).

b) N-[2-Oxo-2(2-ethoxy-5-pyridyl)ethyl]monamide

The monamide was prepared according to the general method from the amine salt from (17a) (0.25g, lmmol) to give, after chromatography, the title monamide (115mg, 22%); δ_H (CD₃OD) 0.96 (3H, d, J 7.0Hz, 17-H₃), 1.21 (3H, d, J 6.5Hz, 14-H3), 1.40 (3H, t, J 7.0Hz, -CH₂CH₃), 2.17 (3H, s, 15-H₃), 4.43 (2H, q, J 7.0Hz, -CH₂CH₃), 4.68 (2H, s, 1'-H₂), 5.90 (1H, s, 2-H), 6.86 (1H, d, J 9.0Hz, 3"-H), 8.23 (1H, dd, J 9.0 and 2.3Hz, 4"-H) and 8.83 (1H, d, J 2.3Hz, 6"-H); m/z 506 (M⁺, 12%) and 150 (100).

c) 5-(2-Ethoxy-5-pyridyl)-2-(1-normon-2-yl)oxazole

The monamide from (17b) (95mg, 0.185mmol) was cyclised according to the general method to give the title oxazole (35mgs, 40%); λ_max (EtOH) 303.5nm (ε_m 24,000); δ_H (CDCl₃) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.23 (3H, d, J 6.5Hz, 14-H₃), 1.43 (3H, t, J 7.0Hz, CH₃CH₂O-), 2.33 (3H, s, 15-H₃), 4.40 (2H, 1q, J 7.0Hz, CH₃CH₂O-), 6.29 (1H, s, 2-H), 6.78 (1H, d, J 8.5Hz, 3"-H), 7.28 (1H, s, 4'-H), 7.78 (1H, dd, J 8.5 and 2.2Hz, 4"-H) and 8.47 (1H, d, J 2.2Hz, 6"-H); m/z 488 (M⁺, 24%) and 244 (100). (Found: M⁺, 488.2525. C₂₆H₃₆N₂O₇ requires M 488.2523). Example 18

5-(3-Bromo-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 5-Chloroacetyl-3-bromoρyridine

5-Bromonicotinic acid (1.61g, δmmole) was reacted as described in (16a) and the title product isolated (1.6g, 85%); v_max (CHCl₃) 1420cm-¹.

b) 5-Azidoacetyl-3-bromoρyridine

The chloroketone from (18a) was reacted as described in (16b) and the title azide isolated (1.12g, 69%); v_max (CHCl₃) 2100 and 1710cm-¹; δ_H (CDCI₃) 4.72 (2H, s,

-COCH₂N₃), 8.33-6.45 (1H, m, 4-H), 8.68-8.80 (1H, m, 2-H) and 8.89-9.08 (1H, m, 6-H).

c) 2-Amino-1-(3-bromo-5-pyridyl)ethan-1-one hydrochloride

The azidoketone from (18b) was reacted as described in (16c) and the title compound isolated as a yellow solid (0.5g); δ_H (D₂O) inter alia 4.70 (2H, s, -COCH₂NH₂), 8.82 (1H, s, 4-H), 9.03 (1H, s, 2-H) and 9.14 (1H, s, 6-H).

d) N-[2-(3-Bromo-5-pyridyl)-2-oxoethyl]monamide

The title monamide was prepared according to the general method from the amine salt from (18c) (500mgs, 1.5mmole) in THF/water (1:1, 5ml) and triethylamine (360μl, 2.6mmol) and isolated after chromatography as a yellow foam (280mgs, 34%); λ_max (EtOH) 214.5nm (ε_m 31,900); δ_H (CD₃OD) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.16 (3H, s, 15-H₃), 4.70 (2H, s, 1'-H₂), 5.88 (1H, s, 2-H), 8.52-88.58 (1H, m, 4"-H), 8.39 (1H, d, J 2.0Hz, 2"-H) and 9.10 (1H, d, J 1.5Hz, 6"-H); δ_C (CD₃OD) 12.2 (C-17), 18.9 (C-15), 20.2 (C-14), 32.9 (C-9), 43.7 (C-4 and C-12), 47.3 (C-1'), 56.6 (C-10), 61.2 (C-11), 66.2 (C-16), 69.9 (C-6), 70.6 (C-7), 71.6 (C-13), 76.2 (C-5), 120.4 (C-2), 120.6 (C-5"), 133.6 (C-3"), 139.3 (C-2"), 148.2 (C-4"), 153.5 (C-3), 155.3 (C-6"), 169.8 (C-1) and 194.6 (C-2'); m/z (FAB, Matrix thioglycerol) 541 (MH⁺).

e) 5-(3-Bromo-5-pyridyl)-2-(1-normon-2-yl)oxazole

The monamide from (18d) was cyclised according to the general method to give the title oxazole (105mgs, 50%); λ_max (EtOH) 317nm (ε_m 20,469); δ_H (CD₃OD) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.32 (3H, s, 15-H₃), 6.29 (1H, s, 2-H), 7.75 (1H, s, 4'-H),

8.31 (1H, t, J 2.0Hz, 4"-H), 8.60 (1H, d, J 2.0Hz, 2"-H) and 8.87 (1H, d, J 2.0Hz, 6"-H); δ_V (CD₃OD) 12.3 (C-17),

20.0 (C-15), 20.4 (C-14), 33.1 (C-9), 41.8 (C-8), 43.8 (C-12), 44.1 (C-4), 56.9 (C-10), 61.3 (C-11), 66.5 (C-16),

70.1 (C-6) , 70.8 (C-7), 71.7 (C-13), 76.5 (C-5), 113.3 (C-2), 122.3 (C-3"), 126.7 (C-4'), 127.5 (C-5"), 135.0 (C-4"), 144.2 (C-6" ) , 146. 8 (C-3), 150.5 (C-2"), 151.1 (C-5') and 163.9 (C-2'); m/z 522 (M⁺, 4%) and 43 (100). (Found: M⁺, 522.1357. C₂₄H₃₁N₂O₆Br requires M, 522.1365).

Example 19

5-(2-Dimethylamino-5-pyridyl)-2-(1-normon-2-yl)oxazole

a) 5-t-Butoxycarbonylaminoacetyl-2-dimethylaminopyridine

A solution of 5-bromo-2-dimethylaminopyridine (1.2g, 6mmol) in dry THF (20ml) at -100°C under an atmosphere of argon was treated with n-butyl lithium (3.75ml, 1.6M in hexane, 6mmol) maintaining the temperature of reaction below -85°C. After 1 hour at -90°C a solution of

N-1-methoxy-N-1-methyl-N-(t-butoxycarbonyl)-glycinamide (0.44g, 2mmol) in dry THF (10ml) was added maintaining the temperature at -85°C. After 2 hours the cooling bath was removed and a saturated solution of ammonium chloride (20ml) was added. The mixture was extracted with ethyl acette and the organic phase washed with brine, dried (MgSO₄) and evaported. The residue was chromatographed (17g silica, eluent:hexane: ethyl acetate 2:1) to give material containing the title compound (0.06g); δ_H (CDCl₃) inter alia 1.46 (9H, s, ^tBu protons), 3.20 (2H, d, J 4.5Hz, -COCH₂NH-), 5.60 (1H, bs, >NH), 6.52 (1H, d, J 9.0Hz, 3-H), 7.98 (1H, dd, J 9.0 and 2.5Hz, 4-H) and 8.76 (1H, d, J 2.5Hz, 6-H).

b) 2-Amino-1-(2-dimethylamino-5-pyridyl)ethan-1-one hydrochloride

A solution of the pyridine from (19a), (200mg, 0.7mmol) in methanol (3.4ml) at 5°C was treated with concentrated HCl (1.7ml). After 0.5 hours at 5°C followed by 2.5 hours at ambient the solution was evaporated to dryness, the residue triturated with diethyl ether and dried under vacuo to give an impure product containing the title compound (200mg); δ_H (D₂O) inter alia 3.32 (6H, s, -N(CH₃)₂), 4.56 (2H, s, -COCH₂NH₂), 17.23 (1H d, J 10.0Hz, 3-H), 8.27 (1H, dd, J 10.0 and 2.0Hz, 4-H) and 8.53 (1H, d, J 2.0Hz, 6-H)

c) N-[2-(2-Dimethylamino-5-pyridyl)-2-oxoethyl]monamide

The title monamide was prepared according to the general method from the amine salt from (19b) (190mg, 0.7mmol) in THF/water (1:1, 3ml) and triethylamine (300μl, 2.1mmol) and isolated after chromatography as a pink foam (135mg, 38%); δ_H (CD₃OD) 0.96 (3H, d, J 7.0Hz, 17-H₃), 1.21 (3H, d, J 6.5Hz, 14-H₃), 2.17 (3H, s, 15-H₃), 3.20 (6H, s, -N(CH₃)₂), 4.60 (2H, s, 1'-_H2), 5.90 (1H, s, 2-H), 6.70 (1H, d, J 9.0Hz, 3"-H), 8.06 (1H, dd, J 9.0 and 2.5Hz, 4"-H) and 8.75 (1H, d, J 2.5Hz, 6"-H); m/z (FAB, thioglycerol) 506 (MH⁺, 42%) and 126 (100).

d) 5-(2-Dimethylamino-5-pyridyl)-2-(1-normon-2-yl)oxazole

The monamide from (19c) was cyclised according to the general method to give the title oxazole (70mg, 55%); λ_max (EtOH) 330nm (ε_m 23,500); δ_H (CD₃OD) 0.96 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.29 (3H, s, 15-H₃), 3.12 (6H, s, -N(CH₃)₂), 6.23 (1H, s, 2-H), 6.73 (1H, d, J 9.0Hz, 3"-H), 7.30 (1H, s, 4'-H), 7.78 (1H, dd, J 9.0 and 2.5Hz, 4"-H) and 8.38 (1H, d, J 2.5Hz, 6"-H); δ_C (CD₃OD) 12.3 (C-17), 19.8 (C-15), 20.4 (C-14), 33.1 (C-9) , 38.5 (-N(CH₃)₂), 41.7 (C-8), 43.8 (C-12), 43.9 (C-4), 56.9 (C-10), 61.3 (C-11), 66.4 (C-16), 70.1 (C-6), 70.8 (C-7), 71.7 (C-13), 76.5 (C-5), 107.5 (C-2), 113.6 (C-5"), 113.7 (C-4'), 120.9 (C-3"), 134.6 (C-4"), 144.7 (C-6" ) , 148.3 (C-5'), 150.2 (C-3), 160.1 (C-2") and 161.9 (C-2); m/z 487 (M⁺, 80%) and 243 (100); (Found: M⁺, 487.2704. C₂₆H₃₇N₃O₆ requires 487.2682).

Example 20

5-(2-Fluoro-3-pyridyl)-2-(1-normon-2-yl)oxazole

a) 3-t-Butoxycarbonylaminoacetyl-2-fluoropyridine

A solution of lithium diisopropylamide mono (tetrahydrofuran) (5.72ml, 1.5M in cyclohexane, 8.6mmol) at -90°C under argon was treated with a solution of 2-fluoropyridine (0.74ml, 8.5mmol) in THF (16ml) whilst maintaining the temperature below -70°C. After 2.5 hours at -80°C a solution of N-1-methoxy-N-1-methyl-N-(t-butoxycarbonyl)glycinamide (0.88g, 4mmol) in THF (16ml) was added maintaining the temperature belowe -70°C. After 2 hours glacial acetic acid (0.68ml) was added with thorough mixing and the reaction partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO₄), evaporated and the residue chromatographed (25g silica, eluent:hexane: ethyl acetate 1:1) to give the title compound (120mgs, 11%); δ_H (CDCl₃) 1.47 (9H, s, (CH₃)₃C-), 4.63 (2H, s, -COCH₂NH-), 5.40 (1H, broad s, >NH), 7.33-7.43 (1H, m, 5-H) and 8.39-8.50 (2H, m, 4H and 6-H).

b) 2-Amino-1-(2-fluoro-3-pyridyl)ethan-1-one trifluoroacetate

A solution of the protected aminomethyl ketone from (20a) (243mgs, 0.95mmol) in dichloromethane (12ml) at 5°C was treated with trifluoroacetic acid (2.5ml). After 10 minutes at 5°C followed by 2 hours at ambient the mixture was evaporated and the residual gum dried in vacuo. The residue was then triturated with dry diethyl ether and the resulting cream coloured solid separated and dried to give the title compound (250mgs); δ_H (D₂O) inter alia 4.62 (2H, s, -COCH₂NH₂), 7.50-7.62 (1H, m, 5-H) and 8.45-8.60 (2H, m, 4-H and 6-H).

c) N-[2-(2-Fluoro-2-pyridyl)-2-oxoethyl]monamide

The title monamide was prepared according to the general method from the amine salt from (20b) (250mg, 0.95mmol) in THF/water (1:1, 4ml) and triethylamine (390μl, 2.85mmol) and an impure product isolated (270mg) which contained the title monamide; δ_H (CD₃OD) inter alia 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.14 (3H, s, 15-H₃), 5.88 (1H, s, 2-H), 7.44-7.53 (1H, m, 5'-H) and 8.40-8.47 (2H, m, 4' and 6'-H). d) 5- (2-Fluoro-3-pyridyl ) -2- ( 1-normon-2-yl ) oxazole

The monamide from (20c) (270mg, 0.56mmol) was cyclised according to the general method to give the title oxazole (27mg, 10%); λ_max (EtOH) 317nm (ε_m 22,690); δ_H

(CD₃OD) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.5Hz, 14-H₃), 2.33 (3H, s, 15-H₃), 6.30 (1H, s, 2-H), 7.40-7.49 (1H, m, 5"-H), 7.57 (1H, d, J 4.0Hz, 4'-H fluorine coupling) and 8.12-8.34 (2H, m, 4"-H and 6"-H); m/z 462 (M⁺, 8%) and 218 (100). (Found: M⁺, 462.2170. C₂₄H₃₁N₂O₆F requires M, 462.2166).

Biological Data

The activity of the normonyl derivatives of the Examples against various bacteria (H.influenzae Ql; B.catarrhalis 1502; Strep.pyogenes CN10; Strep.pneumoniae PU7; and Staph.aureus Oxford) which are important in the diseases of humans was assayed in vitro using serial dilutions in nutrient agar with 5% chocolated horse blood.

The MIC values were determined after incubation for 18h at 37°C and were found to be in the range 0.25 to 32 μg/ml.

Claims

Claims

1. A compound of formula (I):

in which R¹ represents a pyridyl group which is bonded via a carbon atom thereof to the oxazolyl moiety, which pyridyl group may be unsubstituted or substituted by up to five substituents which may be the same or different.

2. A compound as claimed in claim 1 in which a substituent for the pyridyl group of R¹ is selected from:

(i) halogen, cyano, azido, nitro, formyl, carboxy, carboxylate salts, sulpho, or sulphonate salts,

(ii) amino, ureido, carbamoyl, or sulphonamido, in each of which groups a nitrogen atom may be further optionally substituted by one or two groups (which may be the same or different) selected from the groups listed in sub-paragraphs (iv), (v) and (vi);

(iii) hydroxy, or mercapto, in each of which groups hydrogen may be replaced by one of the groups listed in subparagraphs (iv), (v) and (vi); (iv) a group R^p wherein R^p denotes aryl or heterocyclyl;

(v) a group R^q wherein R^q denotes (C_1-6)alkyl,

(C_3-7)cycloalkyl, (C_2-6)alkenyl, (C_3-8)cycloalkenyl or (C_2-6)alkynyl, each of which may be optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in sub-paragraphs (i), (ii), (iii), (iv) and (vi);

(vi) a group R^pCO-, R^pOCO-, R^qCO-, R^qOCO-, R^pSO-, R^pSO₂-, R^qSO-, or R^qSO₂- wherein R^p and R^q are as defined in subparagraphs (iv) and (v) respectively; and

(vii) a divalent group Y° which together with two carbon atoms of the pyridyl group to which it is bonded form a heterocyclic or carbocyclic ring.

3. A compound as claimed in claim 1 in which a substituent for the pyridyl group of R¹ is selected from hydroxy, halogen, cyano, nitro, optionally substituted

(C_1-6)alkyl, aryl, heterocyclyl, (C_1-6)alkoxy, carboxy and salts thereof, (C_1-6)alkoxycarbonyl, acyl, amino, mono- or di-(C_1-6)alkylamino, carbamoyl, mono- or di-(C_1-6)alkylcarbamoyl, carbamoyloxy, mono- or di- (C_1-6)alkylcarbamoyl, acylamino, (C_1-6)alkoxycarbonylamino, (C_1-6)alkylthio, arylthio, (C_1-6)alkylsulphinyl, arylsulphinyl, (C_1-6)alkylsulphonyl, arylsulphonyl, sulphamoyl, mono- or di-(C_1-6)alkylsulphamoyl.

4. A compound as claimed in claim 1 in which the pyridyl group has a single substituent.

5. A compound as claimed in claim 1 in which the pyridyl group R¹ is bonded to the oxazole ring by a carbon atom which is β- to the pyridyl nitrogen atom.

6. A compound selected from the group consisting of:

2-(1-Normon-2-yl)-5-(2-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(3-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(4-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(2-methyl-5-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(1,2-dihydro-2-oxo-5-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(2-methoxy-5-pyridyl)oxazole;

2-(1-Normon-2-yl)-5-(1,2-dihydro-1-methyl-2-oxo-5- pyridyl)oxazole;

5-(2-Methoxy-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Chloro-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2,3-Dichloro-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Methylthio-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Methylsulphinyl-5-pyridyl)-2-(1-normon-2-yl)oxazole; 5-(2-Methylsulphonyl-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-[2-(N,N-Diethylcarbamoyloxy)-5-pyridyl]-2-(1-normon- 2-yl)oxazole;

5-(2-Bromo-5-ρyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Fluoro-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Ethoxy-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(3-Bromo-5-pyridyl)-2-(1-normon-2-yl)oxazole;

5-(2-Dimethylamino-5-pyridyl)-2-(1-normon-2-yl)oxazole; and

5-(2-Fluoro-3-pyridyl)-2-(1-normon-2-yl)oxazole,

7. A process for the preparation of a compound according to claim 1 which process comprising cyclising a compound of formula (III):

in which R¹ is as defined in claim 1, and Z¹, Z² and Z³ are the same or different and each is hydrogen or a hydroxyl-protecting group; to form a compound of formula (I) and thereafter, and if necessary, removing any hydroxyl-protecting groups.

8. A compound of formula (III), as defined in claim 7.

9. A compound selected from the group consisting of:

N-[2-oxo-2-(2-pyridyl)ethyl]monamide; N-[2-oxo-2-(3-pyridyl)ethyl]monamide;

N-[2-oxo-2-(4-pyridyl)ethyl]monamide;

N-[2-oxo-2-(2-methyl-5-pyridyl)ethyl]monamide;

N-[2-oxo-2-(1,2-dihydro-2-oxo-5-pyridyl)ethyl]monamide;

N-[2-(2-methoxy-5-pyridyl)-2-oxoethyl]monamide; N-[2-(2-chloro-5-pyridyl)-2-oxoethyl]monamide;

N-[2-(2,3-dichloro-5-ρyridyl)-2-oxoethyl]monamide;

N-[2-(2-methylthio-5-pyridyl)-2-oxoethyl]monamide;

N-[2-(2-Bromo-5-pyridyl)-2-oxoethyl]monamide;

N-[2-Oxo-2(2-fluoro-5-pyridyl)ethyl]monamide; N-[2-Oxo-2(2-ethoxy-5-pyridyl)ethyl]monamide; N-[2-(3-Bromo-5-pyridyl)-2-oxoethyl]monamide;

N-[2-(2-Dimethylamino-5-pyridyl)-2-oxoethyl]monamide; and

N-[2-(2-Fluoro-2-pyridyl)-2-oxoethyl]monamide.

10 A process for the preparation of a compound according to claim 1 which process comprises reacting a compound of formula (V):

m which Z¹, Z² and Z³ are the same or different and each is hydrogen or a hydroxyl-protecting group;

with a compound of formula (VI):

in which R¹ is as defined in claim 1;

M⁺ is a metal cation; and

R² is an anion-stabilismg group which will spontaneously eliminate with a β-hydroxyl group to produce an olefin; and, thereafter and if necessary, removing any hydroxyl-protecting groups.

11. A process for the preparation of a compound according to claim 1 which process comprises treating a compound of formula (VIII):

in which: Z¹ , Z², and Z³ are the same or different and each is hydrogen or a hydroxyl-protecting group,

R¹ is as defined in claim 1, and Y is a leaving group;

with a strong base, and thereafter and if necessary removing any hydroxyl-protecting groups.

12. A compound of formula (VIII), as defined in claim 11.

13. A process for preparing a compound according to claim 1 which process comprises isomerising the carbon-carbon double bond of a compound of formula (XI):

in which R¹, Z¹, Z² and Z³ are as defined in claim 7.

14. A pharmaceutical or veterinary composition comprising a compound of formula (I) and a pharmaceutically or veterinarily acceptable carrier or excipient.

15. A compound according to any one of claims 1 to 6 for use in therapy.

16. A method of treating bacterial and/or mycoplasmal infection in human or non-human animals, which comprises administering an effective amount of a compound according to any one of claims 1 to 6 to a human or non-human animal in need of such therapy.