SI9300036A - Nove compounds on thiazol-5-yl ketones basis - Google Patents

Abstract

Optionally substituted 2-(C1-10)alkoxythiazol-5-yl normonyl ketones of formula (I), in which R<1> is 2-(optionally substituted (C1-10)alkoxy)-thiazol-5-yl group are of use in anti-bacterial or anti-mycoplasmal therapy.

Description

Various suggestions have been made to improve the metabolic stability of mupirocin relative to enzymatic hydrolysis by adapting the C-l ester functional group, including e.g. C-l heterocyclic derivatives (EP-A-0 087 953 and ΕΡΆ-0 123 578) C-l amides (EP-A-0 001 914) and C-l ketones, including heterocyclic ketones (EP-A-0 029 665). In addition, Klein et al described (on a poster presented at the Third Annual North American Chemical Congress in Toronto, June 1988) the preparation of C-1 fur-2-yl, pyrid-2-yl, and N-methylimidazol-2-yl ketones. These are characterized in that they have a heteroaryl group attached to a ketone carbonyl group with a ring carbon atom adjacent to the heteroatom. Limited data deepened on these derivatives indicated that these compounds were less effective than the analog butyl and phenyl ketones, which were inversely less effective, than methyl pseudomonates. No results of the in vivo effect are described, with the conclusion that the in vitro effect was insufficient to confirm the in vivo investigation.

Several examples of heteroaryl ketones, including 2-methylmercapto- and 2-methyl-sulfinyl-thiazol-5-yl ketones, have recently been described in WO 92/02518 (published after the priority date requested for the submission of the application).

We have now surprisingly discovered that an increased antibacterial profile can be obtained with a narrow group of other thiazol-5-yl ketones.

Thus, the present invention relates to a compound of formula (I):

OH

R

OH in which R ^{1 is a} 2- (optionally substituted (C ₁₁₀ ) alkoxy) thiazol-5-yl group, i.e. a group of the formula:

R wherein R is optionally substituted (C _xw ) alkoxy.

Suitable optional substituents for the (C ₁₁₀₎ an alkoxy group include, for example. halogen, cyano, azido, nitro, carboxy, (C ^ jalkoksikarbonil, carbamoyl, mono- and di- (C ₁ Jalkilkarbamoil, sulfo, sulfamoyl, mono- or di- (C ^ jalkilsulfamoii, amino, mono- and di- (C ₆ ) alkylamino, acylamino, ureido, (C _1-6 ) alkoxycarbonylamino, 2,2,2 trichloroethioxycarbonylamino, trialkylthiomethyl optionally substituted aryl, optionally substituted heterocyclyl, hydroxy, (C 1-6 alkoxy, acyloxy, oxo, acyl, 2 acyl, acyl, 2 (C ₁₆₎ alkylthio, (Cl ₆₎ alkylsulphinyl, _(C1-6) alkylsulphonyl, hydroxyimino, _{(C 6)} alkoxyimino, hydrazino, hydrazono, benzohidroksimoil, guanidino, amidino and iminoalkilamino.

Accordingly, R is optionally substituted (C 1-6 alkoxy, preferably, optionally substituted methoxy ethoxy or hexoxy, more preferably methoxy, most preferably unsubstituted methoxy. Preferably R ^{1 is} 2-methoxythiazol-5-yl.

When used herein, the term aryl includes, unless otherwise defined, phenyl or naphthyl. The aryl ring may optionally be substituted with up to five, preferably up to three, substituents. Suitable substituents include e.g. halogen, cyano, (C of the shaft, phenyl, (C, _M) alkoxy, halo (C ^) alkyl, hydroxy, amino, mono- or di- (Cl ₆₎ alkylamino, acylamino, nitro, carboxy, (C ^ alkoxycarbonyl, ( C ₆₎ alkoxycarbonyl (C ₁ ^) alkyl, (C ^ jalkilkarboniloksi, (C ^ jalkiltio, (C ^ jalkilsulfinil, (C ^ jalkilsulfonil, sulfamoyl, mono- or di- (C ₁ ^) alkylsulfamoyl, carbamoyl and mono- or di- (C _1?) alkylcarbamoyl.

When used herein, it includes the term heterocyclyl aromatic and non-aromatic single or fused rings containing up to four hetero atoms in the ring selected from oxygen, nitrogen and sulfur. A suitably heterocyclic ring contains from 4 to 7, preferably 5 to 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and must include only one heterocyclic ring. The heterocyclic ring may optionally be substituted with up to three substituents. Suitable substituents include, e.g. halogen, (C ^) alkyl, (Cl ₆₎ alkoxy, halo _(C1 ^) alkyl, hydroxy, amino, mono- or di- _(C1 ^) alkylamino, carboxy, (C ^ alkoxycarbonyl, (C, _M) alkoxycarbonyl (C1-6) alkyl, aryl and oxo.

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

Compounds of formula (I) may be appropriately named (l-normon-2-yl) -ketones. Normonyl is a trivial name for 3 - [(2S, 3R, 4R, 5S) -5 - [(2S, 3S, 4S, 5S) -2,3-epoxy-5-hydroxy-4-methylhexyl] -3,4- a dihydroxytetrahydro-pyran-2-yl] -2-methylprop-1 (E) -enyl radical as shown in formula (II):

Preferably, in the compounds of formula (I), substituents within the group R ¹ may contain one or more chiral centers. The present invention encompasses all such emerging isomeric possibilities.

Because the compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions, it is understood that they are all provided in substantially pure form, e.g. at least 50% pure, more preferably at least 75% pure and preferably at least 95% pure (% based on w / w basis). The crude preparations of the compounds of formula (I) can be used to prepare the purer forms used in the pharmaceutical compositions. Although the purity of the intermediate compounds of the present invention is less critical, it is readily understood when it comes to the compounds of formula (I) that a substantially pure form is preferred. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.

When some of the compounds of the present invention are allowed to crystallize or recrystallized from organic solvents, the crystallization solvent may be present in the crystalline product. The present invention relates to such solvates. Similarly, some of the compounds of the present invention can be crystallized or recrystallized from solvents containing water. In such cases, hydration water may form. The present invention relates to stoichiometric hydrates as well as to compounds containing various amounts of water which can be prepared by processes such as lyophilization.

A preferred example of a compound of the present invention is 2-methoxy- (thiazol-5-yl) -1 (normon-2-yl) ketone.

The compounds of the present invention can be prepared by methods known for the preparation of α, 3-unsaturated ketones. Some of these procedures are more appropriate than others.

Compounds of formula (I) may be prepared by a process involving the treatment of an acid of formula (III)

wherein Z ¹ , Z ² and Z ³ are the same or different and each is a hydrogen or hydroxyl protecting group or an activated derivative thereof, with an organometallic reagent and thereafter and, if necessary, removing all hydroxyl protecting groups.

Suitable organometallic reagents include:

(i) a Grignard reagent of formula R? MgX, in which R ^{1 is} defined according to formula (I) and X represents chlorine, bromine or iodine, this reaction can optionally be carried out in the presence of copper (I) iodide, as a catalyst;

(ii) an organolithium reagent of the formula R ¹ in which R ^{1 is} defined according to formula (i);

(iii) an organomanganic reagent of formula R ¹ MnCl in which R ^{1 is} defined according to formula (I) and (iv) an oranocerium reagent R ^{1 of} Li-CeX ₃ in which R ^{1 is} defined according to formula (I) and X represents chlorine, bromine or iodine.

The reaction with an organometallic reagent can be conveniently carried out in an ether or hydrocarbon solvent, the choice depending on the specific requirements of the organometallic reagent. Preferably, the Grignard reagent is generated and used in diethyl ether or tetrahydrofuran.

The reaction is generally carried out in an inert atmosphere such as argon or nitrogen and at or below ambient temperature. The period for which the reaction is allowed to elapse depends on the particular starting materials used. The course of the reaction can be followed by conventional methods such as thin layer chromatography and the reaction can be stopped when the optimum amount of product is present in the reaction mixture.

The compound of formula (III) in which each Z ¹ , Z ² and Z ^{3 is} hydrogen is a monoic acid, the preparation of which is described in GB 1 587 058 (Beecham Group).

Suitable activated acid derivatives of formula (III) include thio-esters of formula (IV):

(IV)

containing Z ¹ , Z ² and Z ³ as defined by yarn and part:

represents a 5- or 6-membered heterocyclic ring which may contain, in addition to the nitrogen atom, one or two further heteroatoms selected from oxygen, nitrogen and sulfur, and which may be substituted or fused to a benzene ring which may be independently substituted.

Preferred are thio esters of formula (IVa):

in which Z ¹ , Z ² and Z ³ are as defined above.

The compound of formula (IVa) can be prepared by treating the compound of formula (III) with 2,2-dipyridyl disulfide in the presence of triphenylphosphine, analogous to the procedure described by E. J. Corey and D. A. Clark in Tetrahedron Letters, 1979,31,2875.

Other suitable activated acid derivatives of formula (III) include mixed anhydrides of formula (V):

wherein Z is ¹ , Z ² and Z ³ as defined by yarn and R ^{2 is} (C 1 _M ) alkyl, and of formula (VI):

wherein Z ¹ , Z ² and Z ³ are as defined above and R ³ and R ^{4 are the} same or different and each denotes an optionally substituted aryl group, e.g. phenyl, or ( _C1-6 ) alkoxy group, e.g. ethoxy.

The compound of formula (V) can be obtained by treating a compound of formula (III) with, e.g. a suitable derivative of the formula R ² OCOC1; using the procedure described by Crimmin MJ et al., JCS Perkin 1,1989,2047.

The compound of formula (VI) can be obtained by treating the compound of formula (III) with C1POR ³ R ⁴ , using the procedure described by Baxter AJG et al., In Tetrahedron Letters, 1980, 21, 5071.

Further suitable activated acid derivatives of formula (III) include amides with for-

ch ₃ o

(VII) wherein Z ¹ , Z ² and Z ³ are as defined in yarns, R ⁵ and R ⁶ are the same or different and each is (Cl 45) alkyl, or the substituents R ⁵ and R ⁶ form (C 2 7) alkylene chain; and of formula (VIII):

wherein Z ¹ , Z ² and Z ³ as defined by yarns and R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form an imidazolyl or triazolyl ring.

A preferred compound of formula (VII) is N-methoxy-N-methylamide (i.e., R ⁵ and R ⁶ are each methyl) as described in WO 91/09855 (Beecham Group). The reaction of N-methoxy-Nmethylamide with an organolithium or Grignard reagent to obtain a ketone was described by Nahm and Weinreb in Terahedron Letters, 1981, 3815.

A preferred amide of formula (VIII) is an imidazol-1-yl derivative. The reaction of α, β-unsaturated acid or its imidazolyl derivative with the Grignard reagent is described in Chem Ber., 1965, 95,1284.

The amides of formulas (VII) and (VIII) can be obtained from monoic acid by treating it with zo-butyl chloroformate in tetrahydrofuran in the presence of triethylamine at a temperature of -5 to 20 ° C for about 30 minutes to give an intermediate mixed anhydride (monic acid anhydride and iso-butyl carbon anhydride). This intermediate can then be treated with the amine HN (OR ⁵ ) R ⁶ in dichloromethane at about 20 ° C for about 2 hours, or with the amine HNR ⁷ R ⁸ .HC1 in the presence of triethylamine and

Of 4-dimethylaminopyridine in THF at about 20 ° C to give a compound of formula (VII) in which all Z ¹ , Z ² and Z ^{3 are} hydrogen (with R ¹ , R ⁵ , R ⁶ , R ⁷ and R ⁸ Its hydroxyl groups can be protected by treatment with a suitable hydroxyl protecting agent such as chlorotrimethylsilane in a solvent such as THF in the presence of triethylamine and

4-dimethylamino priridine as catalyst.

The thio ester of formula (IV) is preferably treated with an organomanganese reagent of the formula R ¹ MnCl as defined by yarn, while the amide of the formula (VII) or (VIII) is preferably treated with an organolithium reagent of the formula R 1 as defined yarn.

A preferred compound of formula (I) is prepared by a process that involves treating a compound of formula (VII) as defined by yarn with an organolithium reagent of formula R1b as defined by yarn.

Suitable organometallic reagents can be prepared by conventional procedures. For example, suitable organomanganese reagents of the formula R ^ nCl can be conveniently prepared by adding the organolithium reagent R ^ i to a solution of manganese chloride and lithium chloride in dry THF or to a suspension of anhydrous manganese chloride in dry THF. Preferably, a R ^ nCl pebit is used. Alternatively, the Grignard reagent may be used instead of the oragnolithium reagent to generate the organomanganic reagent R ^x MnCl.

Other organomanganese reagents that can be used in place of iVMnCl include:

(i) (R ¹ ) 3MnId or (R ¹ ) 3MnMgX, wherein X is as defined in yarns, as described in Synthetic Communications, 1979,9,639;

(ii) R ¹ MnJ in ether; as described in Syntehtic Communications, 1979,1,639; and (iii) R ¹ MnBr in ether as described in Tetrahedron Letters, 1976.3155.

As in the case of R ¹ MnCl, the above organomanganese reagents can be prepared in situ if required.

Organocerium reagents may be generated in situ by treatment of an organo lithium compound of formula R i, wherein R ¹ is as hereinbefore defined, with cerium (III) halide, in analogy to the procedure described by Imammoto et al., J Chem Soc , Chem Commun, 1982,1042.

Further procedures for the preparation of compounds of formula (I) are described in EP-A-0 029 665

in which R ¹ , Z ¹ , Z ² and Z ^{3 are} as defined in yarn, with an oxidizing agent that converts the allyl alcohols into α, 3-unsaturated ketones and then, if necessary, removes all hydroxyl protecting groups.

Suitable such oxidizing agents include activated manganese dioxide, pyridinium dichromate and pyridinium chlorochromate. A suitable oxidation reaction is carried out in a non-polar organic solvent, such as e.g. benzene or toluene.

The compounds of formula (IX) are novel and useful intermediates in the aforementioned process. Thus, the present invention further relates to compounds of formula (IX) as defined by yarns.

The allyl alcohol of formula (IX) can be prepared by treating the corresponding aldehyde of formula (X):

wherein Z ¹ , Z ² and Z ³ are as defined in yarn, with an organometallic reagent as defined in yarn and then, if necessary, all hydroxyl protecting groups are removed.

An aldehyde of formula (X) can be treated with a Grignard reagent of formula R ^{in * * * * x} MgX ah, more preferably, with an organocerium reagent R ¹ Li-CeX ₃ as defined by yarn. An aldehyde of formula (X) can be prepared by treating an amide of formula (VII) as defined in yarn with a suitable reducing agent such as di-iso-butyl aluminum hydride, and then removing any hydroxyl protecting agent if necessary group. Other suitable processes for preparing an aldehyde of formula (X) are described in EP-A-0 029 665 (Beecham Group).

The compound of formula (I) can also be prepared by treating a ketone of formula (XI):

wherein Z ¹ , Z ² and Z ³ , as defined by yarn, with a terminal alkyne of formula (XII):

HCUC-R ¹ CXII) in which R ¹ is as defined in yarn to give an intermediate treated with tris (triphenylsilyloxy) vanadate and triphenylsilanol as described by H. Pauling in Helvetica, 1976, 59,1233 and GL Olson v Helvetica, 1976,59, 567 and then, if necessary, all hydroxyl protecting groups are removed.

The preparation of the compound of formula (XI) is described in GB 1 587 060 (Beecham Group).

As used herein, the term hydroxyl protecting group refers to all such groups known in the art that can be removed without degradation of the residue of the molecule. Suitable hydroxyl protecting groups include those described in Protective Groups and Organic Synthesis, T. W. Greene, Wiley-Interscience, New York 1981.

The hydroxyl groups of the compounds of formulas (III) to (XI) can be protected at any stage of the above processes using conventional methods. The hydroxyl protecting group can be removed by methods known in the art, including enzymatic processes.

Particularly suitable hydroxyl protecting groups are silyl groups because they can be easily removed under mild conditions. Such groups are introduced using conventional silylating agents, including halosilanes and silasines of the formulas:

L ₃ SiY

L ₂ SiY ₂

L ₃ SiNL ₂

L ₃ SiNHSiL ₃

LsSiNHCOL

L ₃ SiO-C = NSiL ₃

L ₃ SiNHCONHSiL ₃

LNHCONHSiL ₃ tBuMe ₂ Si-O-SO ₂ -CF ₃

Me, Si- N N

BuMe _{2 is} Si-N where Me is methyl and 'Bu is t-butyl, Y is halogen and each group L is independently selected from hydrogen, (C 1-6 alkyl, (C 1-6 alkoxy, aryl or aryl (C 1 _M ) alkyl. The silylating agent is trimethylsilyl chloride. Particularly suitable protecting groups are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal.

The glycol function of compounds of formulas (III) to (XI) can be protected by the formation of a cyclic derivative using a compound of formula (XIII):

R ⁹ C (OR ¹⁰ ) (OR ⁿ ) (OR ¹² ) (XIII) wherein R ^{9 is} hydrogen or (C 1-6 alkyl) and each of R ¹⁰ , R ¹¹ and R ¹² is (C 1-6 alkyl) such that they are in a cyclic derivative Z ¹ and Z ² together are a portion of R ⁹ C (OR ¹² ) Suitable R ⁹ is hydrogen, methyl, ethyl, n- or isopropyl; hydrogen is most suitable. R ¹⁰ , R ¹¹ and R ¹² are suitably methyl, ethyl, n- or iso-propyl or n-, iso-, sec, or ί-butyl, most preferably methyl, Similarly, the hydroxyl groups of a compound of formula (I) can be protected from conversion to a further compound of formula (I), as In each case, the hydroxyl protecting groups described above can be removed by soap acid hydrolysis followed by alkaline hydrolysis, e.g., as described by Clayton, et al, JCS Perkin Trans 1,1979,308 .

The present invention also relates to a pharmaceutical or veterinary composition comprising a compound of formula (I) (hereinafter referred to as a medicament) together with a pharmaceutically or veterinarily acceptable carrier or excipient. The ingredients can be formulated for administration by any route and depend on the disease being treated. The compositions may be in the form of tablet 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 dosage presentation form and may contain conventional carriers such as binders, e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g. light blood glucose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricant tablets, e.g. magnesium stearate, talc, polyethylene glycol or silica, disintegrants, e.g. potato starch or acceptable wetting agents, such as sodium lauryl sulfate. The tablets may be overdosed according to methods well known in the ordinary pharmaceutical practice.

Oral liquid preparations may take the form of, e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable carrier, before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats, emulsifiers, e.g. lecithin, sorbitan monooelate or acacia; non-aqueous vehicles (which may include edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, e.g. methyl or propyl p-hydroxy benzoate or sorbic acid and, if desired, conventional flavors and coloring agents.

For topical use on the skin, the product may be incorporated into a cream, lotion or ointment. Cream or ointment preparations that can be used for a medicament are commonly known in the art, e.g. as described in standard pharmacy and cosmetics manuals such as Harry's Cosmeticology 7 ^th Ed., ed Wilkinson JB and Moore RJ, George Goodvvin, London, 1982 and the British Pharmacopoeia. For topical use at the ear, the drug may be incorporated into a suspension in a suitable liquid carrier such as water, glycerol, dilute ethanol, propylene glycol, polyethylene glycol or fixed oils. For topical ocular use, the drug is formulated as a suspension in a suitable, sterile aqueous or nonaqueous vehicle. Additives may also be included, e.g. buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents such as phenylmercury acetate or nitrate benzalkonium chloride or chlorohexidine, and host agents such as hypromellose. The dose to be used for topically administered compositions depends, of course, on the size of the surface being treated. For the ears and eyes, each dose will typically be in the range of 10 to 100 mg.

Spark plugs contain conventional suppository substrates, e.g. cocoa butter or other glycerides.

For parenteral administration, liquid unit dosage forms, with the association, of the drug and of a sterile vehicle are prepared. Depending on the vehicle and the concentration used, the drug can be suspended in the vehicle. Preferably, adjuvants such as topical anesthetic, preservative and buffering agents can be dissolved in the carrier. To increase stability, the composition may be frozen after being filled into a vial and removing the water under vacuum. The dried lyophilized powder is then sealed in a vial. The drug can be sterilized by exposure to ethylene oxide before being suspended in a sterile vehicle. A preferred surfactant or wetting agent is incorporated into the composition to facilitate even distribution of the drug.

Veterinary compositions for intramammary treatment of mammalian disorders in animals, in particular bovine mastitis, generally contain a suspension of the product in an oily vehicle.

The compositions may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, depending on the administration process. Where the compositions are in unit dosage form, each dosage unit preferably contains from 50 to 500 mg of the drug. The dosage used for the treatment of an adult (typically weighing about 70 kg) is preferably in the range of 100 mg to 3 g per day, e.g. 250 mg to 2 g of drug per day, depending on the route and frequency of administration. Alternatively, the drug may be administered to animals as part of a full daily meal. In this case, the amount of drug used may be less than 1% by weight of the prescribed feeding and preferably not more than 0.5% by weight. Prescribed animal feeding may consist of conventional feedingstuffs to which a medication may be added or the product may be incorporated into a compounding compound for feedingstuffs. A suitable procedure for administering a drug to animals is to add it to animal drinking water. In this case, the appropriate concentration of the drug in drinking water is about 5 - 500 / ig / ml, e.g. 5 200 µL / ml.

The compounds of the present invention are useful for the treatment of bacterial and

The compounds of the present invention are useful for treating bacterial and mycoplasma-induced infections in animals and humans, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in humans, bovine mastitis and respiratory infections in animals such as pigs and cattle. Thus, in a further aspect, the present invention relates to a method for treating humans and animals, which involves administering an effective amount of a compound of formula (I) as defined by yarn to a human or animal in need of such therapy. Alternatively, a pharmaceutical composition such as that described for yarn may be used in the treatment.

Certain treatments provide methods for treating bacterial infections in humans and animals, especially respiratory infections in humans and animals. The compounds of the present invention act against both Gram positive and Gram negative organisms including Haemophilus, e.g. H. influenzae Ql; Branhamella, e.g. B. Catarrhalis 1502; Streptococci, e.g. S. pyogenes CN10 and S.pneumonia PU7; and Staphylococci, e.g. 5. aureus Oxford; Legionella, e.g. L.pneumophila. In addition, the compounds of the present invention act against Staphylococci organisms such as S.aureus and S.epidermis, which are resistant (including repeatedly resistant) to other anti-bacterial agents, e.g. / 3-lactam antibiotics, such as e.g. methicillin, macrolides; aminoglycosides and lincosamides.

The compounds of the present invention also act against mycoplasma-induced infections, especially infections caused by Mycoplasma fermentans, which is involved as a cofactor in the pathogenesis of AIDS. Thus, in a further aspect, the present invention relates to a method of treating people infected with M.fermentans, especially people also infected with HIV, this method includes treating people who need such therapy with an antimycoplasma effective amount of a compound of formula (I).

In a further aspect, the present invention relates to a compound of formula (I) for use in the manufacture of a medicament for antibacterial and / or antimycoplasmic therapy in humans and animals.

Due to the administration of the compound of formula (I), no adverse toxicological effects are expected.

The following examples illustrate the invention but do not limit the scope in any way.

Example 1

2-methoxy- (thiazol-5-yl) -1- (normon-2-yl) ketone

A solution of 2-methoxythiazole (G. Lein and B. Prijs, Helv Chim Acta, 1954, 37, 2057) (7.27 g) in dry THF (100 ml) at -78 ° C and under an argon atmosphere was treated dropwise with / t-butyl lithium (1.5 M, 42 ml) in hexane. After 0.75 hours at -70 ° C, N-methoxyN-methyl-6,7,13-O-risis (trimethylsilyl) monamide (15.4 g, 1.00 mmol) (WO 92/02518, Beecham Group pic) in dry THF (160 ml) was added dropwise while maintaining the temperature below -65 ° C (lh addition time). After 1.25 h at -70 ° C, acetic acid (7.7 ml) was added. After extraction with diethyl ether, drying (magnesium sulfate) and evaporation, the residue was dissolved in THF (842 ml) and treated, in one addition, with hydrochloric acid (0.4 M, 210 ml). After 2 minutes of rapid stirring, saturated sodium hydrogen carbonate solution (250 ml) was added rapidly. The reaction mixture was partitioned between ethyl acetate and water, the organic phase separated, washed with brine, dried (magnesium sulfate) and evaporated to give the crude title compound (21 g).

The material from the above procedure (eg 36 g) is subjected to flash chromatography. The material was dissolved in dichloromethane / toluene and used on dry silica (1 kg) under suction, and the column was then eluted with ether followed by methanol / ether mixtures (2% - 6%) to give the title compound as an amorphous solid (24 g);

δκ (CD ₃ OD) 0.94 (3H, d, J 7.1Hz,

17-H ₃ ), 1.20 (3H, d, J 6.5 Hz, 14-H ₃ ), 1.32-1.46 (1H, m, 12-H), 1.65-1.73 (2H, m, 9-H ₂ ), 1.91 -2.01 (1H, m, 8-H), 2.23 (3H, s, 15-H ₃ ), 2.33 (1H, dd, J 14.3 and 9.5Hz, 4-H), 2.68-2.85 (3H, m, 4 , 10 and 11-H), 3.39 (1H, dd, £

9.0 and 3.0Hz, 6-H), 3.60 (1H, d, and 11.3Hz, 16-H), 3.74-3.93 (4H, m, 5, 7, and 16-H), 4.13 (3H, s, OCH N, 6.73 (1H, s, 2-H), 7.95 (1H, s, 4'-H); 6 _C (CD ₃ OD) 12.2 (C-17), 20.2 (C-15), 20.3 (C- 14), 33.0 (C-9), 41.8 (C-8), 43.7 (C-12), 44.3 (C-4), 56.9 (C-10), 59.8 (C-11), 61.2 (O £ H) ₃ ), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.4 (C-5), 121.8 (C-2), 137.1 (C-5) '), 143.9 (C-4'), 159.8 (C-3), 181.1 (C-2 '), 184.6 (Cl).

The amorphous title compound (48 g) was dissolved in ethyl acetate (200 ml) and the solution was initially cooled to 10 ° C for 5 h and then to -10 ° C for a further 16 h. The resulting solid was recovered by filtration and dried to give the crystalline title compound (40 g); m.p. 115 C; [α] _D (20 ° C) = -6 ° (c, 1, MeOH); in _max (KBr) 3452, 3301, 1639, 1592, 1484 cm ¹ ; X _max (EtOH) 301 nm ( _{£ ffl} 20.710).

Example 2

2- (2-methoxyethoxy) thiazol-5-yl-1- (normon-2-yl) ketone

a) 2- (2-methoxyethoxy) thiazole

Sodium hydride (12.75 mmol, 0.384 g) was added to 2-methoxyethanol (13.5 mmol, 1.023 g) in tetrahydrofuran (1.0 ml). After 0.5 hours 2-bromothiazole (15 mmol, 2.457 g) was added and the reaction was heated to 40 ° C for 1.5 hours. The suspension was cooled, diluted with diethyl ether, filtered, evaporated to dryness under reduced pressure and purified by column chromatography over silica using diethyl ether / hexane (20%) as eluent to give 2- (2-methoxyethoxy) thiazole (1.171 g. 58%) as yellow oil; δ _h (CDC1 ₃ ) 3.4 (3H, s, -OMe), 3.75 (2H, m, ΟΤ, -ΟΜβ), 4.5 (2H, m, Ar OCH ₂ ), 6.7 (1H , d, J 3.7 Hz, 4-H), 17.1 (1H, d, J 3.7 Hz, 5-H).

b) [2- (2-methoxyethoxy) thiazol-5-yl] -1- (6,7,13-O-tri-trimethylsilyl normon-2-yl) ketone n-butyllithium (1.6 M in hexane) (2, 25 mmol, 1.5 ml) was added dropwise to 2- (2methoxyethoxy) thiazole in tetrahydrofuran (5 ml) at -78 ° C. After 20 min. at -78 ° C N-methoxy-N-methyl-6,7,13-O-tris (trimethylsilyl) monamide (1.5 mmol, 0.905 g) in THF (5 ml) was added dropwise while maintaining the temperature below -65 ° C. After a further 1 hour at -78 ° C, acetic acid (0.23 g) was added followed by water (20 ml). Extract with diethyl ether, dry (MgSOJ, evaporate to dryness under reduced pressure and purify by silica column chromatography using ethyl acetate / hexane (0 - 20%) as eluent to give the title compound as a yellow oil (0.263 g, 25 %); S _H (CDCl ₃ ) 0.01-0.2 (27H, m, 9 x SiCH ₃ ), 0.7-0.8 (3H, d, J 7.0Hz, 171¾ 1.0-1 , 1 (3H, d, J 6.3Hz, 14-H ₃ ), 2.1 (3H, s, 15-H ₃ ), 3.2-3.3 (3H, s, OMe), 4.44 , 5 (2H, m, J 9.0Hz, Ar 002 6.35 (1H, s, 2-H), 7.55 (1H, s, ArH).

c) 2- (2-methoxyethoxy) thiazol-5-yl-1- (normon-2-yl) ketone

The above ketone (0.25 mmol, 0.173 g) and hydrochloric acid (0.4M, 1.2 ml) in THF (5 ml) were stirred at room temperature for two minutes. Saturated sodium bicarbonate was added, extracted with diethyl ether, dried (MgSO ₄ ), evaporated to dryness under reduced pressure and purified by column chromatography over silica using methanol in dichloromethane (0-8%) as eluant to give the title compound (93 , 2 mg, 78%) as pale yellow foam; in _max (KBr 2883, 2359, 2330,1729,1528 cm &^lt; ^-1 &^gt;; K ^ EtOH) 302 nm (e _m 16,580); 6 _H (CD ₃ OD) 0.9 (3H, d, J 7.1Hz, 17-1¾ 1.2 (3H, d, J

6.4Hz, 14-Hj), 2.72-2.82 (2H, m, 10 and 11-H), 3.4 (3H, s, OMe), 4.55-4.6 (2H, ra , ArOCH2, 6.72 (1H, s, 2-H), 7.9 (2H, s, ArH); m / z (EI) 485 (M ⁺ , 20%), 59 (100%), ( found: M ⁺ 485.2090, C ^ H ^ NOgS requires M 485.2083).

Example 3

2- (2-isopropoxyethoxy) thiazol-5-yl-1- (normon-2-yl) ketone

a) 2- (2-Isopropoxyethoxy) thiazole

Sodium hydride (12.75 mmol, 0.384 g) was added to 2-isopropoxyethanol (13.5 mmol,

1.6 ml) in tetrahydrofuran (2.0 ml) at 40 ° C. After 0.5 hours, 2-bromothiazole (15 mmol, 1.35 ml) was added and the reaction was heated at 40 ° C for 3 hours followed by 1 hour at 80 ° C. The suspension was cooled, diluted with diethyl ether, filtered, evaporated to dryness under reduced pressure and purified by silica gel column chromatography using diethyl ether / hexane (10%) as eluant to give 2- (2-isopropoxyethoxy) thiazole (0.644 g) 27%) as oil; e ^ CDCf), 1.2 (6H, d, 2 x CH ₃ ), 3.65 (1H, m, CH-OCH ₂ ),

3.8 (2H, m, CH-OCH ₂ ), 4.5 (2H, m, ArOCH ₂ ), 6.6 (1H, d, / 3.88Hz, 5-H), 7.1 (1H, d, / 3.88 Hz, 4-H).

b) [2- (2-Isopropoxyethoxy) thiazol-5-yl] -i- (6,7,13-O-tristrimethylsilyl normon-1-yl) ketone n-butyllithium (1.6 M in hexane) (3 mmol , 1.88 ml) was added dropwise to 2- (2isporopoxyethoxy) thiazole in tetrahydrofuran (7 ml) at -78 ° C. After 35 minutes at -78 ° C, N-methoxy-N-methyl-6,7,13-0- / rw (trimethylsilyl) monamide (2 mmol, 1.205 g) in THF (10 ml) was added dropwise while maintaining temperature below -65 ° C. After a further 1.5 hours at -78 ° C, glacial acetic acid (5 mmol, 0.3 ml) was added followed by water (15 ml). Extract with diethyl ether, dry (MgSO ₄ ), evaporate to dryness under reduced pressure and purify by silica column chromatography using ethyl acetate / hexane (0-20%) as eluant to give the title compound as a yellow oil (0.3122) g, 21%); _δ Η (CD ₃ OD) 0.1-0.2 (27H, m, 9 x sich ^), 0.9 (3H, d, 17-H _3),

1.15 (6H, d, 2 x CH ₃ ), 1.2 (3H, d, 14-H ₃ ), 2.2 (3H, s, 15-H ₃ ), 3.8 (2H, m, CH ₂ OCH), 4.55 (2H, m, ArOCH 2, 6.7 (1H, s, 2-H), 7.9 (1H, s, ArH).

IS

c) 2- (2-Isopropoxyethoxy) thiazol-5-yl-1- (normon-2-yl) ketone

The above ketone (0.425 mmol, 0.310 g) and hydrochloric acid (0.4 M, 2.13 ml) in THF (8.5 ml) were stirred at room temperature for two minutes. Saturated sodium bicarbonate was added, extracted with ethyl ether, dried (MgSO ₄ ), evaporated to dryness under reduced pressure and purified by column chromatography over silica using methanol in dichloromethane (0-7%) as the eluent to give the title compound (177 mg, 81%) as foam; in _max 2926, 2324, 1776, 1379, 806 cm ⁴ ; X _max (EtOH) 301 nm ( _{£ m} 19.539); 6 _H (CD ₃ OD) 0.95 (3H, d, J 7.12Hz, 17-1 ^), 1.15 (6H, d, / 6.44Hz, 2x CH2, 2.75-2.85 (2H, m, 10 and 11-H), 4.55 (2H, m, ArOCTT,), 6.7 (1H, s, 2-H), 17.95 (1H, s, ArH); z (EI) 513 (M ⁺ , 45%), 45 (100%); (Found: M ⁺ 513.2391, C ^ H ^ NOgS requires M 513.2395).

Example 4

2- (7,7,7- / R5- (methylthio) heptoxy) -thiazol-5-yl-1-normon-2-yl-ketone

a) 2- (7,7,7-Trismethylthioheptoxy) -thiazole

3.4-Dihydro-2H-pyran (33.1 mmol, 3.02 ml) was added to 6-bromohexanol (27.65 mmol, 5 g) in 80 ml of diethyl ether. After 1.5 hours at room temperature, a further portion was added

3.4-dihydro-2H-pyran (33.1 mmol, 3.02 ml) and stirred for 2.5 hours. A saturated solution of sodium hydrogen carbonate (100 ml) was added, extracted with diethyl ether, dried (MgSO ₄ ), evaporated to dryness under reduced pressure and purified by silica column chromatography using dichloromethane / hexane (70-100%) as eluent to give 2 -6-bromohexyloxytetrahydropyran as a colorless oil (6.459 g 88%); δ _Η (CDC1 ₃ ) 1.5-1.75 (8H, m, 4 x CH ₂ ), 3.4-3.6 (4H, m, CH ^ Br and CH ₂ O), 4.5 (1H , t, OCHO). n-Butyllithium (1.6 M in hexane (29.24 mmol, 19.5 ml) was added dropwise to tris (methylthio) methane (24.37 mmol, 3.24 ml) in tetrahydrofuran (80 ml) at -78 After 1.5 hours, the above compound (24.37 mmol, 6.459 g) in THF (20 ml) was added and stirred for 1 hour at 65 ° C. A saturated solution of ammonium chloride (30 ml) was added, extracted with diethyl ether. dried (MgSO ₄ ), evaporated to dryness under reduced pressure and purified by column chromatography over silica using methanol / dichloromethane (0 - 20%) as eluant to give 7,7,7-trismethylthio-1-tetrahydropyran-2-yloxyheptane as a colorless oil (7.1124 g, 86%); 0 _h (CDCl ₃ ) 2.1 (9H, s, 3 x SCH ₃ ), 3.35-3.5 (2H, m, OCH ₂ ), 3 , 7-3.9 (2H, m, cyclic OCH ₂ ), 4.55 (1H, t, O-OCH-O) H of the above compound (20.98 mmol, 7.11 g) in methanol (150 ml) ) Amberlyst-15 (0.3 g) was added After 4 hours, filtered, evaporated to dryness under reduced pressure and purified by column chromatography over silica using diethyl ether / hexane (4%) as eluant to give 7,7,7- tr ismethylthio-heptanol as a colorless oil (3.73 g, 70%); 1.2-1.9 (10H, m, 5 x CH ₂ ), 2.1 (9H, s, 3 x SCH ₃ ), 3.6 (2H, t, OCH ₂ ). To the above compound (2 mmol, 0.508 g) in THF (3 ml) was added sodium hydride (1.89 mmol, 0.057 g). After 0.5 hours, 2-bromothiazole (2.2 mmol, 0.2 ml) was added and the reaction mixture was heated to 40 ° C for 4 hours. It was cooled, diluted with diethyl ether, filtered, evaporated to dryness under reduced pressure and purified by silica column chromatography using diethyl ether / hexane (0 -10%) as eluent to give the title compound (0.232 g, 34%); 6 _H (CDCl ₃ ) 1.3-1.9 (10H, m, 5 x CH ₂ ), 2.1 (9H, s, 3 x SCH ₃ ), 4.4 (2H, t, OCH ₂ ), 6.6 (1H, d, 5-H), 7.1 (1H, d, 4-H).

b) [2- (7,7,7- / Thy (methylthio) heptoxy) -thiazol-5-yl] -1- (6,7,13-O-tristrimethylsilyl normon-2-yl) ketone n-butyllithium ( 1.6 M in hexane) (2 mmol, 1.25 ml) was added dropwise to 2- (7,7,7trismethylthioheptoxy) thiazole (2 mmol, 0.674 g) in THF (6 ml) at -78 ° C. After 40 minutes, N-methoxy-N-methyl-6,7,13-O- / ris (trimethylsilyl) monamide (2 mmol, 1.206 g) in THF (10 ml) was added dropwise. After 2 hours and warming to -50 ° C, acetic acid (4 mmol, 0.2 ml) was added followed by water (10 ml). Extracted with diethyl ether, dried (MgSOJ, evaporated to dryness under reduced pressure and purified by column chromatography over silica, using ethyl acetate / hexane (0 - 20%) as eluent to give the title compound (0.422 g 25%); 6 _H (CDC1 ₃ ) 0.1-0.2 (27H, m, 9 x SiCH ₃ ) 0.9 (3H, d, 17¾ 1.2 (3H, d, 14-H ₃ ), 1.3- 1.9 (10H, m, 5 x CFLj), 2.05 (9H, s, 3 x CHg), 2.2 (3H, s, 15¾ 2.6 (2H, m, 10 and 11-H), 3.35 (1H, dd, 6-H), 4.4 (2H, t, OCH ₂ ), 6.5 (1H, s, 2-H), 7.7 (1H, s, Ar-H) .

c) 2- (7,7,7-ftxs- (methylthio) heptoxy) -thiazol-5-yl-1-nonnon-2-yl ketone

The above ketone (0.5 mmol, 0.439 g) and hydrochloric acid (0.4 M, 2.5 ml) in THF (10 ml) were stirred at room temperature for 2 minutes. Saturated sodium bicarbonate was added, extracted with ethyl acetate, dried (MgSOJ, evaporated to dryness under reduced pressure and purified by column chromatography over silica using methanol / dichloromethane (0 - 7%) as eluant to give the title compound as a colorless oil (0.310 g, 93%); in _max (KBr) 2328, 1734, 1527, 1297, 838, 569 cm ⁴ ; X _max (EtOH) 302nm (e _m 17,227); 6 _H (CD ₃ OD) 0.9 (3H. d, / 7.1Hz, 17¾ 1.2 (3H, d, / 6.6Hz, 14¾ 2.1 (9H, s, 3 x SCI ^), 2.25-2.35 (2H, m, 4¾ 2 , 65-2.8 (2H, m, 10 and 11-H), 3.4 (1H, dd, 6-H), 3.55 (1H, d, 16-H), 3.75-3, 9 (4H, m, 5.7.13, 6-H), 4.45 (2H, t, OCH,), 6.7 (1H, s, 2-H), 7.9 (1H, s, Ar-H).

Example 5

2- (6-Methoxycarbonylhexoxy) -thiazol-5-yl-1-normon-2-yl ketone

Mercury II oxide (3.38 mmol, 0.072 g) and mercury II chloride (1.01 mmol, 0.27 g) were added to the ketone in Example 5c (0.338 mmol, 0.224 g) in methanol (6.3 ml) at - 41 ° C. After 55 minutes, it was filtered through celite, washed with saturated ammonium chloride solution (10 ml), extracted with dichloromethane (12 ml), dried (MgSOJ, evaporated under reduced pressure and purified by column chromatography over silica using methanol / diethyl ether (0 - 4%) as eluent to give the title compound (0.113 g, 60%); in KBr) 1646, 1479, 1258, 1187, 1055 cm &^lt; ¹ &^gt;; X _max (EtOH) 302 (e _m 20, 224); 5 _H (CD ₃ OD) 0.95 (3H, d, 17¾ 1.2 (3H, d, 14¾ 2.2 (3H, s, 15¾ 2.252.4 (3H, m, CI ^ CC ^ and 4-H ), 2.7-2.85 (3H, m, 4.10 and 11-H), 3.4 (1H, dd, 6-H), 3.55 (1H, d, 16-H), 3 , 6 (3H, s, CO ₂ CH ₃ ), 3.75-3.9 (4H, m, 5.7.13 and 16-H), 4.45 (2H, t, OCH ^, 6.7 (1H, s, 2-H), 7.9 (1H, s, Ar-H); m / z (EI) 569, (M ⁺ , 50%), 83 (100%), (found: M ⁺ 569.2667, C ^ H ^ NO ^ requires M 569.2659).

Example 6

Sodium 2- (6-carboxylatohexoxy) -thiazol-5-yl-1-normon-2-yl ketone

Carlsberg Protease Subtilisin (20 mg) was added to the ketone in the previous example (0.069 mmol, 39 mg) in water (5 ml), maintaining the pH at 6.5 24 hours by slowly adding sodium hydroxide solution (0.01 M). The reaction mixture was lyophilized, taken up in ethanol, filtered through celite and evaporated under reduced pressure to give the title compound (42 mg 100%); in _max (KBr) 2925.1644, 1455.1261, 1053 cm ^-1 ; X _max (EtOH) 303 (g _m 13.512); δ _Η 0.85 (3H, d, 17¾ 1.1 (3H, d, 14¾ 1.2-1.6 (9H, m, 4 x CFL, n 12H), 1.7 (2H, m, 9¾ 1 , 9 (1H, m, 8-H), 2.05 (2H, t, CH ₂ CO ₂ ), 2.15 (3H, s, 15¾

2.2 (1H, dd, 4-H), 2.6 (3H, m, 4, 10 and 11-H), 3.25 (1H, dd, 6-H), 3.45 (1H, m , 16H), 3.65-3.85 (4H, m, 5.7.13 and 16-H), 4.3 (2H, t, OCH ₂ ), 6.6 (1H, s, 2-H) ), 17.8 (1H, s, Ar-H); m / z (FAB) 578 (MH ⁺ , 13%).

Biological data

The activity of these compounds against H.influenzae Ql, B. catarrhalis 1502, S. pyogenes CN10, S. pneumoniae PU7 and S. aureus Oxford was tested in vitro using serial dilutions in nutrient agar with 5% chocolate horse blood. Minimum inhibitory concentrations are determined after incubation for 18 hours at 37 ° C and values are measured in the range of 0.06 to 4 mg / ml. In addition, the antibacterial activity of the compound of Example 1 against the Legionella organism, L. pneumophila 1624, sulfur group 1, was determined as follows:

The culture is thawed from the stock of frozen skim milk and applied in strips to a supplemented charcoal yeast extract agar (BCYEa, Oxoid). Three days later, the colonies were suspended in tissue culture medium (TCM = Eagle's minimum essential medium + Earles salts supplemented with 10% calf fetal serum, 2mM L-glutamine and 1% non-essential amino acids) to MacFarland's barium sulphate option standard 0.5. The suspension was further diluted 1: 100 in TCM to give a final vaccine of 4.83 χ 10 ⁶ cfu / ml. Human embryonic lung fibroblast (MRC-5) cells are then vaccinated. These cells had previously grown to 80% confluence in 6-well plates, the medium was removed, and the monoplasts were washed twice with Dulbecc's PBS. Sixteen hours after cleavage (time 0 h), the medium was removed and the grafted monoplasts washed twice to remove all adherent, non-intracellular organisms. The test compound prepared at the required concentrations in TCM was added to the cells. The compound of Example 1 was tested at 0.5, 2 and 8 μg / ml, while erythromycin at 0.5 and 2 / ig / ml was used as a control. At 0, 3, 12, 24, 36, 48 and 72 h after the dose, the medium is removed from one well / treatment and the monoplasts are washed twice. Add sterile distilled water and allow the cells to decompose for 30 min. After vigorous trituration, the lysate was serially diluted in a Mueller Hinton brother and placed on BYCEa and 5% equine blood agar. L. pneumophila colonies were counted after 72 hours of incubation at 37 ° C. Positive antibacterial activity against L. pneumophila was observed.

In addition, and with confirmation, we tested the stability of the compounds in TCM within 72 h. Solutions of 2 µg / ml of each compound were prepared in TMC and incubated at 37 ° C or 4 ° C and aliquots removed at intervals. The compound of Example 1 and erythromycin were tested against Bacillus subtilis ATCC 6633 or Sarcina lutea NCTC 8340 using the standards prepared in TCM.

Claims (12)

A compound of formula (I): in which R ^{1 is a} 2- (optionally substituted (C ₁₁₀ ) alkoxy) thiazol-5-yl group. A compound according to claim 1, characterized in that the (C ₁₁₀ ) alkoxy group in R ¹ is optionally substituted methoxy, ethoxy or hexoxy. A compound of formula (I) wherein 2-methoxy- (thiazol-5-yl) -1- (normon-2yl) ketone. A compound of formula (I), which is: 2- (2-methoxyethoxy) thiazol-5-yl-1- (normon-2-yl) ketone; 2- (2-iso-propoxyethoxy) thiazol-5-yl-1- (normon-2-yl) ketone; 2- (7,7,7- [zis- (methylthio) heptoxy) -thiazol-5-yl-1-normon-2-ylketone: 2- (6-methoxycarbonylhexoxy) -thiazol-5-yl-1-normone- 2-yl ketone; 2- (6-carboxyhexoxy) -thiazol-5-yl-1-normon-2-yl ketone or its sodium salt; 5. A pharmaceutical or veterinary composition comprising a compound of formula (I) as defined in any one of claims 1 to 4, together with a pharmaceutically or veterinarily acceptable carrier or excipient. A compound of formula (I) as defined in any one of claims 1 to 4 for use in treatment. Use of a compound of formula (I) as defined in any one of claims 1 to 4 for the manufacture of a medicament for use in antibacterial therapy. Use of a compound of formula (I) as defined in any one of claims 1 to 4 for the manufacture of a medicament for use in antimycoplasmic treatment. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 4, characterized in that it includes: (i) treating an acid of formula (ΠΙ): in which Z ¹ , Z ² and Z ³ are the same or different and each is a hydrogen or hydroxyl protecting group or its activated derivative with an organometallic reagent. (ii) treatment of lyl alcohol of formula (IX): wherein R ¹ is as defined in claim 1 and Z ¹ , Z ² and Z ³ are as defined in yarn, with an oxidizing agent which converts allyl alcohols into α, 3-unsaturated ketones; in which Z ¹ , Z ² and Z ^{3 are} as defined yarns, with a terminal alkyne of formula (ΧΠ): HCUC-R ¹ (XII) in which R ^{1 is} as defined in yarn to give an intermediate treated with (lis- (trifemlsilyloxy) -vanadate and triphenylsilanol); and then if necessary remove all hydroxyl protecting groups. A process according to claim 9, characterized in that the activated acid derivative of formula (III) is an amide of formula (VII): ZO in which Z ¹ , Z ² and Z ^{3 are} as defined yarns, R ⁵ and R ⁶ are the same or different and each (C 1-6 alkyl or substituents R ⁵ and R ⁶ form an (C _{2 7} ) alkylene chain. Process according to claim 10, characterized in that each R ⁵ and R ^{6 are} methyl. A process according to any one of claims 9 to 11, characterized in that the organometallic reagent is the organolithium reagent R ¹ Li.