Pleuromutilin derivatives as antimicrobials

Abstract

The present invention relates to pleuromutilin derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medical therapy, particularly antibacterial therapy.

Description

where R^2A is R² as defined for formulae IA and IB or a group convertible to R², under ester forming conditions and, where required or desired,

converting Y to hydrogen,

converting an R^1A, R^2A or R^3A group to a R¹, R² or R³ group, and/or

converting one R¹, R² or R³ group to another R¹, R² or R³ group.

Conventional methods for ester formation are described in the literature, for example in Comprehensive Organic Functional Group Transformations, Vol. 5, ed. C J Moody, p. 123-130, Elsevier Scientific, Oxford, 1995. The active derivative used as an acylating agent may be for example an acid chloride, acid bromide, a mixed anhydride, or an N-acyl-imidazole. The preferred agent is an acid chloride. General methods for forming such acylating agents are described in the chemical literature (see I O Sutherland, Comprehensive Organic Chemistry, Vol. 2, ed. I O Sutherland, pages 875-883 (Pergamon Press, Oxford, 1979), and references therein).

The ester-forming reaction can be carried out in the presence of an organic base, an inorganic base, or an acid. Organic bases include pyridine, 2,6-lutidine, triethylamine, and N,N-dimethylaniline. Inorganic bases include sodium hydride, lithium hydride, potassium carbonate, lithium hexamethyldisilazide, and sodium hexamethyldisilazide. Acids include p-toluenesulphonic acid, benzene sulphonic acid, and sulphuric acid. Optionally, when the reaction is carried out in the presence of a base, an acylation catalyst (G Hofle and W Steglich, Synthesis, 1972, 619) such as 4-dimethyamino-pyridine or 4-pyrrolidino-pyridine may also be added to the reaction mixture. Solvents for the ester forming reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, diethyl ether, dichloromethane, and chloroform. A preferred solvent is tetrahydrofuran.

Useful methods for acylating the 14-hydroxyl in the present invention include the use of the following: acid chloride in N,N-dimethylformamide at elevated temperature (e.g. 100° C. to 120° C.), acid chloride in the presence of an organic base (e.g. pyridine, 2,6-lutidine, 2,4,6-collidine, di-iso-propylethylamine) or an inorganic base (e.g. sodium or lithium hexamethyldisilazide); carboxylic acid in the presence of dicyclohexylcarbodiimide and an acylation catalyst (e.g. 4-dimethylamino-pyridine, 4-pyrrolidino-pyridine); a mutilin 14-chloroformate derivative plus carboxylic acid, tertiary base (e.g. triethylamine, di-iso-propylethylamine), and an acylation catalyst (e.g. 4-dimethylamino-pyridine, 4-pyrrolidino-pyridine).

Conversions of an R^1A, R^2A or R^3A group to a R¹, R² or R³ group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below. Interconversion of one R¹, R² or R³ group to another typically arises when one compound of formula IA/B is used as the immediate precursor of another compound of formula IA/B or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.

Preferably Y is a hydroxyl protecting group such as an acyl group, for example so that —OY is trifluoroacetyl or dichloroacetyl. When the intended R³ is also hydroxyl, then R^3A is also preferably acyloxy, for example acetyl or dichloroacetyl. Hydroxyl groups at positions 11 and 2 (as groups OY and R^3A) may be protected using, for example, dichloroacetic anhydride and pyridine in tetrahydrofuran or N-trifluoroacetyl-imidazole in tetrahydrofuran at 0° C. After the reaction with the derivative of acid III is complete the protecting acyl groups may be removed to restore the hydroxyl groups by hydrolysis e.g. using NaOH in MeOH.

It may also be necessary to protect substituent groups in the acid component (III) prior to reaction with the the compound of formulae (IIA) or (IIB), for example protecting N atoms with alkoxycarbonyl, for example t-butoxycarbonyl.

Suitable hydroxy, carboxy and amino protecting groups are those well known in the art and which may be removed under conventional conditions and without disrupting the remainder of the molecule. A comprehensive discussion of the ways in which hydroxy, carboxy and amino groups may be protected and methods for cleaving the resulting protected derivatives is given in for example “Protective Groups in Organic Chemistry” (T. W. Greene, Wiley-Interscience, New York, 2nd edition, 1991). Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as, for instance, trialkylsilyl and also organocarbonyl and organooxycarbonyl groups such as, for instance, acetyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl. Particularly suitable carboxy protecting groups include alkyl and aryl groups, for instance methyl, ethyl and phenyl. Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

R^1A is typically the R¹ group vinyl, and this may be converted to the alternative R¹ ethyl group by hydrogenating the vinyl group to form an ethyl group, typically by hydrogenation over a palladium catalyst (e.g. 10% palladium-on-carbon) in a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.

R^3A is typically hydrogen or protected hydroxyl, such as acyloxy. After the coupling reaction, protecting acyl groups may be removed to restore the hydroxyl groups by hydrolysis e.g. using NaOH in MeOH.

Alternatively a compound of formula (IA) in which R³ is hydrogen may be prepared by treating a compound of formula (IIC): ##STR00004##
where R^1A is as defined for formula (IIA) and (IIB),

• • with an active derivative of the acid of formula (III) under ester forming conditions, and
  • then treating the product with an acid, and, where required or desired,
  • converting an R^1A or R^2A group to a R¹ or R² group, and/or
  • converting one R¹ or R² group to another R¹ or R² group.

The acid treatment indicated above converts the epi-mutilin configuration of formula (IIC) to the usual mutilin nucleus of formula (IIA). Typically this conversion is carried out by treatment with conc. HCl or Lukas reagent (conc. HCl saturated with ZnCl₂) in dioxane.

As in formulae (IIA) and (IIB), R^2A is typically the R² group vinyl, and this may be converted to the alternative R² group by hydrogenating the vinyl group to form an ethyl group. Also it may again be necessary to protect substituent groups in the derivative of acid compound (III) prior to reaction, for example protecting N atoms with , for example, t-butoxycarbonyl.

In cases where the intermediate of formula (IIA) and (IIB) (such as Y=acetyl) are used, a base-labile protecting group may conveniently be removed at the same time as the group Y is deprotected. In cases when the intermediate of formula (IIC) is used, an acid-labile protecting group may conveniently be removed at the same time as the acid treatment that converts the epi-mutilin configuration into the desired configuration of the compounds of the invention.

The compounds of formulae (IIA), (IIB) and (IIC) may be prepared from compounds of formulae (IV) and (V) ##STR00005##
Suitable compounds as formula (IV) include 11-O-acyl mutilin derivatives, e.g. mutilin 11-acetate (A J Birch, C W Holzapfel, R W Richards, Tetrahedron (Suppl.), 1966, 8, Part II, 359) or mutilin 11-dichloroacetate or mutilin 11-trifluoroacetate. Formula (V) is (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (H Berner, G Schulz and H Schneider, Tetrahedron, 1980, 36, 1807).

Compounds (IV) and (V) are effectively the compounds of formula (IIA) and (IIC) respectively in which R^1A is vinyl and R^3A is hydrogen (compound IIA). They may be converted into the corresponding compounds in which R^1A is ethyl by hydrogenation, typically by hydrogenation over a palladium catalyst (e.g. 10% palladium-on-carbon) in a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.

Copmpounds of formula (IIA) in which R^3A is hydroxyl may be obtained by first preparing 2-hydroxymethylene mutilin from a compound of formula (IV). Using procedures based on that described by A. J. Birch, C. W. Holzapfel and R. W. Rickards (Tet (Suppl) 1996 8 part III 359), a compound of formula (IV) in toluene and methyl formate is treated with sodium methoxide and stirred under argon. The product is a mixture of the desired 2-hydroxymethylene compound and corresponding compounds substituted by formate at position 11 (if OY is OH) and/or position 14. The formate groups may be removed when desired by treatment with potassium hydroxide in methanol.

The product mixture may however be used directly to prepare 2-diazo-mutilin derivatives using the method described by H Berner, G Schulz, and G Fisher, Monatsh. Chem., 1981, 112, 1441, for example reacting a solution of a 2-hydroxymethylene-mutilin and the formate derivatives in dichloromethane at −10° C. under argon with tosylazide and triethylamine. Removal of the formate groups as described above leaves 2-diazo-mutilin. which may be reacted with a carboxylic acid to give a 2-acyloxy-mutilin, effectively a compound of formula (IIA) in which R^3A is protected hydroxyl. Suitably reaction with dichloroacetic acid gives 2-dichloroacetoxy-mutilin, which can be deprotected as described above to provide 2-OH. preferably after coupling with the derivative of acid (III). This reaction produces (2S)-2-hydroxy derivatives.

Compounds of formula (IIB) are either 1,2-didehydro-mutilin or obtainable therefrom by manipulation of OY and R^1A as described above. 1,2-Didehydro-mutilins may be prepared using the method described by G Schulz and H Berner in Tetrahedron, 7, 1984, 40, 905.

The above described modifications to the mutilin nucleus may also be carried out after coupling of compounds of formula (IIA) and (IIC) where R^3A is hydrogen (i.e. based on mutilin an d epi-mutilin) with the active derivative of acid (III).

In another aspect, the present invention provides a method for preparing compounds of the invention in which X is O, S, NH, CO.O or CONH which comprises reacting a compound of formula VIA o r VIB ##STR00006##
where Y is hydrogzen or a removable hydroxy-protecting, group. and R^1A and R^3A are R¹ and R³ as defined for formulae IA and IB or groups convertible to R¹ and R³, n is as defined for formulae IA and IB, and R^L is a leaving group or OH or NH₂, with a compound of formula (VII):
R^2A—(CH₂)_m—XH  (VII)
where R^2A is R² as defined for formula (IA) and (IB) or a group convegible to R², and X and m are as defined for formulae IA and IB, or

• • when X is CO.O with an active derivative of the acid of formula (VII),
  • by one of the procedures set out below,
  • and where required or desired
  • converting Y to hydrogen,
  • converting an R^1A or R^3A group to an R¹, R² or R³ group, and/or
  • converting one R¹, R² or R³ group to another R¹, R² or R³ group.

As in the method discussed above startin from compounds (IIA/B/C), preferably Y is a hydroxyl protecting group such as an acyl group, for example so that —OY is trifluoroacetyl or dichloroacetyl. When the intended R³ is also hydroxyl then R^3A is also preferably acyloxy, for example acetyl or dichloroacetyl.

It may also be necessary to protect substituent groups in the compound of formula (VII) prior to reaction with the compound (VIA) or (VIB), for example protecting N atoms with alkoxycarbonyl, for example t-butoxycarbonyl.

Suitable hydroxy, carboxy and amino protecting croups are those well known in the art and are discussed above.

R^1A is typically the R¹ group vinyl, and this may be converted to the alternative R¹ ethyl group by hydrogenating the vinyl group to form an ethyl group, typically by hydrogenation over a palladium catalyst (e.g. 10% palladium-on-carbon) in a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.

R^3A is typically hydrogen or protected hydroxyl, such as acyloxy. After the coupling reaction, protecting acyl groups may be removed to restore the hydroxyl groups by hydrolysis e.g. using NaOH in MeOH.

Procedures for coupling the group R^L(CH₂)_nCH₂CO.O— with compound R^2A—(CH₂)_m—XH include the following:

• • (a) when R^L is a leaving group, such as 4-MeC₆H₄SO₂O, MeSO₂O, F₃CSO₂O, Br or Cl, and X is O, S or NH:
    • (i) where X=O, the alcohol R²—(CH₂)_m—OH may be converted into the alkoxide by reaction with an inorganic base, such as sodium hydride, lithium hydride, sodium hexamethyldisilazide, or lithium hexamethyldisilazide, in a non-hydroxylic solvent, such as N,N-dimethylformamide or tetrahydrofuran, prior to reaction with the compound of formula VIA/B;
    • (ii) where X=S, the thiol R²—(CH₂))_m—SH may be reacted with the compound of formula VIA/B in the presence of an inorganic base, such as sodium methoxide, sodium ethoxide, sodium hydride, sodium hexamethyldisilazide, or lithium hexamethyldisilazide, in a solvent such as 2-propanol, ethanol, methanol, N,N-dimethylformamide, or tetrahydro furan.
    • (iii) where X=NH, the amine R²—(CH₂)_m—NH₂ may be reacted with the compound of formula VIA/B in a solvent such as N,N-dimethylformamide or tetrahydrofuran, optionally in the presence of a base such as potassium carbonate, pyridine, N,N-di-(isopropyl)-ethylamine, or triethylamine.
  • (b) when X is CONH, a compound of formula VIA in which R^L is amino may be reacted with a compound of formula R^2A—(CH₂)_m—CO₂H, or an acylating agent derived therefrom, using one of the general methods for amide formation that are described in the chemical literature. General methods for amide formation are described by B C Challis and J A Challis in Comprehensive Organic Chemistry, Vol. 2, ed. I O Sutherland, pages 959-964 (Pergamon Press, Oxford, 1979).
  • (c) when X is CO.O, a compound of formula VIA/B in which R^L is hydroxy may be reacted with an acylating agent derived from a compound of formula R^2A—(CH₂)_m—CO₂H, using one of the general methods that are described in the chemical literature, for example treating the acid with oxalyl chloride and reacting with R^L=hydroxy in a suitable solvent such as DMF.

Alternatively the above reactions may be carried out using a compound of formula (VIC): ##STR00007##
where Y and R^1A are as defined for formulae IIA and IIB and R^L is as defined for formulae (VIA) and (VIB)
with the compound (VII) by the procedures (a), (b) or (c) set out above,
and then
treating the product with an acid,
and where required or desired
converting an R^1A or R^2A group to a R¹ or R² group, and/or
converting one R¹ or R² group to another R¹ or R² group.

As mentioned previously, the acid treatment indicated above converts the epi-mutilin configuration of formula (VIC) to the usual mutilin nucleus of formula (VIA). Typically this conversion is carried out by treatment with conc. HCl or Lukas reagent (conc. HCl saturated with ZnCl₂) in dioxane.

As in formulae (VIA) and (VIB), R^1A is typically the R¹ group vinyl, and this may be converted to the alternative R¹ group by hydrogenating the vinyl group to form an ethyl group. Also it may again be necessary to protect substituent groups in the compound (VII) prior to reaction, for example protecting N atoms with alkoxycarbonyl, for example t-butoxycarbonyl.

The compounds of formulae (VIA), (VIB) and (VIC) may be prepared by reacting the corresponding compounds of formula (IIA), (IIB) and (IIC) by conventional methodology to introduce acyl groups substituted by hydroxyl or amine or a leaving group.

Reference is directed to the preparation of the chloride and tosylate by K Riedl in J. Antibiotics, 1976, 29, 132; and the tosylate and mesylate described by H Egger and H Reinshagen in J. Antibiotics. 1976, 29, 915; starting from pleuromutilin or 19,20-dihydro-pleuromutilin (n=0) . Also compounds where R^L is chloro or bromo may be prepared by reacting Br(CH₂))_n(CH₂)COOCl or Cl(CH₂)_n(CH₂)COOCl with compounds IV and V above. It will be appreciated that when n=0, compounds where R^L is hydroxy are pleuromutilin and 19,20-dihydro-pleuromutilin. Compounds where R^L is NH₂ may be prepared from the compound where R^L is a leaving group, for example treating a tosylate with sodium azide, followed by treatment with triphenyl phosphine and a base.

Compounds of formula (IA) wherein X is S(O) or SO₂ may be obtained by preparing the corresponding compound in which X=S and treating it with an oxidising agent; for example, 3-chloroperoxybenzoic acid in chloroform, or catalytic osmium tetroxide plus N-methylmorpholine N-oxide in tetrahydrofuran and tertiary-butanol.

It will be appreciated that it is also possible to carry out the reaction of the compounds VIA/B/C with compound VII with the substituents reversed, i.e. with —CH₂(CH₂)_nXH as a 14-mutilin substituent and R^L on the R^2A—(CH₂)_m— residue. For example 22-deoxy-22-sulfanyl-pleuromutilin (U.S. Pat. No. 4,130,709) may be reacted with a compound of formula R^2A—(CH₂)_m—R^L, where R^L is a leaving group, such as 4-MeC₆H₄SO₂O, MeSO₂O, CF₃SO₂O, or Cl, in the presence of an inorganic base, such as sodium methoxide, sodium ethoxide, or sodium hydride, in a solvent such as 2-propanol, ethanol, methanol, or tetrahydrofuran.

The compounds (III) and (VII) are commercially available or may be formed by conventional methodology from compounds that are commercially available compounds or described in the literature.

Where intermediates disclosed for the above processes are novel compounds, they also form part of this invention.

The compounds of the present invention may contain a chiral centre, and therefore the products of the above processes may comprise a mixture of diastereoisomers or a single diastereoisomer. A single diastereoisomer may be prepared by separating such a mixture of diastereoisomers which has been synthesised using a racemic starting material, or by synthesis using an optically pure starting material.

The products of the processes of this invention may be in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. 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 present in the crystalline product. 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.

The compounds obtained according to the processes of the invention are suitably worked up to a substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight. An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding derivative) suitable for pharmaceutical use.

The present invention also includes pharmaceutically acceptable salts and derivatives of the compounds of the invention. Salt formation may be possible when one of the substituents carries an acidic or basic group. Salts may be prepared by salt exchange in conventional manner

Acid-addition salts may be pharmaceutically acceptable or non-pharmaceutically acceptable. In the latter case, such salts may be useful for isolation and purification of the compound of the invention, or intermediates thereto, and will subsequently be converted into a pharmaceutically acceptable salt or the free base. Pharmaceutically acceptable acid-addition salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Suitable salts include the hydrochloride, maleate, and methanesulphonate; particularly the hydrochloride.

It will also be understood that where the compound of the invention contains a free carboxy moiety, it can form a zwitterion.

The compounds of the present invention and their pharmaceutically acceptable salts or derivatives have antimicrobial properties and are therefore of use in therapy, in partiuclar for treating microbial infections in animals, especially mammals, including humans, in particular humans and domesticated animals (including farm animals). The compounds may be used for the treatment of infections caused by, for example, Gram-positive and Gram-negative bacteria and mycoplasmas, including, for example, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Haemophilius sp., Neisseria sp., Legionella sp., Chlamydia sp., Moraxella catarrhalis, Mycoplasma pneumoniae, and Mycoplasma gallisepticum.

The present invention also provides a method of treating microbial infections in animals, especially in humans and in domesticated mammals, which comprises administering a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof, or a composition according to the invention, to a patient in need thereof.

The invention further provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the preparation of a medicament for use in the treatment of microbial infections.

Compounds of the present invention may be used to treat skin and soft tissue infections and acne, by topical application. Accordingly, in a further aspect the present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the preparation of a medicament adapted for topical administration for use in the treatment of skin and soft tissue infections and also in the treatment of acne in humans.

Compounds of the present invention may be also used for the elimination or reduction of nasal carriage of pathogenic bacteria such as S. aureus, H. influenzae, S. pneumonia and M. catarrhalis, in particular colonisation of the nasospharynx by such organisms, by the administration of a compound of the present invention thereto. Accordingly, in a further aspect, the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament adapted for administration to the nasal cavity, for reducing or eliminating the nasal carriage of pathogenic organisms. Preferably, the medicament is adapted for focussed delivery to the nasopharynx, in particular the anterior nasopharynx.

Such reduction or elimination of nasal carriage is believed to be useful in prophylaxis of recurrent acute bacterial sinusitis or recurrent otitis media in humans, in particular in reducing the number of episodes experienced by a patient over a given period of time or reducing the time intervals between episodes. Accordingly, in a further aspect, the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament adapted for administration to the nasal cavity, for prophylaxis of recurrent acute bacterial sinusitis or recurrent otitis media.

Compounds of the present invention are also useful in treating chronic sinusitis. Accordingly, in a further aspect, the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament, for treating of chronic sinusitis.

The compounds according to the invention may suitably be administered to the patient at a daily dosage of from 1.0 to 50 mg/kg of body weight. For an adult human (of approximately 70 kg body weight), from 50 to 3000 mg, for example about 1500 mg, of a compound according to the invention may be administered daily. Suitably, the dosage for adult humans is from 5 to 20 mg/kg per day. Higher or lower dosages may, however, be used in accordance with normal clinical practice.

To lessen the risk of encouraging the development of resistant organisms during prophylaxis of recurrent otitis media or recurrent acute bacterial sinusitis, it is preferred to administer the drug on an intermittent, rather than a continual, basis. In a suitable intermittent treatment regimen for prophylaxis of recurrent otitis media or recurrent sinusitis, drug substance is administered on a daily basis, for a small number of days, for instance from 2 to 10, suitably 3 to 8, more suitably about 5 days, the administration then being repeated after an interval, for instance, on a monthly basis over a period of months, for instance up to six months. Less preferably, the drug substance may be administered on a continuing, daily basis, over a prolonged period, for instance several months. Suitably, for prophylaxis of recurrent otitis media or recurrent sinusitis, drug substance is administered once or twice a day. Suitablyv drug substance is administered during the winter months when bacterial infections such as recurrent otitis media and recurrent sinusitis tend to be more prevalent. The drug substance may be administered at a dosage of from 0.05 to 1.00 mg, typically about 0.1 to 0.2mg, in each nostril, once or twice a day.

More generally, the compounds and compositions according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.

Accordingly, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof toether with a pharmaceutically acceptable carrier or excipient.

The compounds and compositions according to the invention may be formulated for administration by any route, for example oral, topical or parenteral. The compositions may, for example, be made up in the form of tablets, capsules, powders, granules, lozenges, creams, syrups, sprays or liquid preparations, for example solutions or suspensions, which may be formulated for oral use or in sterile form for parenteral administration by injection or infusion.

Tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients including, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrollidone; 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: and pharmaceutically acceptable wetting agents, for example 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 another suitable vehicle before use. Such liquid preparations may contain conventional additives, including, for example, suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters (for example glycerine), propylene glycol, or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring and colour agents.

Compositions according to the invention intended for topical administration may, for example, be in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, nose drops, nasal sprays, impregnated dressings, and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams. Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, ethanol or oleyl alcohol for lotions and aqueous bases for sprays. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.

Compositions according to the invention intended for topical administration, in addition to the above, may also contain a steroidal anti-inflammatory agent; for example, betamethasone.

Compositions according to the invention may be formulated as suppositories, which may contain conventional suppository bases, for example cocoa-butter or other glycerides.

Compositions according to the invention intended for parenteral administration may conveniently be in fluid unit dosage forms, which may be prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle. In preparing solutions, the compound may be dissolved in water for injection and filter-sterilised before being filled into a suitable vial or ampoule, which is then sealed. Advantageously, conventional additives including, for example, local anaesthetics, preservatives, and buffering agents can be dissolved in the vehicle. In order to enhance the stability of the solution, the composition may be frozen after being filled into the vial, and the water removed under vacuum; the resulting dry lyophilised powder may then be sealed in the vial and a accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions may be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound may instead by sterilised by exposure to ethylene oxide before being suspended in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in such suspensions in order to facilitate uniform distribution of the compound.

A compound or composition according to the invention is suitably administered to the patient in an antimicrobially effective amount.

A composition according to the invention may suitably contain from 0.001% by weight, preferably (for other than spray compositions) from 10 to 60% by weight, of a compound according to the invention (based on the total weight of the composition), dependin on the method of administration.

When the compositions according to the invention are presented in unit dosage form, for instance as a tablet, each unit dose may suitably comprise from 25 to 1000 mg, preferable from 50 to 500 mg, of a compound according to the invention.

Preferred compositions of the present invention include those adapted for intranasal administration, in particular, those that will reach into the nasopharynx. Such compositions are preferably adapted for focussed delivery to, and residence within, the nasopharynx. The term ‘focussed delivery’ is used to mean that the composition is delivered to the nasopharynx, rather than remaining within the nares. The term ‘residence’ within the nasopharynx is used to mean that the composition, once delivered to the nasopharynx, remains within the nasopharynx over a course of several hours, rather than being washed away more or less immediately. Preferred compositions include spray compositions and creams. Representative spray compositions include aqueous compositions, as well as oily compositions which contain amphiphilic agents so that the composition increases in viscosity when in contact with moisture. Creams may also be used, especially creams having a rheology that allows the cream to spread readily in the nasopharynx.

Preferred aqueous spray compositions include, in addition to water, further excipients including a tonicity modifier such as a salt, for instance sodium chloride: preservative, such as benzalkonium salt; a surfactant such as a non-ionic surfactant, for instance a polysorbate; and buffer, such as sodium dihydrogen phosphate; present in low levels, typically less than 1%. The pH of the composition may also be adjusted, for optimum stability of the drug substance during storage. For compounds of the present invention, a pH in the range 5 to 6, preferably about 5.3 to 5.8, typically about 5.5 is optimal

Representative oily spray and cream compositions are described in WO 98/14189 (SmithKline Beecham).

Suitably, the drug substance is present in compositions for nasal delivery in between 0.001 and 5%, preferably 0.005 and 3%, by weight of the composition. Suitable amounts include 0.5% and 1% by weight of the composition (for oily compositions and creams) and from 0.01 to 0.2% (aqueous compositions).

Preferably, an aqueous spray composition is used. Such compositions are found to show similar retention in the target area (nasal cavity and nasopharynx) in gamma scintigraphy studies and have superior release rates in synthetic membrane diffusion studies when compared to an oily composition as described in WO 98/14189. In addition, an aqueous base was found to be preferred to an oily base in sensory analysis studies.

Spray compositions according to the present invention may be delivered to the nasal cavity by spray devices well known in the art for nasal sprays, for instance an air lift pump. Preferred devices include those which are metered to provide a unit volume of composition prefereably about 100 μl, and optionally adpated for nasal administration by addition of a modified nozzle.

The following Examples illustrate the present invention and particularly the preparative procedures outlined above, by reference to the preparation of specific compounds within the scope of the present invention.

Note on Naming of Pleuromutilin Analogues

In the Examples, compound (a), which in the IUPAC system has the systematic name (1S, 2R, 3S, 4S, 6R, 7R, 8R, 14R)-3,6-dihydroxy-2,4,7,14-tetramethyl-4-vinyl-tricyclo[5.4.3.0^1,8]tetradecan-9-one, is referred to using the trivial name mutilin and with the numbering system described by H Berner, G Schulz, and H Schneider in Tetrahedron, 1981, 37, 915-919. ##STR00008##

Likewise, compound (b), which has the systematic name (1R, 2R, 4S, 6R, 7R, 8S, 9R, 14R)-6-hydroxy-9-methoxy-2,4,7,14-tetramethyl-4-vinyl-tricyclo[5.4.3.0^1,8]tetradecan-3-one, is named as (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin. ##STR00009##

Claims

1. A compound of general formula (IA) or (IB): ##STR00010##

2. A compound according to claim 1 in which R² is substituted by alkyl, alkyloxy, alkenyl or alkenyloxy, which are optionally further substituted by one or more groups selected from aryl, heterocyclyl, (C_1-6)alkoxy, (C_1-6)alkylthio, aryl(C_1-6)alkoxy, aryl(C_1-6)alkylthio, amino, mono- or di-(C_1-6)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amides of carboxy, ureido, carbamimidoyl (amidino), guanidino, alkyl-sulfonyl, aminosulfonyl (C_1-6)acyloxy, (C_1-6)acylamino, azido, hydroxy, and halogen.

3. A compound according to claim 1 in which n is 0.

4. A compound according to claim 1 in which m is 0 or 1.

5. A compound according to claim 1 in which R² is quinuclidinyl.

6. A compound according to claim 1 which has the formula (IA).

7. A compound according to claim 1 selected from:

mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;

19,20-dihydromutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;

mutilin 14-(quinuclidin-3-yloxy)-acetate;

mutilin 14-(quinuclidin-3-ylsulfonyl)-acetate;

mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;

mutilin 14-[N-(2,2-dimethylazabicyclo[4.3.0]non-4-ylmethyl)]-aminoacetate;

mutilin 14-(quinuclidin-4-ylcarbonylamino)-acetate;

mutilin 14-[(3R,4R)-azabicyclo[2.2.1]hept-3-ylcarbonylamino]-acetate;

mutilin 14-(quinuclidin-4-ylmethylsulfanyl)-acetate;

19,20-dihydromutilin 14-(quinuclidin-4-ylsulfonyl)acetate;

19,10-dihydromutilin 14-(quinclidin-4-ylsulfoxy)-acetate;

mutilin 14-{(3RS,4SR)-1-aza-bicyclo[2.2.1]hept-3-yl-sulfanyl}-acetate;

mutilin 14-(quinuclidin-3-ylidene)-acetate;

mutilin 14-[quinuclidin-3-yl]-acetate;

mutilin 14-[quinuclidin-3-ylacetoxy]-acetate;

mutilin 14-(quinuclidin-3-ylmethylsulfanyl)-acetate;

1,2-didehydromutilin 14-(quinuclidin-4-ylsulfanyl)-acetate;

2α-hydroxymutilin 14-(quinuclidin-4-ylsulfanyl)-acetate;

mutilin 14-(quinuclidin-4-yl)-acetate;

mutilin 14-(quinuclidin-4-ylmethyl)-aminoacetate;

mutilin 14-[3-(quinuclidin-4-yl)-acrylate;

mutilin 14-[3-(quinuclidin-4-yl)]-propionate;

mutilin 14-(quinuclidin-4-ylmethyloxy)-acetate;

mutilin 14-[(3R)-quinuclidin-3-ylamino]-acetate;

mutilin 14-(quinuclidin-4-yl-amino)-acetate;

mutilin 14-[(3R)-quinuclidin-3-ylamino )]-acetate;

mutilin 14-(quinuclidin-4-yl-amino)-acetate;

mutilin 14-[4-(quinuclidin-4-yl)]-butyrate;

mutilin 14-(1-azabicyclo[3,3,0]oct-4-ylmethylsulfanyl)-acetate;

mutilin 14-(1-azabicyclo[3,3,0]oct-3-ylsulfanyl)-acetate;

mutilin 14-(endo 8-methyl-8-azabicyclo[3,2,1]oct-3-ylsulfanyl)-acetate;

mutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate;

19,20-dihydromutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate;

mutilin 14-{(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-acetate;

mutilin 14-(quinuclidin-2-ylmethylsulfanyl)-acetate;

mutilin 14-(1-azabicyclo[2.2.1]hept-4-ylmethylsulfanyl)-acetate;

mutilin 14-{(3R,4S)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-acetate;

mutilin 14-(1-azabicyclo[3.2.1]oct-5-ylmethylsulfanyl)-acetate;

mutilin 14-(quinuclidin-4-ylmethylsulfanyl)-acetate;

mutilin 14-(8-methyl-8-azabicyclo [3.2.1]oct-3-ylmethylsulfanyl)-acetate;

mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate;

mutilin 14-[(3-(quinuclidin-4-ylsulfanyl)]-propionate;

mutilin 14-[3-(quinuclidin-4-ylmethylsulfanyl)]-propionate;

19,20-dihydromutilin 14-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethylsulfanyl)-acetate;

mutilin 14-[4-(quinuclidin-4-ylsulfanyl)]-butyrate; and

mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate.

8. A process for preparing a compound according to claim 1 which comprises:

(a) coupling mutilin or epi-mutilin having a protected hydroxy group at position 11, with an active derivative, such as an acid chloride, of a carboxylic acid R^2A—(CH₂)_m—X—(CH₂)_n—CH₂CO₂H, where R^2A is R² as defined in claim 1 or a group convertible thereto, and n, m, and X are as defined in claim 1, and if necessary converting the epi-mutilin to mutilin, and where necessary or desired, before or after the coupling, modifying the mutilin nucleus to introduce 2—OH; 19,20-dihydro; or 1,2-dehydro substituents; or

(b) providing a mutilin or epi-mutilin derivative having (CH₂)_nCH₂CO as an O-acyl group at position 14, where the acyl group is substituted with R^L, which is a leaving group, OH or NH, coupling the 14-O-acyl-(epi) mutilin derivative with a compound R^2A(CH₂)_mXH or an active derivative therof, and if necessary converting the epi-mutilin configuration to mutilin, and where necessary or desired, before or after the coupling, modifying the mutilin nucleus to introduce 2-OH; 19,20-dihydro; or 1,2-dehydro substituents.

9. A process for preparing a compound according to claim 8(b) in which

(a) when X is O, S or NH, R^L is a leaving group and is reacted with

(i) the alcohol R²—(CH2)_m—OH;

(ii) the thiol R²—(CH₂)_m—SH;

(iii) the amine R²—(CH₂)_m—NH₂;

(b) when X is CONH, R^L is amino and is reacted with the acid R^2A—(CH₂)_m—CO₂H, or an acylating agent derived therefrom;

(c) when X is CO.O, R^L is hydroxy and is reacted with an acylating agent derived from the acid R^2A—(CH₂)_m—CO₂H.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition according to claim 10 in the form of a spray adapted for administration to the nasal cavity.

12. A pharmaceutical composition according to claim 11 in which the spray is an aqueous spray.

13. A method of treating bacterial infection which method comprises administering an anti-bacterial effective amount of a compound of formula (IA) or (IB) according to claim 1 to a patient in need thereof.

14. A method of reducing or eliminating the nasal carriage of pathogenic organisms which method comprises administering an effective amount of a compound of formula (IA) or (IB) according to claim 1 to a patient in need thereof.

15. A method of prophylaxis of recurrent otitis media or recurrent acute bacterial sinusitis which comprises administering an effective amount of a compound of formula (IA) or (IB) according to claim 1 to a patient in need thereof.

16. A compound according to claim 1 wherein X is —S—, n is 0 and m is 0 or 1.

17. A pharmaceutical composition according to claim 10 adapted for topical administration.

18. A pharmaceutical composition according to claim 17 in the form of an ointment.

19. A pharmaceutical composition according to claim 17 in the form of a cream.

20. A pharmaceutical composition according to claim 17 in the form of a lotion.

21. A method of treating bacterial infections of skin or soft tissue which method comprises topically administering an antibacterially effective amount of a compound of formula (IA) or (IB) according to claim 1 to a patient in need thereof.

22. A method according to claim 21 wherein the infection is caused by a Gram-positive bacteria.

23. A method according to claim 21 wherein the infection is caused by a Gram-negative bacteria.

24. A method according to claim 21 wherein the infection is caused by a mycoplasma.

25. The compound mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate.

26. A compound selected from

mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;

19,20-dihydromutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate;

mutilin 14-(quinuclidin-3-yloxy)-acetate;

mutilin 14-(quinuclidin-3-ylsulfanyl)-acetate;

mutilin 14-[N-(2,2-dimethylazabicyclo[4.3.0]non-4-ylmethyl)]-aminoacetate;

mutilin 14-(quinuclidin-4-ylcarbonylamino)-acetate;

mutilin 14-[(3R,4R)-acabicyclo[2.2.1]hept-3-ylcarbonylamino]-acetate;

mutilin 14-(quinuclid-4-ylmethylsulfanyl)-acetate;

19,20-dihydromutilin 14-(quinuclidin-4-ylsulfonyl)acetate;

19,20-dihydromutilin 14-(quinclidin-4-ylsulfoxy)-acetate;

mutilin 14-{(3RS,4SR)-1-aza-bicyclo[2.2.1]hept-3-yl-sulfanyl}-acetate;

mutilin 14-(quinuclidin-3-ylidene)-acetate;

mutilin 14-[quinuclidin-3-yl]-acetate;

mutilin 14-[quinuclidin-3-ylacetoxy]-acetate;

mutilin 14-(quinuclidin-3-ylmethylsulfanyl)-acetate;

1,2-didehydromutilin 14-(quinuclidin-4-ylsulfanyl)-acetate;

2α-hydroxymutilin 14-(quinuclidin-4-ylsulfanyl)-acetate;

mutilin 14-(quinuclidin-4-yl)-acetate;

mutilin 14-(quinuclidin-4-ylmethyl)-aminoacetate;

mutilin 14-[3-(quinuclidin-4-yl)-acrylate;]

mutilin 14-[3-(quinuclidin-4-yl)]-propionate;

mutilin 14-(quinuclidin-4-ylmethyloxy)-acetate;

mutilin 14-[(3R)-quinuclidin-3-ylamino]-acetate;

mutilin 14-(quinuclidin-4-yl-amino)-acetate;

mutilin 14-[4-(quinuclidin-4-yl)]-butyrate;

mutilin 14-(1-azabicyclo[3,3,0]oct-4-ylmethylsulfanyl)-acetate;

mutilin 14-(1-azabicyclo[3,3,0]oct-3-ylsulfanyl)-acetate;

mutilin 14-(endo 8-methyl-8-azabicyclo[3,2,1]oct-3-ylsulfanyl)-acetate;

mutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate;

19,20-dihydromutilin 14-(1-azabicyclo[4,3,0]non-4-ylsulfanyl)-acetate;

mutilin 14-{(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-acetate;

mutilin 14-(quinuclidin-2-ylmethylsulfanyl)-acetate;

mutilin 14-(1-azabicyclo[2.2.1]hept-4-ylmethylsulfanyl)-acetate;

mutilin 14-{(3R,4S)-1-azabicyclo[2.2.1]hept-3-ylmethylsulfanyl}-;

mutilin 14-(1-azabicyclo[3.2.1]oct-5-ylmethylsulfanyl)-acetate;

mutilin 14-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethylsulfanyl)-acetate;

mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate;

mutilin 14-[(3-(quinuclidin-4-ylsulfanyl)]-propionate;

mutilin 14-[3-(quinuclidin-4-ylmethylsulfanyl)]-propionate;

19,20-dihydromutilin 14-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethylsulfanyl)-acetate; and

mutilin 14-[4-(quinuclidin-4-ylsulfanyl)]-butyrate;