DEOXYTHIOMARINOL DERIVATIVES, PROCESS AND INTERMEDIATES FOR THEIR PREPARATION AND THEIR USE AS MICROBICIDES AND HERBICIDES

DEOXYTHIOMARINOL DERIVATIVES PROCESS AND INTERMEDIATES FOR THEIR PREPARATION AND THEIR USE AS MICROBICIDES AND HERBICIDES

This invention relates to a novel class of compounds having antibacterial, antimycoplasmal and antifungal activity, to processes for their preparation and to 5 their use in human and veterinary' medicine, and also to intermediates for use in the preparation of such compounds. These compounds also have herbicidal activity and therefore will be of use in agriculture.

The microorganism Pseudomonas floor escens produces three closely related tetrahydropyranyl compounds known as pseudomonic acids A, B and C which are of 10 interest on account of their antibacterial properties.

Pseudomonic acid A (now known as mupirocin) has the structure (A):

(A)

It is an ester of monic acid, the compound of formula (B);

(B) in which the ester forming radical is derived from 9-hydroxynonanoic acid. Pseudomonic acid A exhibits good anti-bacterial activity, mainly against Gram- positive bacteria, but also against some Gram-negative bacteria such as Haemophilus

20 inflnenzae and Moraxella catarrhalis. It acts as selective reversible inhibitor of bacterial isø-leucyl t-RNA synthetase, thereby inhibiting bacterial protein synthesis. It also has anti-mycoplasma and anti-fungal activity (see Merck Index, 11th edn, 1989, 993 (and references therein) and EP 0 251 434-A). The compound is marketed by SmithKline Beecham under the trade mark Bactroban, as a topical formulation.

25 Systematic use is precluded by a rapid metabolism to monic acid, which is inactive. More recently, it has been disclosed that esters of monic acid also have useful herbicidal activity (WO 93/19599, Zeneca Ltd).

Pseudomonic acid C has the structure (C):

(C) (EP 0003 069, Beecham Group Ltd) and is distinguished from pseudomonic acid A by the presence of a C10-C11 trαns-double bond.

More recently, there have been reports of compounds produced by marine microrganisms which are closely related to pseudomonic acid and have antibacterial activity. These compounds have the C10-C11 trans-double bond of the "C" series and are characterised by the presence of a hydroxyl substituent at C-4. In addition, the ester forming radical is derivable from 8-hydroxyoctanoic acid in which the carboxy terminal is present as an amide formed from an amine containing a heterocyclic moiety.

The compound of formula (D):

(D) in which R is hydrogen or hydroxyl is produced by an Alteromonas species associated with a marine sponge (Stierle D B and Stierle A A, 200th National Meeting of ACS, Washington DC, Aug 26-31, 1990 and Experientia, 1992, 48, 1165). The stereochemistry of the C-4 hydroxyl was inferred to be β-, based on spectroscopic studies.

In addition, a further compound, named thiomarinol, is produced by Alteromonas rava. This compound has the general formula (E):

(E) the stereochemistry being the same as that in pseudomonic acid C at each of the common chiral centres. The stereochemistry of the 4-hydroxyl substituent, however, remains undefined (EP 0 512 824-A1, Sankyo Co Ltd and Shiozawa et al, J Antibiotics, 1993(12), 46, 1834-1842). Thiomarinol is said to possess good anti¬ bacterial activity against both Gram-positive and Gram-negative organisms, as well as being active against mycoplasma. The amine forming the terminal amide is a pyrrothine, in particular a holothin. The acetamides thereof include the known anti¬ bacterial compounds thiolutin (Merck Index, 11th edn, 1989, 1471) and holomycin (Merck Index, 11th edn, 1989, 747). Thiolutin also has anti-fungal activity.

We have now found that further pyrrothine derivatives have useful therapeutic properties.

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

(I) in which:

A-- is a group of atoms for linking C(O)O with CONRl;

R! and R , which may be the same or different, is each selected from hydrogen or

(Cι_6)alkyl, (C3_7)cycloalkyl, (C2-6)al-<enyl, aryl, aryl(C^*ι_4)alkyl or heterocyclyl, each of which may be optionally substituted; and

X is an epoxy moiety or an E-double bond moiety:

Compounds of formula (I) have improved anti-bacterial properties, in terms of absolute potency and/or an enhanced spectrum, compared to pseudomonic acids A and C.

The linking group of atoms A comprises one or more carbon atoms which could include carbon atoms in a carbocyclic, for instance, an aryl, ring and/or heteroatoms, for instance nitrogen, sulphur and oxygen, which could include heteroatoms in a heterocyclic ring.

Suitable values for A-* include the following: C(R3)(R4_); [C(R3)(R4)]_mA2_; [C(R3)(R4)]_mA2_A3_; [C(R3)(R4)]_mA3_; and [C(R3)(R4)]_mA3_A2_; in which: m is 0 or 1 (such when m is 0, [C(R3)(R4)]_m represents a bond);

R3 and R^, which may be the same or different, is each selected from hydrogen or (Cι_₆)al yl;

A2 is a (C3_7)cycloalkylene group, an optionally substituted aryl group, preferably phenylene, or an optionally substituted heterocyclyl group; and

A3 is a polymethylene chain having between between 1 and 20 carbon atoms, preferably 4 and 9 carbon atoms, which chain may be optionally substituted, for instance by a (C].6)alkyl group, and which chain may be optionally interrupted at one or more places by a moiety M in which:

M is a chain of one or more atoms for linking two polymethylene chains and which may be the same or different if there is more than one interruption.

Suitable values for M include a heteroatom selected from oxygen, sulphur or nitrogen, preferably oxygen; a (C3_7)cycloalkylene group; a carbon-carbon double bond; a carbon-carbon triple bond; CO; OC(O); C(O)O; NRCO; C(O)NR; NRCONR;

NRC(O)O; OC(O)NR: SO₂NR; NRSO₂; CONRSO₂; SO₂NRCO and phenyloxy; in which R is hydrogen or (Cj.gjalkyl.

Suitably, R-* is hydrogen or (Cι._6)alkyl, preferably hydrogen. Suitably, R2 is hydrogen or (Cj^alkyl, for instance methyl, preferably hydrogen.

Suitably, A 1 is an optionally substituted polymethylene chain (CH₂)_n in which n is an integer from 1 to 10, preferably from 5 to 9, more preferably 6, 7 or 8.

Suitable substituents include (C g)alkyl, in particular on the α-carbon (carbon attached to carboxy). In compounds of formula (I) in which X is an epoxy moiety (A series), A Ms preferably (CH₂)7 or (CH₂)g whilst in compounds of formula (I) in which X is a E-double bond (C series), A-* is preferably (CH₂)6 or (CH₂)7.

Suitable substituents for a (Cμ6)alkyl, (C3_7)cycloalkyl, (C₂-6)alkenyl group or polymethylene chain include for example, halogen, cyano, azido, nitro, carboxy, (Cι_6)alkoxycarbonyl, carbamoyl, mono- or di-(Cι_6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C^*[ _6)alkylsulphamoyl, amino, mono- or di-(Cι_6)alkylamino, acylamino, ureido, (C^*j_6)alkoxycarbonylamino,

2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (C_j.^alkoxy, acyloxy, oxo, acyl, 2-thenoyl, (Cμgjalkylthio, (Cι_6)alkylsulphinyl, (Cι_6)alkylsulphonyl, hydroxyimino, (C^*[_6)alkoxyimino, hydrazino, hydrazono, benzohydroximoyl, guanidino, amidino and iminoalkylamino.

When used herein, the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents. Suitable substituents for an aryl group include, for example, halogen, cyano, (Cι_6)alkyl, phenyl, (Cj_6)alkoxy, halo(Cι_6)alkyl, hydroxy, amino, mono- or di-(Cι_6)alkylamino, acylamino, nitro, carboxy, (Cι_6)alkoxycarbonyl, (C ι.6)-alkoxycarbonyl(C \ _6)alkyl, (C \ _6)alkylcarbonyloxy, (C _6)alkylthio, (Cι.6)alkylsulphinyl, (Cι_6)alkylsulphonyl, sulphamoyl, mono- or di-(Cι.6)alkylsulphamoyl, carbamoyl, and mono- or di-(Cι_6)alkylcarbamoyl.

When used herein, the term 'heterocyclyl' includes aromatic and non-aromatic single or fused rings comprising up to four heteroatoms 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, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Suitable substituents for a heterocyclyl group include those hereinbefore defined for an aryl group, as well as oxo.

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

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 which may lead to the formation of hydrated products. 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.

It will be readily appreciated that compounds of formula (I) are esters of either monic acid A or monic acid C. Monic acid A is the name given to the compound 4-[(2S,3R,4R,5S)-5-[(2S,4S,5S)-2,3-epoxy-5-hydroxy- 4-methylhexyl]-3,4-dihydroxytetrahydropyran-2-yl]-3-methyl-but-(E)-enoic acid which has the following structure:

Monic acid C is the name given to the compound 4-{(2S,3R,4R,5S)-5-[(4S,5S)-5- hydroxy-4-methylhex-2(E)-enyl]-3,4-dihydroxytetrahydropyran-2-yl}-3-methylbut-

2(E)-enoic acid which has the following structure:

Accordingly, within the compounds of formula (I), there exists a first sub-set of compounds which are esters of monic acid A and which may be represented by formula (II):

(II) and a second sub-set of compounds which are esters of monic acid C and which may be represented by formula (III):

(III) in which formulae A--, R2 and R3 are as hereinbefore defined.

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, for instance, tablets, capsules, powders, granules, suppositories, lozenges and liquid or gel preparations, including oral, topical and 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, 7th edn, ed Wilkinson and Moore, 1982, George Godwin, Harlow, England and the British Pharmacopoeia.

Suitable ointment formulations include those described in EP 0095 897-A(Beecham Group pic), for pseudomonic acid A (mupirocin), and comprise a polyethylene glycol or a polyethylene glycol analogue or derivative, preferably polyethylene glycol 400 optionally admixed with polyethylene glycol 4000.

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 mg/ml, for example 5-200 mg/ml, is suitable.

Compounds of this invention are of use in therapy, in particular for treating bacterial, mycoplasma and/or fungal infections in animals, including humans.

Compounds of this invention are active against both Gram negative and

Gram positive organisms, including Bacteroides, for instance B.fragilis BC1, Haemophilus, for instance H. influenτae Ql ; Moraxella, for instance M. catarrhalis

1502; Streptococci, for instance S. pyogenes CN10 and S. pneumoniae PU7;

Staphylococci, for instance S. aureus Oxford; Escherichia, for instance E. Coli DC0,

Legionella, for instance L. pneumophila; Pseudomonas, for instance P. aeruginosa Dalgleish and Enterobacter, for instance Ent.faecelis I. Generally , it has been found that compounds in the A series have superior antibacterial activity, when compared with the corresponding compounds in the C series, with the exception of activity against P. aeruginosa where the C series compounds tend to be the more active. In addition, compounds of this invention are active against Staphylococci organisms such as S. aureus and coagulase negative strains of Staphylocci such as S. epidermidis which are resistant (including multiply-resistant) to other anti-bacterial agents, for instance, β-lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides. Compounds of the present invention are therefore useful in the treatment of MRSA, MRCNS and MRSE. Furthermore, compounds of the present invention are useful in the treatment of Staphylococci organisms which are resistant to mupirocin. Bacterial infections which may be treated include 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. Accordingly, in a further aspect, the present invention provides a method of treating bacterial infection in human or non-human animals, 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. Compounds of this invention are also active against mycoplasma-induced infections in humans and animals, for instance those caused by Mycoplasma pneumonia (human, primary atypical pneumonia), Mycoplasma gallisepticum (avian, chronic respiratory diseases), Mycoplasma bovis (cattle, mastitis, respiratory diseases and arthritis), Mycoplasma dispar (calf, pneumonia), Mycoplasma hypopnewnoniae (pigs, enzootic pneumonia), Mycoplasma hyorhinis (pigs, arthritis) and Mycoplasma hyposinoviae (pigs, arthritis). Accordingly in a further aspect, the present invention provides a method of treating mycoplasmal infection in human or non-human animals, 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 In addition, compounds of the present invention are of use in treating infections caused by Mycoplasma fermentans, which has been implicated as a co- factor in the pathogenesis of AIDS. Accordingly in a further aspect, the present invention provides a method of treating humans infected with M. fermentans, in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula (I).

Compounds of this invention also have antifungal activity. They may, for example, be used in treating fungal infections in man caused by, among other organisms, species of Trichophyton, Trichosporon, Hendersonula, Microsporum, Epidermophyton, Candida, Cryptococcus , Saccharomyces, Paecilomyces and Pityrosporum. They may also be used in the treatment of a variety of other fungal infections caused by, for example Aspergillus, Coccidioides, Paracoccidioides, Histoplasma and Blastomyces species. Accordingly, in a further aspect, the present invention provides for a method of treating fungal infections in animals, including man, which method comprises treating a patient in need of antifungal therapy with an effect amount of a compound of formula (I).

No adverse toxicological effects are expected from the administration of a compound of formula (I).

Compounds of the present invention are also useful as herbicides and are active against a broad range of weed species, including monocotyledonous and dicotyledonous species. Many compounds show good selectivity in crops, particularly wheat, barley, maize, oil seed rape, sugar beet and rice. Compounds for use in hebicidal compositions of the present invention are preferably applied directly to unwanted plants (post-emergence application) but may also be applied to the soil before the unwanted plants emerge (pre-emergence application). Therefore, in a further aspect, the present invention provides for a process of severely damaging or killing unwanted plants which process comprises applying to the plants or the growth medium of the plants a herbicidally effective amount of a compound of formula (I), as hereinbefore defined.

For herbicidal use, compounds of the present invention are preferably used in the form of a composition further comprising a carrier which may be a liquid or solid diluent. Suitable such compositions may be dilute compositions which are ready for immediate use or concentrated compositions which are diluted prior to use, usually with water. Suitable liquid compositions may comprise a solution or a dispersion of the active ingredient in water, optionally with a surfactant, or may comprise a solution or a dispersion of the active ingredient in a water-immiscible organic solvent which is dispersed as droplets in water. Suitable solid compositions may be in the form of granules or dusting powders or dispersible powders or grains, further comprisng a wetting agent to facilitate dispersion. Suitable herbicidal formulating agents are well known in the an; see, for instance, WO 93/19599 (Zeneca Ltd).

A suitable rate of application for herbicidal use will will depend upon the particular application but will usually be in the range 0.0001 to 20kg/hectare, preferably 0.001 to lOkg hectare, more preferably 0.001 to 2kg/hectare.

Compounds of the present invention may be used alone or in admixture with other another herbicide which will preferably have a complementary herbicidal activity in the particular application. Suitable such complememtary herbicides are disclosed in WO 93/19599 (Zeneca Ltd)

Compounds of formula (I) may be readily prepared by adapting procedures well known in the art. It will be readily appreciated that compounds of formula (I) are esters of either monic acid A or monic acid C and are therefore obtainable by adapting procedures previously described for other esters of monic acid A in

GB 1 587 059 (Beecham Group Ltd). Suitable such procedures include conventional esterification procedures using optionally protected monic acid A or C or an activated derivative thereof and an appropriate "alcohol" comprising a terminal pyrrothin moiety. Accordingly, in a further aspect, the present invention provides a process for preparing a compound of formula (I) which process comprises esterifying an acid of formula (IV):

(IV) in which X is as hereinbefore defined and Z*-*, z and z3, which may be the same or different, is each hydrogen or a hydroxyl protecting group; or a salt or an activated derivative thereof: with a compound of formula (V):

(V) in which:

Y-* is a reactive esterifying leaving group; and A-*, R-* and R are as hereinbefore defined; under ester forming conditions; and thereafter, and if necessary, removing any hydroxyl protecting groups.

Suitably, Y-* is hydroxy, halogen, preferably bromine or iodine, or sulphonate, preferably halogen or sulphonate.

Suitable ester forming conditions are well known in the art and are described in, for instance, Comprehensive Organic Synthesis, Pergamon Press, 1991, 6, 323- 380. Suitable ester forming conditions include: (a) reacting a salt of the acid of the formula (IV), for instance, a sodium or a tertiary amine salt such as triethylamine, with a compound of the formula (V), in a polar aprotic solvent such as dimethyl formamide, dimethyl sulphoxide or acetonitrile, at moderate temperature, for instance in the range 0 to 100°C; (b) reacting the acid of formula (IV) with a compound of formula (V) in the presence of a base such as an alkali metal carbonate or a tertiary amine, in a polar aprotic solvent and temperature as for (a);

(c) reacting the acid of formula (IV) with a compound of formula (V) in which Y-- is hydroxyl, under dehydrating conditions, for instance the Mitsunobu reaction employing an azodicarboxylate and a trivalent phosphorus reagent (Mitsunobu, Synthesis, 1981, 1); or

(d) reacting an activated derivative of the acid of formula (IV), for instance a mixed anhydride, for instance an wo-butylcarbonic or a methane sulphonic anhydride, with a compound of formula (V) in which Y-* is hydroxyl, in the presence of a suitable base such as a tertiaryamine, for instance, triethylamine, in an aprotic solvent such as tetrahydrofuran, at a moderate temperature, preferably in the range -20 to +20°C, or alternatively, in the absence of a base but using a preformed salt of the alcohol, for instance the magnesium or lithium alkoxide.

Preferred conditions include the use of the sodium salt of the hydroxyl- protected derivative of the acid of formula (IV) in combination with the halide or the sulphonate derivative of the compound of formula (V).

Compounds of formula (V) are novel and useful as intermediates in the preparation of compounds of formula (I). Accordingly, in a further aspect, the present invention provides a compound of formula (V), as hereinbefore defined. Compounds of formula (V) comprise an amide bond and are therefore readily obtainable by conventional amide forming reactions using appropriate acid and amine precursors. A suitable such process compromises reacting an acid of formula (VI):

Y A¹CO₂H (VI) in which: γ is a protected hydroxyl group or Y-* (other than hydroxy); and

A Ms as hereinbefore defined; or an activated derivative or salt thereof, with an amine of formula (VII):

(VII) in which R-* and R are as hereinbefore defined; under amide forming conditions, as described in, for instance, Comprehensive

Organic Synthesis, Pergamon Press, 1991, 6, 381-417.

Particularly suitable amide forming conditions include reacting an activated derivative of an acid of formula (VI), for instance an acyl halide or a mixed anhydride such as a wo-butylcarbonic or methane sulphonic anhydride, with an amine of the formula (VII) in the presence of a suitable base such as a tertiary amine, for instance pyridine, 2, 6-lutidine or 4-dimethylaminopyridine, in an aprotic solvent such as chloroform, dichloromethane or tetrahydrofuran, at a moderate temperature, preferably in the range -30 to +30°C.

Acids of formula (VI) are ω-hydroxycarboxylic acids or derivatives thereof which may be obtained directly from commercial suppliers or by conventional modification of compounds which are available from such sources. An amine of formula (VII) may be obtained according to the processes described in GB 2 170498 A (Imperial Chemical Industries pic) or by semi-synthetic processes starting from natural sources such as thiolutin and holomycin.

In a second process, compounds of formula (I) may be prepared by a sequence in which the final step comprises forming an amide bond between appropriate acid and amine precursors.

Accordingly, in a further process, a compound of formula (I) may be prep

(VIII) in which A-^, X, Z-*, z2 and z3 are as hereinbefore defined; or an activated derivative thereof; with an amine of formula (VII), as hereinbefore defined, under amide forming conditions; and thereafter, and if necessary, removing any hydroxyl protecting groups. Suitable amide forming conditions are well known in the art, as hereinbefore described.

Compounds of formula (VIII) are useful as intermediates in the preparation of compounds of formula. Accordingly, in a further aspect, the present invention provides a compound of formula (VIII), as hereinbefore defined, other than pseudomonic acids A and C and hydroxyl-protected derivatives thereof (A^=(CH₂)g). An acid of formula (VIII) may be obtained by treating a compound of formula (IV) with a compound of formula (VI) in which the carboxyl group is protected by a carboxy protecting group, under esterifying conditions, as hereinbefore described. Suitable carboxy protecting groups are described in Protective Groups in Organic Synthesis, T.W. Greene, Wiley-Interscience, New York, 2nd ed, 1991 and include lower alkyl, preferably methyl, allyl and tetrahydropyranyl.

Monic acid A may be readily obtained from pseudomonic acid A by the carefully controlled hydrolysis thereof, according to the process described in GB 1 587 058 (Beecham Group Ltd). A similar process may be used to obtain monic acid C form pseudomonic acid C (Clayton J P et al, JCS Perkin Trans I, 1982, 2827). Alternatively, monic acid C may be obtained from monic acid A by the deoxygenation thereof, according to the process described in EP 0003 069 (Beecham Group Ltd). It will be readily appreciated that derivatives of monic acid A and monic acid

C, such as the compounds of the present invention, are readily interconvertible by suitable deoxygenation (A→C) and epoxidation (C→A) procedures, for instance those described in EP 0 003 069-A (Beecham Group pic) and by Clayton J P et al, JCS Perkin Trans I, 1982, 2827. 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, 2nd ed, 1991.

The hydroxyl groups of monic acids A and C and the compound of formula (Vπi) 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 following formulae :

L₃SiY; L₂SiY₂; L₃SiNL₂; L₃SiNHSiL₃; L₃SiNHCOL; L₃SiO-C(L)=NSiL₃; L₃SiNHCONHSiL₃; LNHCONHSiL₃; ^tBuMe₂Si-O-SO₂-CF₃; Me₃Si- N ^V 'βuMe-.Si- ^^

in which Me denotes methyl, t-Bu denotes t-butyl, Y is halogen and each group L is independently selected from hydrogen, (Cj-gjalkyl, (Cj-^alkoxy, aryl or aryl(C*- -4)alkyl. A preferred silyating agent is trimethylsilyl chloride. Particularly suitable hydroxyl-protecting groups are trimethylsilyl, triethylsilyl and t-butyldimethylsilyl groups. Preferred hydroxyl-protecting groups are trimethylsilyl groups because of their ease of removal.

The glycol function of monic acids A and C and the compound of formula (Vπi) may be protected by forming a cyclic derivative using a compound of formula (IX):

RaC(OR^b)(OR^c)(OR^d) (^ιχ) in which R^a is hydrogen or (Cj-6)alkyl and each of R^D, R^c and R^d is (C-- _6)alkyl such that in the cyclic derivative z2 and z together are a moiety R^DC(OR^c). Suitably R^a is hydrogen, methyl, ethyl, n- or wø-propyl; most suitably it is hydrogen. The groups R^b, R^c and R^d are suitably methyl, ethyl, n- or wø-propyl, or n-, iso-, sec- ox t-butyl; most suitably methyl. The hydroxyl groups of a compound of formula (I) may also 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 Clayton J P et al, JCS Perkin Trans I, 1979, 308.

The following examples illustrate the invention, but are not intended to limit the scope in any way:

Preparation 1 - 6-(8-bromooctanoyIamino)-4-methyl-l,2-dithiolo[4,3-b]-pyrroI- 5(4H)-one: To a stirred mixture of 6-amino-4-methyl-l,2-dithiolo[4,3-b]pyrrol- 5(4H)-one hydrochloride (J Amer Chem Soc, 1955, 77, 2861) (50mg, 0.225mmol), pyridine (0.1ml, 1.24mmol) and chloroform (2ml), 8-bromooctanoyl chloride (150mg, 0.622mmol) was added and stirring continued for lOmin. The reaction mixture was evaporated to dryness, toluene (c .10ml) added to the residue and the toluene evaporated. This process was repeated. Chromatography of the residue over silica eluting with 0-2% dichloromethane-methanol, followed by a second chromatography of the major yellow product, eluting with dichloromethane gave the title compound (64.7mg, 73%) as a yellow solid; υ_max (KBr)/cm^~l 3261s (NH), 1660 and 1646 (CO); δ_H (250Mz; CDC1₃; Me₄Si) 1.3-1.55 (6H, m, CH₂), 1.62-1.8 (2Η, m, CH₂), 1.8- 1.96 (2Η, m, CH₂CH₂CO), 2.36 (2H, t, J 7.3Hz, CH₂CO), 3.29 (3Η, s, NΛfe), 3.33 (2H, t, J 6.8Hz, CH₂Br), 6.59 (1Η, s, 3-Η) and 7.75 (1H, s, NHCO); λmax (MeOΗ)/nm 388 (ε_m/dm3mol-¹cm-¹ 10011), 312.5 (3609) and 245.5 (5654); mlz (El) (Found M+, 390.0083 C₁₄H₁₉BrN2O2S₂ requires m/z, 390.0071). Preparation 2 - Ethyl monate C - Trichloroacetyl chloride (3.3ml, 30mmol) was added dropwise to a solution containing ethyl monate A (2.8g, 7.5mmol) in a mixture of dichloromethane (50ml) and pyridine (2.6ml, 32.5mmol) at 20°C. After lh at 20°C the solution was washed consecutively with aqueous sodium hydrogen carbonate, aqueous citric acid twice, and brine, dried, and evaporated to dryness to give the crude trw-(trichloroacetate). Trifluoroacetic anhydride (1.0ml, 7mmol) was added to a mixture of sodium iodide (3.5g, 25mmol) and acetonitrile (20ml) at 20°C. After 5min at 20°C the above t -(trichloroacetate) in acetonitrile (10ml) was added and the solution stirred at 20°C for 18h. Diethyl ether (100ml) was added and the mixture then washed with aqueous sodium hydrogen sulphite twice, aqueous sodium hydrogen carbonate twice, and brine, then dried and evaporated to dryness to give the crude protected olefin. This crude material was dissolved in ethanol (50ml) and potassium carbonate (7g, 50mmol) was added. After stirring for 2h at 20°C, ethyl acetate (200ml) was added and the mixture washed with water then brine, dried, and evaporated to dryness. Chromatography on silica gel eluting with ethyl acetate- hexane mixtures gave the title olefin (2.0g, 75%), m.p.97°C (from diethyl ether) G t., 96.5°C-97°C, Clayton et al, J.Chem.Soc, Perkin Trans. I, 1982, 2827). Preparation 3 - Methyl pseudomonate C - In an exactly similar way, methyl pseudomonate A (10.6g, 20mmol) was converted to methyl pseudomonate C (7.5g, 75%), identical to that reported previously, by Clayton, et al, J.Chem.Soc, Perkin Trans. I, 1982, 2827.

Preparation 4 - Pseudomonic Acid C - A solution of methyl pseudomonate C (390mg) in acetone (39ml) was diluted with 0.1M disodium hydrogen phosphate (350ml, adjusted to pH 7.0 with concentrated hydrochloric acid) and treated with Subtilisin Carlsberg Protease (150mg). After 24 hours at room temperature the solution was evaporated to low volume (ca 50ml), layered with ethyl acetate (50ml) and acidified to pH 3 with 5M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50ml). The combined organic phases were dried (MgSO₄) and evaporated to yield the title compound (360mg, 95%).

Example 1 - 6-[4-{5S-(2S,3S-Epoxy-5S-hydroxy-4S-methyIhexyl)-3R,4R- dihydroxy-tetrahydropyran-2S-yl}-3-methyI-but-2E-enoyl-oxyoctanoyIamino-4- methyM,2-dithioIo[4,3-b]pyrroI-5(4H)-one a) Sodium monate A (lOOmg, 0.273mmol) and 6-(8-bromooctanoyl-amino)-4- methyl- l,2-dithiolo[4,3-b]pyrrol-5(4H)-one (lOOmg, 0.256mmol) in dimethylformamide were heated with stirring at 70°C under argon for 30min. The reaction mixture was cooled to room temperature, the dimethylformamide removed under vacuum and the product purified by chromatography on silica eluting with 0- 5% methanol-dichloromethane to yield the title compound (9.5mg, 7%) as a yellow gum. b) Sodium 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-3R,4R- dihydroxytetrahydropyran-2S-yl)-3-methyl-but-E-enoyl-oxyoctanoate (65mg, 0.127mmol) was treated with 0.5M HC1 (0.255ml) and methanol (1ml) and the solution evaporated to dryness. To the residue THF (1ml) and triethylamine (19μl, 0.14mmol) was added and the stirred solution cooled to 0°C. Isobutylchloroformate (19μl, 0.14mmol) was added and the mixture stirred at 0°C for 20min. then pyrridine (lOμl, 0.126mmol) was added followed by 6-amino-4-methyl-l,2-dithiolo[4,3- b]pyrrol-5(4H)-one hydrochloride (30mg, 0.125mmol). After 20min. chloroform (1ml) was added to the reaction mixture and the mixture stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the product purified by chromatography on silica eluting with 0-4% methanol-dichloromethane to yield the title compound (27.6mg) which was 80% pure as determined by analytical h.p.l.c. (Nova Pak M C_jg column; 10cm x 5mm, eluting with 20% solution A and 80% solution B, detection at 386nm. [Solution A, 10% methanol, 90% NH4AC buffer pH 4.5; solution B, 70% methanol, 30% solution A]. The product was purified using preparative h.p.l.c. (C\ 8 Partisil column 20cm x 20mm, eluting with 65% solution C and 35% solution D, detection at 386nm). [Solution C, 90% methanol, 10% NH^Ac buffer pH 4.5; solution D, 35% NH₄Ac buffer pH 4.5, 65% methanol] to yield the title compound (15.1mg, >90% pure by h.p.l.c, yield 18%). c) The products prepared in a) and b) above were combined and chromatographed on silica eluting with 20% methyl acetate-hexane to yield the title compound (7.3mg, 88.7% pure by h.p.l.c); λ_max (MeOH)/nm 391 (ε_m/dm3mol" ¹ 5694) and 303 (4540); δ_H (400MHz; CDCI3; Me₄Si) inter alia 0.94 (3H, d, J 7Hz, 17-H), 1.22 (3H, d, J 6.3Hz, 12-H), 1.36 (8H, s, CH₂), 1.56-1.87 (m, CH₂ and

9-Η), 2.01 (m, 8-H), 2.21 (3H, s, 15-H), 2.27-2.45 (4H, m, 4-H, 14-H and CH₂CO),

2.58 (1Η, dd, J 3 and 14.5Ηz, 4-H), 2.69 (1H, dd, J 2 and 8, 11-H), 2.88 (1H, dt, J 2 and 7Hz, 10-H), 3.35 (3H, s, NMe), 3.48 (1H, m, 16-H), 3.55 (1H, dd, J2.5 and 12,

6-H), 3.7-3.98 (4H, m, 5-H, 13-H, 16-H and 7-H), 4.08 (3H, t, J 6.5, OCH₂), 5.76

Η (1Η, s, 2-Η), 6.65 (1H, s, =^L/ ) and 7.61 (1H, brs, NH); m/z (El) (Found M+ 654 C3lΗ₄6N₂OgS₂ requires 654).

Example 2 - 6-[4-{5S-(5S-Hydroxy-4R-methylhex-2E-eπyI)-3R,4R- dihydroxytetra-hydropyran-2S-yl}-3-methyI-but-2E-enoyl-oxyoctanoylamino]-4- methyl-l,2-dithiolo-[4,3-b]pyrroI-5(4H)-one This compound was prepared by the method described in Example la from sodium monate C and 6-(8-bromooctanoylamino)-4-methyl-l,2-dithiolo[4,3-b]pyrrol-5(4H)- one as a yellow gum in 4.3% yield; ^_ax (MeOH)/nm 387.5 (ε_m/dn_ι mol^"lcm~l 10659) and 314.5 (5329); δ_H(400MHz; CDCI3; Me Si) 0.99 (3H, d, J 7Hz, 17-H), 1.15 (d, J 6Hz, 14-H), 1.35 (6H, brs, CH₂), 1.58-1.74 (4H, m, CH₂), 1-83 (1H, m, 8-

H), 2.05-2.27 (3H, m, 9-H and 12-H), 2.21 (3H, d, J 1.3Hz, 15-H), 2.29 (1H, ddd, J

1,8,14.6Hz, 4-H), 2.33 (2H, t, J 8Hz, CH₂CO), 2.6 (1H, ddd, J 1,3,14.6Hz, 4-H),

3.34 (3H, s, NMe), 3.45 (1H, dd, J 3 and 9Hz, 6-H), 3.51 (1H, dd, J 2 and 11Hz, 16- H), 3.55 (1H, m, 13-H), 3.71 (1H, dt, J 3.2 and 9Hz, 5-H), 3.79 (1H, dd, J 3 and

11Hz, 16-H), 3.89 (1H, t, J 3.4Hz, 7-H), 4.07 (2H, t, J 6.5Hz, 0CH₂), 5.38-5.5 (2Η,

H m, 10 and 11H), 5.76 (1H, d, J 0.8Hz, 2-H), 6.65 (1H, s, =^/ ) and 7.78 (1H, s,

NHCO); mlz (El) [Found M+ 638.2698. C3iΗ₄₆N₂O₈S₂ requires mjz, 638.2696].

Example 3 - N-(4-MethyI-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrroI-6-yI)- pseudomonamide A

A stirred solution of pseudomonic acid A (250mg, 0.5mmol) and triethylamine (0.15ml, lmmol) in dry THF (5ml) at -10°C was treated with isobutyl chloroformate (65μl, 0.5mmol). After 20 minutes 6-amino-4-methyl-l,2-dithiolo[4,3-b]pyrrol-5- (4H)-one hydrochloride (104mg, 0.5mmol) was added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate (50ml), washed with saturated sodium hydrogen carbonate solution (20ml), water (2 x 20ml), saturated sodium chloride solution (20ml), dried (magnesium sulphate) and evaporated to dryness. The residue was chromatographed on silica eluting with 0-7% methanol- dichloromethane to yield the title compound (130mg, 39%); υ_max (CH₂Cl )/cm^~l 3393 br, 2932, 1707, 1668, 1225, 1152; δ_H (250MHz; CD₃OD; Me₄Si) 0.94 (3H, d,

J7Hz, 17-H), 1.19 (3H, d, J 6.5Hz, 14-H), 1.37 (9H, m, 4 x CH₂ and 12-H), 1.68

(6H, m, 2 x CH₂ and 9-H), 1.94 (1H, m, 8-H), 2.18 (3H, s, 15-H), 2.18-3.15 (6H, m,

CH₂, 4-H, 10-H, 11-H), 3.35 (3H, s, NMe), 3.50-3.90 (6H, m, 5-H, 6-H, 7-H, 13-H,

H

16-H), 4.06 (3H, t, 7 6.5Hz, OCH ), 5.73 (lH, s, 2-H), 7.25 (1H, s, =^***/ ); δ_C (CD3OD) 12.26 (C-17), 19.31 (C-15), 20.34 (C-14), 26.64 (C-3'), 27.01 (C-7'), 28.06

(C-4"), 29.77 (C-8'), 30.10-30.19 (C-4',5',6'), 33.00 (C-9), 36.60 (C-2'), 41.65 (C-8),

43.74 (C-12), 43.92 (C-4), 56.9 (C-10), 61.31 (C-l l), 64.82 (C-9'), 66.37 (C-16),

70.03 (C-6), 70.74 (C-13), 71.61 (C-7), 76.24 (C-5), 112.83 (C-3"), 115.44 (C-6a"),

118.35 (C-2), 135.88 (C-3a"), 137.60 (C-6"), 158.92 (C-3), 168.36, 168.61 (C-l, C- 5"), 174.20 (C-l'); mlz (El) (Found: M+, 668.2813. C₃₂H₄₈N₂O₉S₂ requires M,

668.2801).

Example 4 - N-(4-MethyI-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)- pseudo onamide C A stirred solution of pseudomonic acid C (242mg, 0.5mmol) and triethylamine

(0.15ml, lmmol) in dry THF (5ml) at -10°C was treated with isobutyl chloroformate

(65μl, 0.5mmol). After 20 minutes 6-amino-4-methyl-l,2-dithiolo[4,3-b]pyrrol-

5(4H)-one hydrochloride (104mg, 0.5mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was worked-up and chromatographed as described in example 3 to yield the title compound (163mg, 50%); υ_max (KBr)/cm"l

3265 br, 2855, 1647, 1229; δ_H (250MHz; CDCI3; Me₄Si) 0.97 (3H, d, J 6Hz, 17-H),

1.16 (3H, d, J 6Hz, 14-H), 1.33 (9H, m, 4 x CH₂, 12-H), 1.64 (6H, m, 2 x CH₂, 9-

H), 1.86 (1H, m, 8-H), 2.22 (3H, s, 15-H), 2.10-2.70 (4H, m, CH₂, 4H), 3.36 (3H, s, NMe), 3.40-3.95 (6H, m, 5-H, 6-H, 7-H, 13-H, 16-H), 4.08 (2H, t, J 6.5Hz, OCH₂),

H

5.31-5.36 (2H, m, 10-H, 11-H), 5.78 (1H, s, 2-H), 6.67 (1H, s, =^/ ), 7.75 (1H, s,

NH); δ_C (CDCI3) 16.72 (C-17), 19.32 (C-15), 20.46 (C-14), 25.48 (C-3'), 25.99 (C-

7"), 27.97 (C-4"), 28.67 (C-8'), 29.10 (C-4',5',6'), 32.45 (C-9), 36.44 (C-2'), 42.00 (C-

8), 43.13 (C-4), 44.78 (C-12), 63.68 (C-9'), 64.92 (C-l 6), 69.01 (C-6), 70.51 (C-7), 71.30 (C-13), 74.96 (C-5), 109.61 (C-3"), 114.61 (C-6a"), 117.63 (C-2), 129.50 (C- 11), 133.34 (C-3a"), 134.57 (C-10), 136.63 (C-6"), 157.00 (C-3), 166.94, 167.25 (C- 1, C-5"), 171.97 (C-l'); mlz (El) (Found: M+, 652.2856. C3₂H₄₈N₂O₈S₂ requires M, 652.2852). Example 5 - 4-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yOcarbamoylbutyl monate A a) 4-MethoxycarbonyIbutyl monate A - Sodium monate A (0.403g, 1. lmmol) was dissolved in dry dimethylformamide (13ml), and methyl 5-bromovalerate (0.31ml, 2.2mmol) added. The mixture was heated at 70°C for 2h, and then evaporated in vacuo. The residue was taken up in ethyl acetate, washed with dilute sodium hydrogen carbonate solution, and brine, dried and evaporated to give the crude product (0.74g). This was purified by column chromatography on silica (22g), eluting with 0-4% methanol in dichloromethane, to give the title compound as a colourless viscous oil (0.469g, 93%); υ_max (KBr) 3463, 2960, 1737, 1714, and 1151cm'¹; λrøax (EtOH) 220nm (ε_m 12,878); δ_H (CD3OD) (inter alia) 0.95 (3H, d, J 7.1Hz, I7-H3), 1.20 (3H, d, J 6.4Hz, 14-H₃), 1.6-1.8 (6H, m, 9-H₂, 2'-H₂, 3'-H₂), 2.18 (3H, s, I5-H3), 2.37 (2H, t, J 7.0Hz, 4'-H₂), 3.65 (3H, s, OMe), 4.08 (2H, d, J 6.0Hz, l'-H₂), and 5.74 (1H, s, 2-H); δ_C (CD3OD) 12.3 (C-17), 17.3 (C-15), 20.3 (C-14), 22.6 (C-3'), 29.2 (C-2'), 32.8 (C-9), 34.3 (C-4'), 41.7 (C-8), 43.7 (C-12), 43.9 (C-4), 51.8 (OCH3), 56.9 (C-10), 61.3 (C-l l), 64.3 (C-l'), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.2 (C-5), 118.2 (C-2), 159.2 (C-3), 168.2 (C-l), and 175.6 (C-5'); mlz (NH3 DCI) 476 (ΛfNl , 13%), 459 (MH+, 5), 232 (30), and 150 (100). b) 4-Carboxybutyl monate A - 4-Methoxycarbonylbutyl monate A (0.20g, 0.44mmol) was dissolved in acetone (20ml), and disodium hydrogen phosphate buffer solution (0.1M, pH 7, 180ml) added, followed by protease Subtilisin Carlsberg enzyme (O.lOOg). This clear solution was stirred for 42h, then reduced in vacua to a small volume, layered with ethyl acetate, and adjusted to pH 3.5 with dilute phosphoric acid. The mixture was filtered through celite, the phases separated, and the aqueous extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated to give a colourless viscous oil (0.199g, 100%); δ_H (CD OD) (inter alia) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.4Hz, I4-H3), 1.64-1.8 (6H, m, 9-H₂, 2'-H₂, 3'-H₂), 2.18 (3H, d, J l.OHz, 15-H₃), 2.33 (2H, t, J 6.8Hz, 4'-H₂), 4.05-4.15 (2H, m, l'-H₂), and 5.75 (IH, s, 2-H); mlz (NH3 DCI) 462 (MNH₄+, 27%), 445 ( H+, 11), and 279 (100). c) 4-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yI)carbamoyIbutyl monate A - 4-Carboxybutyl monate A (0.125g, 0.28mmol) was dissolved in dry tetrahydrofuran (15ml) and triethylamine (0.043ml, 0.3 lmmol), cooled in an ice-bath, and treated with isobutyl chloroformate (0.036ml, 0.28mmol). The mixture was stirred for \ήh, then triethylamine (0.053ml, 0.38mmol) was added, followed by 6- amino-4-methyl-l,2-dithiolo-[4,3-b]-pyrrol-5(4H)-one hydrochloride (0.075g, 0.34mmol). The mixture was stirred at room temperature for 5\4h, then diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, and brine, dried and evaporated. The yellow residue was absorbed onto silica and purified by column chromatography on silica (8g), eluting with 0-6% methanol in dichloromethane, to give the title compound as a yellow foam (0.095g, 56%); ^■o_τnax (KBr) 3420, 2926, 1707, 1647, 1602, 1228, and 1150cm^"1; λm^ (EtOH) 213 (ε_m 23,878) and 390nm (10,175); δ_H (CD3OD) 0.94 (3H, d, J 7.1Hz, 17-H₃), 1.19 (3H, d, J 6.2Hz, 14-H₃), 1.36-1.45 (IH, m, 12-H), 1.62-1.79 (6H, m, 9-H₂, 2'-H₂, 3'-H₂), 1.93-2.0 (IH, m, 8- H), 2.17 (3H, d, J l.OHz, 15-H₃), 2.22 (IH, dd, J 14.6, 9.7Hz, 4-H), 2.44 (2H, t, J 7.0Hz, 4'-H₂), 2.62 (IH, brd, J 14.1Hz, 4-H), 2.71 (IH, dd, J 7.6, 2.2Hz, 11-H), 2.80 (IH, dt, J 5.8, 2.2Hz, 10-H), 3.34 (3H, s, NMe), 3.35-3.41 (IH, m, 6-H), 3.55 (IH, dd, J 11.5, 1.4Hz, 16-H), 3.69-3.90 (4H, m, 5-H, 7-H, 13-H, 16-H), 4.11 (2H, t, J 5.9Hz, l'-H₂), 5.75 (IH, s, 2-H), and 7.20 (IH, s, 3"-H); δ_C (CD3OD) 12.3 (C-17), 19.3 (C-15), 20.4 (C-14), 23.4 (C-3'), 28.1 (NCH3), 29.4 (C-2'), 33.0 (C-9), 36.1 (C- 4'), 41.7 (C-8), 43.8 (C-12), 44.0 (C-4), 56.9 (C-10), 61.4 (C-l 1), 64.4 (C-l'), 66.4 (C-16), 70.1 (C-6), 70.8 (C-7), 71.7 (C-13), 76.2 (C-5), 1 12.9 (C-3"), 115.5 (C-6a"), 118.3 (C-2), 135.9 (C-3a"), 137.7 (C-6"), 159.2 (C-3), 168.3 (C-l), 168.6 (C-5"), and 173.8 (C-5'); mlz (El) 612 (M⁺, 6%), 368 (2), and 186 (100). (Found: M+, 612.2168. C₂8H₄QN₂O9S₂ requires M, 612.2175).

Example 6 - (4-Methyl-l,2-dithioIo-[4,3-b]-5(4H)-oxopyrrol-6- y carbamoylmethyl monate A a) Methoxycarbonylmethyl monate A - Sodium monate A (0.61g, 1.67mmol) and methyl bromoacetate (0.32ml, 3.34mmol) were reacted as described in Example 5a to give the title compound as a colourless viscous oil (0.604g, 87%); δjj (CD3OD) (inter alia) 0.95 (3H, d, J 7.0Hz, 17-H₃), 1.20 (3H, d, J 6.4Hz, 14-H₃), 2.20 (3H, d, J 1.1Hz, I5-H3), 3.74 (3H, s, OMe), 4.64 (2H, s, l'-H₂), and 5.84 (IH, s, 2_rH); δ_C (CD3OD) 12.3 (C-17), 19.4 (C-15), 20.3 (C-14), 33.0 (C-9), 41.7 (C-8), 43.7 (C-12), 44.0 (C-4), 52.6 (OCH3), 56.9 (C-10), 61.0 (C-l'), 61.3 (C-l l), 66.4 (C-16), 70.0 (C- 6), 70.7 (C-7), 71.6 (C-13), 76.2 (C-5), 117.1 (C-2), 161.2 (C-3), 167.1 (C-l), and 170.5 (C-2'); mlz (El) 417 (MH+, 2%), 416 ( +, 0.2), 227 (55), 111 (100), and 69 (95); mlz (NH₃ DCI) 434 ( NH₄+, 100%) and 417 (MH+, 10). (Found: M⁺, 416.2041. C₂QH₃₂O9 requires M, 416.2046). b) Carboxymethyl monate A - The title compound was prepared using the method described in Example 5b. The product was a colourless viscous oil (0.130g, 75%); δ_H (CD3OD) (inter alia) 0.95 (3H, d, J 7.1Hz, 17-H₃), 1.20 (3H, d, J 6.4Hz, I4-H3), 2.20 (3H, d, J0.8HZ, 15-H ), 4.60 (2H, s, l'-H₂), and 5.85 (IH, s, 2-H). c) (4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoylmethyl monate A - The title compound was prepared using the method described in Example 5c. The product was an orange solid (0.108g) but was impure. Therefore it was repurified by column chromatography on silica (8g), eluting with distilled methyl acetate, to give the pure product as an orange solid (0.080g, 46%); υ_max (KBr) 3414, 3240, 2927, 1722, 1648, 1615, and 1145cm-¹; ^_ax (EtOH) 389 (ε_m 9,229) and 217nm (21,159); δ_H (CD3OD) 0.94 (3H, d, J 7.1Hz, 17-H₃), 1.20 (3H, d, J 6.4Hz, 14-H₃), 1.36-1.45 (IH, m, 12-H), 1.63-1.75 (2H, m, 9-H₂), 1.92-2.00 (IH, m, 8-H), 2.22 (3H, d, 70.7Hz, 15-H₃), 2.29 (IH, dd, J 14.4, 9.6Hz, 4-H), 2.65-2.75 (2H, m, 4- H, 11-H), 2.81 (IH, td, J 5.7, 2.2Hz, 10-H), 3.35 (3H, d, J 1.4Hz, NCH3), 3.38 (IH, dd, J 8.9, 3.1Hz, 6-H), 3.56 (IH, brd, J 10.7Hz, 16-H), 3.72-3.92 (4H, m, 5-H, 7-H, 13-H, 16-H), 4.72 (2H, s, l'-H₂), 5.91 (IH, s, 2-H), and 7.25 (IH, s, 3"-H); δ (CD3OD) 12.3 (C-17), 19.5 (C-15), 20.3 (C-14), 28.1 (NCH3), 33.0 (C-9), 41.7 (C- 8), 43.8 (C-12), 44.1 (C-4), 56.9 (C-10), 61.3 (C-l l), 62.6 (C-l'), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.2 (C-5), 113.5 (C-3"), 114.5 (C-6a"), 117.2 (C-2), 136.3 (C-3a"), 137.6 (C-6"), 161.6 (C-3), 166.8 (C-l), 168.0 (C-5"), and 168.4 (C-2'); mlz 570 (8%), 326 (3), 244 (70), and 186 (100). (Found: M+, 570.1716. C₂5H₃ N₂O9S₂ requires M, 570.1706).

Example 7 - 10-(4-Methyl-l,2-dithiolo-[4 -b]-5(4H)-oxopyrrol-6- yl)carbamoyIdecyl monate A a) 10-Carboxydecyl monate A - Sodium monate A (0.55g, 1.5mmol) was dissolved in dry dimethylformamide (15ml), and (3,4,5,6-tetrahydropyran-2-yl) 11- bromoundecanoate (1.05g, 3mmol) added. The mixture was heated at 70°C for \ά , and then evaporated in vacuo. The residue was taken up in ethyl acetate, washed with dilute sodium hydrogen carbonate solution, and brine, dried and evaporated to give the crude product. This was purified by column chromatography on silica (36g), eluting with 0-4% methanol in dichloromethane, to give 10-(3,4,5,6-tetrahydropyran- 2-yloxycarbonyl) decyl monate A (0.830g, 90%); δ_H (CD3OD) (inter alia) 0.95 (3H, d, 77.1Hz, I7-H3), 1.20 (3H, d, 76.4Hz, 14-H₃), 2.18 (3H, d, 70.9Hz, I5-H3), 2.36 (2H, t, 77.3Hz, 10'-H₂), 4.06 (2H, t, 76.6Hz, 1 '-H₂), 5.73 (IH, s, 2-H), and 5.92 (IH, brs, 2"-H). This ester (0.77g, 1.26mmol) was dissolved in methanol (20ml) and water (15ml), and glacial acetic acid (2 drops) added. The mixture was stirred for 2³/£h, diluted with saturated sodium hydrogen carbonate solution and washed with ether. The aqueous phase was adjusted to pH 3.4 with 1.5M phosphoric acid, and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated to give the title compound as a colourless viscous oil (0.67g, 100%); υ_max (CH₂C1₂) 2927, 1707, 1648, 1226, and 1152cm^{" 1}; 7^^ (EtOH) 221nm (ε_m 12,620): δ_H (CD3OD) (inter alia) 0.95 (3H, d, 77.1Hz, 17-H ), 1.20 (3H, d, 76.4Hz, 14-H₃), 1.3-1.75 (19H, m, 12-H, 9-H₂, 2'-9'-H₂), 2.18 (3H, d, 7 0.9Hz, I5-H3), 2.27 (2H, t, 77.4Hz, 10^*-H₂), 4.06 (2H, t, 76.5Hz, l'-H₂), and 5.74 (IH, s, 2-H); δ_C (CD3OD) 12.3 (C-17), 19.3 (C-15), 20.3 (C-14), 26.1 (C-9"), 27.1 (C-3'), 29.8 (C-2'), 30.2, 30.3, 30.3, 30.4, 30.5 (C-4', 5', 6', 7', 8'), 33.0 (C-9), 35.0 (C-10"), 41.6 (C-8), 43.7 (C-12), 43.9 (C-4), 56.9 (C-10), 61.3 (C-l l), 64.8 (C-l¹), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.2 (C-5), 118.3 (C-2), 159.0 (C- 3), 168.4 (C-l), and 177.7 (C-l l'); mlz (FAB, thioglycerol) 546 (MNH₄+) and 529 ( H+); (FAB, 3-NOBA/Na) 573 (M + 2Na⁺), and 551 (M + Na+). b) 10-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoyIdecyl monate A - The title compound was prepared using the method described in Example 5c, except that the reaction was stirred for 22h. The product was an orange foam (0.126g, 60%); υ_max (KBr) 3430, 3265, 2927, 1710, 1650, 1602, and 1228cm" ^l; ^_ax (EtOH) 210 (^ 26,208), 312 (3,953), and 391nm (10,542); δ_H (CD3OD) 0.94 (3H, d, 77.1Hz, 17-H₃), 1.20 (3H, d, 76.5Hz, 14-H₃), 1.28-1.75 (19H, m, 12- H, 9-H₂, 2'-9'-H₂), 1.91-2.00 (IH, m, 8-H), 2.18 (3H, d, 7 l.OHz, 15-H₃), 2.21 (IH, dd, 7 8.7, 14.5Hz, 4-H), 2.38 (2H, t, 77.5Hz, 10'-H₂), 2.64 (IH, brd, 7 14.3Hz, 4-H), 2.71 (lH, dd, 77.6, 2.2Hz, 1 1-H), 2.81 (IH, td, 75.8, 2.2Hz, 10-H), 3.35 (3H, s, NCH3), 3.35-3.40 (IH, m, 6-H), 3.56 (IH, brd, 7 1 1.5Hz, 16-H), 3.7-3.9 (4H, m, 5, 7, 13, 16-H), 4.05 (2H, t, 76.5Hz, l'-H₂), 5.73 (IH, s, 2-H), and 7.23 (IH, s, 3"-H); δ_C (CD3OD) 12.3 (C-17), 19.3 (C-15), 20.3 (C-14), 26.7 (C-9'), 27.1 (C-3'), 28.1 (NCH3), 29.8 (C-2"), 30.2-30.5 (C-4', 5', 6', T, 8'), 33.0 (C-9), 36.6 (C-10'), 41.7 (C- 8), 43.7 (C-12), 43.9 (C-4), 56.9 (C-10), 61.3 (C-l l), 64.9 (C-l'), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.2 (C-5), 112.9 (C-3"), 115.4 (C-6a"), 118.4 (C-2), 135.9 (C-3a"), 137.6 (C-6"), 159.0 (C-3), 168.4 (C-l), 168.6 (C-5"), and 174.3 (C- 11'); mlz 696 (M+, 2%), 370 (8), and 186 (100). (Found: M+, 696.3129. C3₄H₅₂N₂O9S₂ requires M, 696.3114).

Example 8 - 4-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrroI-6- yl)carbamoyIbutyl monate C a) 4-MethoxycarbonyIbutyl monate C - Sodium monate C (0.30g, 0.86mmol) and methyl 5-bromovalerate (0.2ml, 1.7mmol) were reacted as decribed in Example 5a except the reaction time was only 15 minutes, to give the title compound as a colourless viscous oil (0.275g, 73%); δ_H (CDCI3) ( ter alia) 0.95 (3H, d, 7 6.84Hz, I7-H3), 1.15 (3H, d, 76.25Hz, 14-H₃), 1.55-1.9 (8H, m, 9-H₂, 2-H₂, 3'-H₂, 12-H, 18-H), 2.2( 3H, s, 15-H₃), 2.55 (IH, d, 7 15.27Hz, 4'-H), 3.6 (3H, s, OMe), 4.05 (2H, t, 76.03Hz, l'-H₂), 5.4-5.6 (2H, m, 10-H, 11-H), 5.7 (IH, s, 2-H); υ_max (KBr) 3441, 2924, 1737, 1715, and 1151cm^{" 1}; 7^^ (EtOH) 219nm (ε_m 15,125); mlz (NH3DCI) 460 (MNH₄+, 11%), 443 ( H+, 15), 232 (30), 115 (100). b) 4-Carboxybutyl monate C - 4-Methoxycarbonylbutyl monate C (0.214g, 0.48mmol) was dissolved in acetone (22ml), and disodium hydrogen phosphate

(0.1M, pH 7, 198ml) added, followed by protease Subtilisin Carlsberg enzyme (0.1 lg). This clear solution was stirred in the dark for 88h, then reduced in vacuo to a small volume, adjusted to pH 2 with dilute hydrochloric acid (5M), saturated with solid sodium chloride, extracted with ethyl acetate (x3), washed with brine, dried and evaporated. The colourless residue was purified by column chromatography on silica (8g), eluting with 0-7% methanol in dichloromethane to give the title compound as a colourless oil (0.162g, 79%); δ_H (CDCI3) (inter alia) 0.95 (3H, d, 76.83Hz, I7-H3), 1.15 (3H, d, 76.27Hz, 14-H₃), 1.6-1.85 (4H, m, 9-H₂, 12-H, 8-H), 2.2 (3H, s, 15- H3), 4.05-4.2 (2H, m, l'-H₂), 5.35-5.5 (2H, m, 10-H, 11-H), and 5.7 (IH, s, 2-H); υ_max (KBr) 3414, 2924, 1715, 1645, 1152cm^{" 1}; ^_ax (EtOH) 221nm (ε_m 13,186); mlz (NH3 DCI) 446 ( NH₄+, 22%), 429 ( H+, 26), 117 (75), 101 (100). c) 4-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yI)carbamoylbutyl monate C - 4-Carboxybutyl monate C (0.1 OOg, 0.23mmol) was dissolved in tetrahydrofuran (12ml) and triethylamine (0.03ml, 0.23mmol) was added, cooled in an ice-bath, and treated with iso-butylchloroformate (0.03ml, 0.23mmol). The mixture was stirred for ^λΛh, then triethylamine (0.05ml, 0.3 lmmol) was added, followed by 6-amino-4-methyl-l,2-dithiolo-[4,3-b]-pyrrol-5(4H)-one hydrochloride (0.062g, 0.28mmol). The mixture was stirred at room temperature for 16h, then diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried and evaporated. The yellow residue was absorbed onto silica (8g), eluting with 0-6% methanol in dichloromethane, to give the title compound as a yellow oil (0.048g, 35%); υ_max (KBr) 3402, 2956, 1712, 1644, 1228, 1050cm-¹; ^ (EtOH) 207 (ε_m 28,704) and 390 (11,146); δ_H (CDCI3) 0.95 (3H, d, 76.83Hz, 17-H₃), 1.15 (3H, d, 76.26Hz, 14-H₃), 1.6-1.9 (4H, , 8-H, 9-H₂, 12-H), 2.05-2.4 (7H, m, 15-H₃, 2'-H₂, 3'-H₂), 2.5-2.6 (3H, m, 4'-H₂, 4-H), 2.8 (IH, d, 77.64Hz, 4-H), 3.35 (3H, s, N-Me), 3.4-3.55 (6H, m, 6-OH, 7-OH, 13-OH, 5-H, 7-H, 13-H), 3.6-3.85 (3H, m, 6- H, 16-H₂), 4.0 (2H, t, 75.75Hz, l'-H₂), 5.3-5.5 (2H, m, 10-H, 11-H), 5.75 (IH, s, 2- H), 6.6 (IH, s, 3"-H), 17.85 (IH, s, N-H); δ_c (CD₃OD) 16.6 (C-17), 19.3 (C-15), 20.3 (C-14), 23.4 (C-3'), 28.1 (NCH3), 29.3 (C-2'), 33.7 (C-9), 36.1 (C-4'), 43.8 (C- 8), 44.1 (C-4), 45.3 (C-12), 64.4 (C-l'), 65.7 (C-16), 69.9 (C-6), 71.6 (C-7), 72.1 (C- 13), 76.1 (C-5), 118.2 (C-2), 129.7 (C-l 1), 135.8 (C-10), 137.6 (C-6"), 159.3 (C-3), 168.3 (C-l), 168.7 (C-5"), 173.8 (C-5'); mlz (El) 596 (M+, 3%), 277 (70), 44 (100). Example 9 - (4-(Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrroI-6- yI)carbamoylmethyI monate C a) Methoxycarbonylmethyl monate C - Methoxycarbonylmethyl monte A (0.36g, 0.87mmol) was dissolved in dry dichloromethane (6ml) in an ice-bath and pyridine (0.4ml, 4.57mmol), and trichloroacetyl chloride (0.4ml, 3.65mmol) were added. The reaction was stirred for Λh, washed with water, saturated sodium hydrogen carbonate solution, citric acid solution (5% in water), saturated sodium chloride solution, dried and evaporated to give a colourless oil (0.72g, 98%). This was added dropwise in dry acetonitrile (5ml) to a mixture of sodium iodide (0.637g, 4.25mmol) and trifluoroacetic anhydride (0.17ml, 1.19mmol) dissolved in acetonitrile (5ml) cooled in an ice-bath. The reaction was left in the dark at 4°C for 54h. Diluted with diethylether, washed with sodium metabisulphite solution, taken to pH 7 with sodium hydroxide solution (10%), washed with saturated sodium hydrogen carbonate solution, water, brine, and dried and evaporated to give a pale yellow oil (0.673g). The crude (6,7,13-tristrichloroacetyl)methoxycarbonylmethyl monate C was dissolved in methanol (4ml) and potassium carbonate (0.332g, 2.4mmol) was added. The reaction was stirred at room temperature for 2h, diluted with ethylacetate, sodium hydrogen carbonate and water, organic layer washed with water, brine, dried and evaporated. The yellow residue was purified by column chromatography over silica (6g) eluting with 0-6% methanol in dichloromethane to give the title compound as a colourless oil (0.108g, 31%); υ_max (KBr) 3415, 2923, 1759, 1725, 1145cm-¹; 7^^ (EtOH) 222 (ε_m 13,669); 293 (403); δ_H (CD3OD) (inter alia) 0.95 (3H, d, 76.93Hz, I7-H3), 1.05 (3H, d, 76.37Hz, 14-H₃), 1.75 (IH, s, 8-H), 3.75 (3H, s, OMe), 4.55 (2H, s, l'-H₂), 5.4 (2H, m, 10-H, 11-H), 5.8 (IH, s, 2-H); mlz (FAB) 401 (MR+, 8%), 307 (34%), 154 (100%). b) Carboxymethyl monate C - The title compound was prepared using the method described in Example 8b. The product was a colourless oil (0.075g, 85%); δ_jj (CD3CI) (inter alia) 0.95 (3H, d, 76.62Hz, 17-H₃), 1.05 (3H, d, 75.93Hz, H-H3), 4.55 (2H, s, l'-H₂), 5.8 (IH, s, 2-H); υ_max (KBr) 3423, 2926, 1725, 1645, 1146cm- 1 c) (4-MethyI-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoylmethyl monate C - The title compound was prepared using the method described in Example 8c The product was a yellow solid (0.056g, 53%); υ_max (KBr) 3380, 2926, 1719, 1646, 1144cm^{" 1}; λmax (EtOH) 216nm (ε_m 23,772), 313 (4,267), 388 (11,520); δ_H (CD OD) 0.95 (3H, d, 76.88Hz, 17-H₃), 1.1 (3H, d, 76.35Hz, 14-H₃), 1.7 (IH, m, 8-H), 2.1 (3H, m, 9-H₂, 12-H), 2.2 (3H, s, 15-H₃), 2.25 (IH, d, 79.6Hz, 4-H), 2.6 (IH, d, 7 14.2Hz, 4"-H), 3.85 (3H, s, N-CH3), 3.45 (IH, d, 7 11.6Hz, 16-H), 3.6 (IH, m, 6-H), 3.7-3.85 (4H, m, 5-H, 7-H, 13-H, 16"-H), 4.65 (2H, s, l'-H₂), 5.35 (2H, m, 10-H, 11-H), 5.9 (IH, s, 2-H), 7.3 (IH, s, 3"-H); δ_C (CD3OD) 16.55 (C-17), 19.54 (C-15), 20.25 (C-14), 28.09 (N-CH3), 33.60 (C-9), 43.59 (C-8), 44.19 (C-4), 45.18 (C-12), 62.54 (C-l"), 65.66 (C-16), 69.83 (C-13), 71.46 (C-6), 72.01 (C-7), 75.96 (C- 5), 114.45 (C-3"), 117.02 (C-2), 129.57 (C-l l), 135.68 (C-10), 136.47 (C-3a"), 137.4 (C-6"), 161.59 (C-3), 166.73 (C-2'), 167.93 (C-l), 168.41 (C-5"); mlz (El) 554 (Λ +, 9%), 244 (51), 49 (100). (Found: M⁺, 554.1766. C₂5H₃₄N₂O₈ requires M 554.1757).

Example 10 - 10-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yI)carbamoyldecyl monate C a) 10-Methoxycarbonyldecyl monate C - The title compound was prepared using the method described in Example 8a. The product was a colourless viscous oil

(0.404g, 79%); δ_H (CD3OD) 0.95 (3H, d, 76.88Hz, 17-H₃), 1.1 (3H, d, 76.36Hz, I4-H3), 2.25 (2H, t, 77.36Hz, 10'-H₂), 3.6 (3H, s, OMe), 4.0 (2H, t, 76.62Hz, 1'- H₂), 5.4 (2H, m, 10-H, 11-H), 5.7 (IH, s, 2-H); λ,^ (EtOH) 218 (ε_m 17,054); ^υmax (KBr) 3448, 2953, 1735, 1712, 1165cm^{" 1}; mlz (Thioglycerol) 544 (MNH₄+, 62%), 527 (MH+, 85%), 293 (100). b) 10-Carboxydecyl monate C - To the above ester (0.158g, 0.3mmol) in tetrahydrofuran (2ml) was added dropwise aqueous sodium hydroxide (3.6ml of 2.5M, 0.9mmol). The reaction was stirred for 2Vih at room temperature, evaporated to small volume in vacuo, taken to pH 2 with hydrochloric acid, extracted with ethyl acetate, dried, evaporated and purified by column chromatography over silica (8g) using 0-20% methanol in dichloromethane as eluent to give the title compound as a colourless oil (0.14g, 70%); δ_H (CD3OD) 0.95 (3H, d, 76.94Hz, 17-H₃), 1.05 (3H, d, 76.35Hz, I4-H3), 4.0 (2H, t, 76.5Hz, l'-H₂), 5.4 (2H, m, 10-H, 11-H), 5.75 (IH, s, 2-H); λmax (EtOH) 219 (ε_m 14,950), 201 (12,714); mlz (El) 513 (MH+, 12%), 266 (33%), 111 (100%). c) 10-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoyldecyl monate C - The title compound was prepared using the method described in Example 8c The product was an orange foam (0.069g, 56%); υ_max (KBr) 3402, 2924, 1711, 1646, 1600, 1149cm"¹; λm_ax (EtOH) 213 (ε_m 25,597), 312 (4,920), 390 (10,520); δ_H (CD₃OD) 0.95 (3H, d, 76.9Hz, 17-H₃), 1.1 (3H, d, 76.36Hz, 14-H₃), 1.2 (12H, s, 3'-H₂, 4'-H₂, 5'-H₂, 6'-H₂, 7'-H₂, 8"-H₂), 1.5 (6H, m, 8-H, 12-H, 2'-H₂, 9'-H₂), 2.05 (6H, m, 4-H, 9-H₂, 15-H₃), 2.3 (2H, t, 77.5Hz, 10'-H₂), 2.6 (IH, d, 7 14.01Hz, 4-H), 3.35 (3H, s, N-Me), 3.4 (IH, d, 77.11Hz, 16-H), 3.5 (IH, m, 6-H), 3.6 (4H, m, 5-H, 7-H, 13-H, 16-H), 4.0 (2H, t, 7 6.51Hz, l'-H₂), 5.4 (2H, m, 10-H, 11-H), 5.7 (IH, s, 2-H), 7.2 (IH, s, 3"-H); δ_C (CD₃OD) 16.65 (C-17), 19.34 (C-15), 20.33 (C-14), 26.73 (C-9'), 27.13 (C-3'), 28.056 (N-CH3), 29.85 (C-2'), 30.19-30.43 (C-4', C-5',C-6', C-7', C-8'), 33.71 (C-9), 36.63 (C-10'), 43.75 (C-8), 44.11 (C-4), 45.32 (C-12), 64.85 (C-l'), 65.74 (C-16), 69.94 (C-6), 71.56 (C-7), 172.13 (C-13), 76.14 (C-5), 112.9 (C-3"), 115.48 (C-6a"), 118.33 (C-2), 129.71 (C-ll), 135.80 (C- 10), 137.65 (C-6"), 159.06 (C-3), 168.41 (C-l), 168.68 (C-5"), 174.32 (C-l l'); mlz (3-NOBA/NA) 703 (MNa+, 7%), 329 (54%), 175 (100%). (Found: M+, 680.3180. C3₄H₅₂N₂O S₂ requires M 680.3165). Example 11 - N-(l^-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)pseudomonamide A The title compound was prepared by the method described in Example 3 from the mixed anhydride of pseudomonic acid A and 6-amino-l,2-dithiolo[4,3-b]pyrrol- 5(4H)one hydrochloride in 33% yield; λ_max (EtOH)/nm 387 (ε_m 10,528) and 302.5 (3220); δ_H (250MHz; CD3OD; Me₄Si) 0.94 (3H, d, 77Hz, 17-H₃), 1.19 (3H, d, 7 6.4Hz, M-H3), 1.37 (9H, m, 4 x CH₂ and 12-H), 1.68 (6H, m, 2 x CH₂ and 9-H₂), 1.94 (IH, m, 8-H), 2.18 (3H, s, 15-H₃), 2.18-2.85 (6H, m, CH₂, 4-H₂, 10-H, 11-H), 3.30-3.90 (6H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂), 4.06 (2H, t, 76.5Hz, OCH₂), 5.73 (H, s, 2-H), 7.07 (IH, s, =J ); δ_C (CD3OD) 10.71 (C-17), 17.74 (C-15), 18.76 (C- 14), 25.12 (C-3'), 25.45 (C-7'), 28.20-28.64 (C-4', 5', 6', 8', 4"), 31.43 (C-9), 35.03 (C-2'), 40.13 (C-8), 42.20 (C-12), 42.36 (C-4), 55.35 (C-10), 59.73 (C-l l), 63.26 (C- 9'), 64.80 (C-16), 66.46 (C-6), 69.18 (C-13), 70.05 (C-7), 74.65 (C-5), 112.02 (C-3"), 114.30 (C-6a"), 116.79 (C-2), 133.54 (C-3a"), 136.38 (C-6"), 157.39 (C-3), 166.61 (C-5"), 166.64 (C-l), 172.79 (C-l'). Example 12 - N-(l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)pseudomonamide C The title compound was prepared by the method described in Example 4 from the mixed anhydride of pseudomonic acid C and 6-amino-l,2-dithiolo[4,3-b]pyrrol- 5(4H)one hydrochloride in 17% yield; υ_max (KBrVcm^{" 1}, 3392 br, 2925, 1643; 7^-^ (EtOH)/nm 387 (ε_m 11,009) and 305.5 (3290); δ_H (250MHz; CD3OD; Me₄Si) 0.99 (3H, d, 77Hz, I7-H3), 1.09 (3H, d, 7 6.4Hz, 14-H₃, 1.37 (9H, m, 4 x CH₂, 12-H), 1.40- 1.85 (7H, m, 2 x CH₂, 8-H, 9-H₂), 2.18 (3H, s, 15-H₃), 2.20-2.73 (4H, m, CH₂, 4-H₂), 3.35-3.90 (6H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂), 4.06 (2H, t, 76.5Hz, OCH₂), 5.40-5.47 (2H, m, 10-H, 11-H), 5.74 (IH, s, 2-H), 7.08 (IH, s, _ "); mlz (ammonia CI) 639 (MH+). Example 13 - 6-(4-MethyI-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yI)carbamoylhexyl monate A a) 6-Carboxyhexyl monate A - The title compound was prepared using the method described in Example 7a. Sodium monate A (0.293g, 0.8mmol) was reacted with (3,4,5,6- tetrahydropyran-2-yl) 7-bromoheptanoate (0.2 lg, 0.7 lmmol) to give 6- (3,4,5,6-tetrahydropyran-2-yloxy-carbonyl)hexyl monate A (0.281g, 71%). This material was deprotected to give the title compound as a colourless oil (0.23 lg, 100%); υ_max (KBr) 3465, 2936, 1710, 1647, and 1153cm-¹; λmax (EtOH) 219nm (εm 14,518); δ_H (CD₃OD) (inter alia) 0.94 (3H, d, 77.0Hz, 17-H₃), 1.20 (3H, d, 7 6.4Hz, I4-H3), 2.17 (3H, d, 70.9Hz, 15-H₃), 2.29 (2H, t, 77.3Hz, 6'-H₂), 4.07 (2H, t, 76.5Hz, l'-H₂), and 5.74 (IH, s, 2-H); δ (CD₃OD) 12.2 (C-17), 19.2 (C-15), 20.3 (C-14), 25.9 (C-5'), 26.8 (C-4'), 29.6 and 29.8 (C-2' and 3'), 32.9 (C-9), 34.8 (C-6^*), 41.7 (C-8), 43.7 (C-12), 43.9 (C-4), 56.9 (C-10), 61.2 (C-l l), 64.7 (C-l'), 66.3 (C- 16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.1 (C-5), 118.3 (C-2), 159.0 (C-3), 168.3 (C-l), and 177.6 (C-T);m/z 472 (M+, 1%), 244 (8), 227 (52), 111 (95), and 69 (100). (Found: M+, 472.2679. C₂ H₄₀O9 requires M, 472.2672). b) 6-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yI)carbamoyIhexyl monate A - The title compound was prepared using the method described in Example 5c, except that the reaction was stirred for 18h. The product was an orange solid (0.135g, 78%); υ_maχ (KBr) 3431, 1654, 1642, 1601, and 1228cm-¹; λmax (EtOH) 213 (ε_m 24,780), 312 (4,053), and 389nm (10,385); δ_H(CD₃OD) 0.96 (3H, d, 77.1Hz, I7-H3), 1.22 (3H, d, 76.4Hz, 14-H₃), 1.37-1.49 (5H, m, 12-H, 3'-H₂, 4'- H₂), 1.62-1.78 (6H, m, 9-H₂, 2'-H₂, 5'-H₂), 1.92-2.01 (IH, m, 8-H), 2.19 (3H, s, 15- H₃), 2.24 (IH, dd, 7 14.4, 9.7Hz, 4-H), 2.42 (2H, t, 77.4Hz, 6'-H₂), 2.65 (IH, br.d, 7 14.1Hz, 4-H), 2.73 (IH, dd, 77.6, 1.9Hz, 11-H), 2.83 (IH, dt, 75.6, 1.9Hz, 10-H), 3.36 (3H, s, NCH3), 3.36-3.42 (IH, m, 6-H), 3.58 (IH, br.d, 7 11.3Hz, 16-H), 3.72- 3.93 (4H, m, 5,7,13, 16-H), 4.09 (2H, t, 76.5Hz, 1^*-H₂), 5.75 (IH, s, 2-H), and 7.24 (IH, s, 3"-H); δ_C (CD3OD) 12.3 (C-17), 19.3 (C-15), 20.3 (C-14), 26.6 (C-5'), 26.9 (C-3'), 28.1 (NCH3), 29.6 (C-4'), 29.8 (C-2^*), 33.0 (C-9), 36.5 (C-6'), 41.7 (C-8), 43.8 (C-12), 43.9 (C-4), 56.9 (C-10), 61.3 (C-l l), 64.7 (C-l'), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.2 (C-5), 112.9 (C-3"), 115.4 (C-6a"), 118.3 (C-2), 135.9 (C-3a"), 137.6 (C-6"), 159.1 (C-3), 168.3 (C-l), 168.6 (C-5"), and 174.1 (C-7'); mlz 640 (M⁺, 4%), 396 (2), and 186 (100). (Found: M⁺, 640, 2487. C₃oH₄₄N₂O₉S₂ requires M, 640.2488). Example 14 - 6-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yl)carbamoyIhexyl monate C a) 6-MethoxycarbonyIhexyl monate A - Sodium monate A (1.281g, 3.5mmol) and methyl 7-bromoheptanoate (1.55g, 7mmol) were reacted, for -y£h, as described in Example 5a to give the title compound as a colourless oil (1.664g, 98%); δ_jj (CD₃OD) ( ter alia) 0.95 (3H, d, 77.0Hz, 17-H₃), 1.20 (3H, d, J 6.4Hz, 14-H ), 2.18 (3H, d, 70.9Hz, 15-H₃), 2.33 (2H, d, 77.4Hz, 6'-H₂), 3.65 (3H, s, CO CH₃),

4.07 (2H, t, 76.5Hz, l'-H₂), and 5.74 (IH, s, 2-H); mlz 486 (M⁺, 0.1%), 468 (0.3), 242 (12), and 111 (100). (Found: M⁺, 486.2830. C₂₅H₄₂O9 requires M, 486.2829). b) 6-MethoxycarbonyIhexyI monate C - The title compound was prepared using the method described in Example 9a. The product was a pale yellow oil (1.380g, 93%); υ_maχ (KBr) 3459, 2930, 1737, 1715, and 1151cm"¹; λmax (EtOH) 220nm (ε_m 13,942); δ_H (CD3OD) (inter alia) 0.99 (3H, d, 76.9Hz, 17-H₃), 1.09 (3H, d, 76.4Hz, 14-H₃), 2.18 (3H, d, 70.7Hz, 15-H₃), 2.33 (2H, d, 77.4Hz, 6'-H₂), 2.66 (IH, br.d, 7 14.3Hz, 4-H), 3.65 (3H, s, CO₂CH₃), 4.07 (2H, t, 76.5Hz, l'-H₂), 5.36-5.52 (2H, m, 10,11-H), and 5.74 (IH, s, 2-H); δ_C (CD3OD) 16.6 (C-17), 19.3 (C-15), 20.3 (C-14), 25.9 (C-5^*), 26.7 (C-4'), 29.6 (C-3'), 29.7 (C-2'), 33.6 (C-9), 34.7 (C-6'), 43.7 (C-8), 44.1 (C-4), 45.2 (C-12), 52.0 (OCH3), 64.7 (C-l'), 65.7 (C-16), 69.9 (C-6), 71.5 (C-7), 72.1 (C-13), 76.1 (C-5), 118.2 (C-2), 129.6 (C-ll), 135.7 (C- 10), 159.1 (C-3), 168.3 (C-l), and 175.9 (C-7'); mlz 471 (MH+, 8%), 453 (6), 111 (97), 95 (93), and 82 (100); mlz (NH3, DCI) 488 (MNH₄+, 72%) and 471 (MΗ+, 100). c) 6-Carboxylhexyl monate C - The title compound was prepared using the method described in Example 10b. The product was a colourless oil (0.50g, 69%); δ_H (CD3OD) (inter alia) 0.99 (3H, d, 76.9Hz, 17-H₃), 1.09 (3H, d, 76.4Hz, 14-H₃), 2.18 (3H, s, I5-H3), 2.29 (2H, t, 77.4Hz, 6'-H₂), 2.66 (IH, br.d, 7 14.4Hz, 4-H), 4.07 (2H, d, 76.5Hz, l'-H₂), 5.39-5.56 (2H, m, 10, 11-H), and 5.74 (IH, s, 2-H); mlz 457 ( H+, 3%), 456 (0.1), 111 (98), 95 (95), and 82 (100). (Found: M+, 456.2728. C₂₄H₄QO requires M, 456.2723). d) 6-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrroI-6-yl)carbamoylhexyl monate C - The title compound was prepared using the method described in Example 5c, except that the reaction was stirred for 17h. The product was an orange foam (0.106g, 46%); υ_max (KBr) 3415, 2928, 1705, 1602, and 1229cm-¹; 7^.^ (EtOH) 206 (ε_m 24,293), 311 (4,007), and 391nm (10,549); δ_H (CD3OD) 0.99 (3H, t, 76.9Hz, I7-H3), 1.09 (3H, t, 76.4Hz, 14-H₃), 1.36-1.48 (4H, m, 3'-H₂, 4'-H₂), 1.61-1.82 (5H, m, 12-H, 2^*-H₂, 5'-H₂), 2.08-2.28 (7H, m, 8-H, 9-H₂, 4-H, 15-H₃), 2.39 (2H, t, 77.4Hz, 6'-H₂), 2.65 (IH, br.d, 7 14.4Hz, 4-H), 3.35 (3H, s, NCH3), 3.3- 3.4 (IH, m, 6-H), 3.50 (IH, br.d, 7 11.2Hz, 16-H), 3.54-3.86 (4H, m, 5,7,13, 16-H),

4.08 (2H, t, 76.5Hz, l'-H₂), 5.41-5.49 (2H, m, 10-H, 11-H), 5.74 (IH, s, 2-H), and 7.25 (IH, s, 3"-H); δ_C (CD3OD) 16.6 (C-17), 19.3 (C-15), 20.3 (C-14), 26.6 (C-5"),

26.8 (C-4'), 28.1 (NCH3), 29.6 (C-3'), 29.8 (C-2'), 33.7 (C-9), 36.5 (C-6'), 43.7 (C-8), 44.1 (C-4), 45.3 (C-12), 64.7 (C-l'), 65.7 (C-16), 69.9 (C-6), 71.5 (C-7), 72.1 (C-13), 76.1 (C-5), 112.9 (C-3"), 115.4 (C-6a"), 118.3 (C-2), 129.7 (C-l l), 135.8 (C-10), 135.9 (C-3a"), 137.6 (C-6"), 159.1 (C-3), 168.4 (C-l), 168.6 (C-5"), and 174.1 (C-7'); mlz 624 (M+, 8%) and 186 (100). (Found: +, 624.2515. C3θH₄₄N₂OgS₂ requires M, 624.2539).

Example 15 - 9-(4-MethyM,2-dithiolo-[4,3-b]-5(4H)-oxopyrroI-6- yI)carbamoylnonyl monate A a) 9-CarboxynonyI monate A - The title compound was prepared using the method described in Example 7a. Sodium monate A (0.366g, lmol) was reacted with (3,4,5,6-tetrahydropyran-2-yl)10-bromodecanoate (0.402g, 1.2mmol) to give 9- (3,4,5,6-tetrahydropyran-2-yloxycarbonyl)nonyl monate A (0.5 lOg, 85%). This material was deprotected to give the title compound as a colourless oil (0.320g, 75%); δ_H (CD₃OD) (inter alia) 0.94 (3H, d, 77.0Hz, 17-H₃), 1.20 (3H, d, 76.4Hz, 14-H₃), 2.18 (3H, d, 70.9Hz, 15-H₃), 2.27 (2H, d, 77.4Hz, 9'-H₂), 4.07 (2H, d, 76.5Hz, 1'- H₂), and 5.74 (IH, s, 2-H); mlz (FAB, thioglycerol) 532 (MNH₄+) and 515 ( H+). b) 9-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoyInonyl monate A - The title compound was prepared using the method described in Example 5c, except that the reaction was stirred for 21h. The product was an orange foam (0.202g, 74%); υ_max (KBr) 3422, 2926, 1708, 1648, 1603, and 1228cm"¹; ^^ (EtOH) 214 (ε_m 22,720), 31 1 (3,873), and 391nm (10,327); δ_H (CD3OD) 0.94 (3H, d, 7.0Hz, 17-H₃), 1.19 (3H, d, 76.5Hz, 14-H₃), 1.30-1.48 (HH, m, 12-H, 3'- 7'-H₂), 1.57-1.73 (6H, m, 9-H₂, 2'-H₂, 8'-H₂), 1.9-2.0 (IH, m, 8-H), 2.17 (3H, d, 7 0.9Hz, I5-H3), 2.21 (IH, dd, 79.6, 14.5Hz, 4-H), 2.38 (2H, t, 7.4Hz, 9'-H₂), 2.64 (IH, br d, 7 14.5Hz, 4-H), 2.71 (lH, dd, 77.6, 2.2Hz, 11-H), 2.81 (lH, dt, 75.8, 2.2Hz, 10-H), 3.3-3.4 (IH, m, 6-H), 3.35 (3H, s, NCH3), 3.56 (IH, br.d, 7 11.6Hz, 16-H), 3.67-3.90 (4H, m, 5,7,13, 16-H), 4.05 (2H, t, 76.5Hz, l'-H₂), 5.73 (IH, s, 2- H), and 7.24 (IH, s, 3"-H); δ_C (CD3OD) 12.3 (C-17), 19.3 (C-15), 20.3 (C-14), 26.7 (C-8"), 27.0 (C-3¹), 28.1 (NCH3), 29.8 (C-2'), 30.2-30.4 (C-4", 5', 6', 7"), 33.0 (C-9), 36.6 (C-9^*), 41.7 (C-8), 43.7 (C-12), 43.9 (C-4), 56.9 (C-10), 61.3 (C-l l), 64.8 (C- 1'), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.2 (C-5), 113.0 (C-3"), 115.4 (C-6a"), 118.3 (C-2), 135.9 (C-3a"), 137.6 (C-6"), 159.0 (C-3), 168.4 (C-l), 168.6 (C-5"), and 174.3 (C-10'); mlz 682 (M⁺, 1%) and 188 (100). (Found: M+, 682.2963. C33H₅₀N₂O9S requires M, 682.2958).

Example 16 - 9-(4-MethyM,2-dithiolo-[4,3-b]-5(4H)-oxopyrroI-6- yI)carbamoylnonyl monate C a) 9-Methoxycarbonylnonyl monate A - Sodium monate A (1.281g, 3.5mmol) and methyl 10-bromodecanoate (1.834g, 7mmol) were reacted, for 40 minutes, as described in Example 5a to give the title compound as a colourless oil (1.300g, 70%); δ_H (CD3OD) (inter alia) 0.94 (3H, d, 77.1Hz, 17-H₃), 1.20 (3H, d, 76.5Hz, 14-H₃), 2.18 (3H, d, 7 1.1Hz, 15-H ), 2.31 (2H, t, 77.4Hz, 9'-H₂), 3.64 (3H, s, CO₂CH₃), 4.06 (2H, t, 76.5Hz, l'-H₂), and 5.74 (IH, s, 2-H); mlz 528 ( +, 0.1%), 510 (0.3), 284 (25), 227 (70), and 111 (100). (Found: M⁺, 528.3301. C₂gH₄₈O₉ requires M, 528.3298). b) 9-MethoxycarbonyInonyl monate C - The title compound was prepared using the method described in Example 9a. The product was a pale yellow oil (1.400g, 96%); δ_H (CD₃OD) (inter alia) 0.99 (3H, d, 7 6.9Hz, 17-H₃), 1.09 (3H, d, 7 6.4Hz, 14-H ), 2.18 (3H, d, 7 1.1Hz, 15-H ), 2.31 (2H, t, 77.4Hz, 9'-H₂), 2.66 (IH, br.d, 7 14.4Hz, 4-H), 3.64 (3H, s, CO₂CH₃), 4.07 (2H, d, 76.6Hz, l'-H₂), 5.36-5.52 (2H, m, 10-H, 11-H), and 5.74 (IH, s, 2-H); δ_C (CD3OD) 16.6 (C-17), 19.3 (C-15), 20.3 (C-14), 26.0 (C-8'), 27.0 (C-2'), 29.8-30.4 (C-3', 4', 5', 6', 7'), 33.7 (C-9), 34.8 (C-9'), 43.7 (C-8), 44.0 (C-4), 45.3 (C-12), 52.0 (OCH3), 64.8 (C-l'), 65.7 (C-16), 69.9 (C-6), 71.5 (C-7), 72.1 (C-13), 76.1 (C-5), 118.3 (C-2), 129.7 (C-l l), 135.8 (C- 10), 159.1 (C-3), 168.4 (C-l), and 176.0 (C-10'); mlz 513 (MR+, 0.4%), 512 (M⁺, 0.2%), 494 (0.5), 284 (15), 111 (82), and 55 (100). (Found: M+, 512.3352. ^C28^H48°8 requires M, 512.3349). c) 9-Carboxynonyl monate C - The title compound was prepared using the method described in Example 10b. The product was a colourless oil (0.493g, 61%); δ_H (CD3OD) (inter alia) 0.99 (3H, d, 77.3Hz, 17-H₃), 1.09 (3H, d, 76.5Hz, 14-H₃), 2.18 (3H, d, 7 1.1Hz, 15-H₃), 2.27 (2H, t, 77.4Hz, 9'-H₂), 2.66 (IH, br.d, 7 14.4Hz, 4-H), 4.07 (2H, t, 76.5Hz, l'-H₂), 5.39-5.51 (2H, m, 10-H, 11-H), and 5.74 (IH, s, 2- H); mlz (NH3, DCI) 516 ( NH₄+, 5%), 499 ( H+, 40%), and 74 (100). d) 9-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yI)carbamoylnonyl monate C - The title compound was prepared using the method described in Example 5c, except that the reaction was stirred for 18h. The product was an orange foam (0.178g, 70%); υ_maχ (KBr) 3418, 2925, 1709, 1647, 1602, and 1228cm-¹; λmax (EtOH) 204 (ε_m 25,069), 214 (24,767), 312 (4,289), and 390nm (10,632); δ_H (CD3OD) 0.95 (3H, d, 76.9Hz, 17-H₃), 1.05 (3H, d, 76.3Hz, 14-H₃), 1.19-1.39 (10H, m, 3'-7^*-H₂), 1.50-1.64 (4H, m, 2'-H₂, 8'-H₂), 1.66-1.76 (IH, m, 12-H), 2.03- 2.23 (7H, m, 8-H, 9-H₂, 4-H, 15-H₃), 2.34 (2H, t, 77.4Hz, 9'-H₂), 2.62 (IH, br.d, 7 14.3Hz, 4-H), 3.29 (3H, s, NCH3), 3.25-3.35 (IH, m, 6-H), 3.46 (IH, br.d, 7 11.3Hz, 16-H), 3.52-3.81 (4H, m, 5, 7, 13, 16-H), 4.01 (2H, d, 76.5Hz, l'-H₂), 5.32-5.46 (2H, m, 10-H, 11-H), 5.70 (IH, s, 2-H), and 7.17 (IH, s, 3"-H); δ_C (CD3OD) 16.6 (C-17), 19.3 (C-15), 20.3 (C-14), 26.7 (C-8'), 27.0 (C-2'), 28.1 (NCH3), 29.8-30.4 (C-3'-C-7'), 33.6 (C-9), 36.6 (C-9"), 43.7 (C-8), 44.0 (C-4), 45.2 (C-12), 64.8 (C-l'), 65.7 (C-16), 69.9 (C-6), 71.5 (C-7), 72.1 (C-13), 76.1 (C-5), 112.9 (C-3"), 115.4 (C- 6a"), 118.3 (C-2), 129.6 (C-l l), 135.7 (C-10), 135.9 (C-3a"), 137.6 (C-6"), 159.0 (C- 3), 168.4 (C-l), 168.6 (C-5"), and 174.2 (C-10'); mlz 666 (M⁺, 5%), 356 (9), and 186 (100). (Found: M⁺, 666.3014. C33H₅₀N₂O₈S₂ requires M, 666.3009). Example 17 - 8-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)7- oxacarbamoyloctyl monate A a) Methyl-5-bromopent-l-oxy acetate - Methyl glycolate (1.24ml, 16mmol) was dissolved in dry dimethylformamide (8ml) and sodium hydride (60%) (0.685g , 17.6mmol) added. The mixture was heated at 40²C for 2h, and then dibromohexane (4.9ml, 32mmol) added. The mixture was heated at 40°C for 2V£h. The mixture was diluted with diethyl ether, washed with water and brine, dried and evaporated. The colourless residue was purified by column chromatography on silica (26g), eluting with 0-7% ethyl acetate in hexane, to give the title compound as a colourless oil (1.19g, 29%); δ_H (CDCI3) 1.35-1.55 (4H, m, 2 x CH₂), 1.57-1.70(2H, m, CH₂CH₂,CH₂Br), 1.83-1.95 (2H, m, CH₂CH₂O, 3.4 (2H, t, 76.8 Hz, CH₂Br), 3.51 (2Η, t, 76.4Hz, CH₂O), 3.75 (3H, s, CH3O), 4.10 (2H, s, COCH₂O). b) 8-Methoxycarbonyl-7-oxaoctyl monate A - Sodium monate A (1.72g,

4.7mmol) was dissolved in dry dimethylformamide (40ml), and methyl-5-bromopent- 1-oxy acetate (1.19g, 4.7mmol) added. The mixture was heated at 70°c for 50 minutes, cooled and diluted with ethyl acetate. The solution was washed with water, sodium hydrogen carbonate solution, brine, dried and evaporated. The residue was purified by column chromatography on silica (40g), eluting with 0-8% methanol in dichloromethane, to give the title compound as a colourless oil (1.638g, 68%);υ_max (KBr) 3460,2959, 1754, 1454, 1148cm^{" 1}; λm_ax(EtOΗ) 219.5nm (ε_m 15,380); δ_H (CD3OD) 0.95 (3H, d, 77.0Hz, 17-H₃), 1.25 (3H, d, 76.5Hz, 14- H3), 1.38-1.52 (5H, m, 12H, 4'-H₂, 3'-H₂), 1.58-1.75 (6H, m, 9-H₂, 5'-H₂, 2'-H₂), 1.90-2.05 (IH, m, 8-H), 2.20 (3H, s, 15-H₃), 2.25 (IH, br.d, 79.6Hz, 4"-H), 2.67 (IH, br.d, 7 14.5Hz, 4-H), 2.75 (IH, dd, 72.3, 5.4Hz, 11-H), 2.32 (IH, dt, 73.5, 5.6Hz, 10-H), 3.40 (IH, d, 7 3.1Hz, 6-H), 3.55 (2H, t, 76.4Hz, 6'-H₂), 3.60 (IH, s, 16"-H), 3.70-3.90 (7H, m, 5,7,13,16H, O-CH3), 4.10-4.50 (4H, m, l'-H₂, 8'-H₂), 5.75 (IH, s, 2H); ; mlz (NH3DCI) 517 ( H+, 12%), 327 (100%); δ_C (CD3OD) 12.3 (C-17), 19.3 (C-15), 20.4 (C-14), 26.7 (C-4'), 26.9 (C-3'), 29.8 (C-2'), 30.5 (C-5'), 33.0 (C-9), 41.7 (C-8), 43.8 (C-12), 44.0 (C-4), 52.2 (C-18), 56.9 (C-10), 61.3 (C- 11), 64.7 (C-6¹), 66.4 (C-16), 68.8 (C-3"), 70.0 (C-6), 70.7 (C-13), 71.6 (C-7), 72.7 (C-8'), 76.2 (C-5), 118.3 (C-2), 159.0 (C-3), 166.4 (C-9'), 172.9 (C-l). c) 8-Carboxy-7-oxaoctyI monate A - 8-Methoxycarbonyl-7-oxaoctyl monate A (0.40g, 0.78mmol) was dissolved in acetone (40ml), and disodium hydrogen phosphate buffer solution (0.1M, pH 7, 360ml) added, followed by protease Subtilisin Carlsberg enzyme (0.160g). This clear solution was stirred for lOOh, then reduced in vacuo to a small volume, extracted with ethyl acetate, adjusted the aqueous layer to pH 3.5 with dilute phosphonic acid. The mixture was filtered through celite, the phases separated, and the aqueous extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated to give the title compound as a colourless viscous oil (0.223g, 57%); υ_maχ 3448, 2930, 1712, 1455, 1149cm^{" 1}; λmax (EtOH) 219nm (ε_m 14,059); δ_H (CD3OD) 0.95 (3H, d, 77.1Hz), 1.25 (3H, d, 76.4Hz, 14-H₃), 1.45-1.55 (5H, m, 12-H, 4^*-H₂, 3'-H₂), 1.58-1.75 (6H, m, 9-H₂, 2'-H₂, 5'-H₂), 1.9-2.05 (IH, m, 8-H), 2.19 (3H, s, 15-H₃), 2.25 (IH, br.d, 7 9.7Hz, 4"-H), 2.65 (IH, br.d, 7 14.2Hz, 4-H), 2.75 (IH, dd, 72.3, 5.4Hz, 11-H), 2.85 (IH, d, t, 72.1Hz, 10-H), 3.48 (IH, d, 73.1Hz, 6-H), 3.55 (2H, t, 76.5Hz, 6'-H₂), 3.60 (IH, s, 16"-H), 3.70-3.92 (4H, , 5,7,13, 16-H), 4.05-4.15 (4H, m, l'-H₂, 8'- H₂), 5.75 (IH, s, 2-H); /z (NH₃ DCI) 503( i+, 14%), 96 (100%). d) 8-(4-Methyl-l,2-dithiolo-[4 -b]-5(4H)-oxopyrrol-6-yI)7- oxacarbamoyloctyl monate A - 8-Carboxy-7-oxaoctyl monate A (0.10g, 0.2mmol) was dissolved in dry tetrahydrofuran (4ml) and triethylamine (0.03ml, 0.22mmol), cooled in an ice-bath, and treated with isobutylchloroformate (0.025ml, 0.2mmol). The mixture was stirred for lh at room temperature then triethylamine (0.036ml, 0.25mmol) was added, followed by 6-amino-4-methyl-l,2-dithiolo-[4,3-b]-pyrrol- 5(4H)-one hydrochloride (0.06g, 0.24mmol). The reaction was stirred at room temperature overnight, diluted with ethyl acetate, washed with aqueous solution chloride, dried and evaporated. The yellow residue was absorbed onto silica and purified by column chromatography on silica (3g), eluting with 0-5% methanol in dichloromethane, to give the title compound as a yellow oil (0.107g, 80%);υ_maχ (KBr) 3438, 2925, 1654, 1149cm-¹;λ_maχ (EtOH) 209.5nm (ε_m 22,550); δ_H (CD₃OD) 0.95 (3H, d, 77.1Hz, 17-H₃), 1.25 (3H, d, 76.4Hz, 14-H₃), 1.38-1.55 (5H, m, 12-H, 3'-H₂, 4'-H₂), 1.65-1.78 (6H, m, 9-H₂, 2'-H₂, 5'-H₂), 1.90-2.05 (IH, m, 8- H), 2.20 (3H, s, 15-H₃), 2.25 (IH, br.d, 79.8Hz, 4"-H), 2.65 (IH, br.d, 7 14.5Hz, 4- H), 2.70-2.75 (IH, m, 1 1-H), 2.78-2.85 (IH, m, 10-H), 3.48 (4H, m, 6-H, N-Me), 3.55 (IH, s, 16"-H), 3.65 (2H, t, 76.3Hz, 6'-H₂), 3.70-3.91 (4H, m, 5,7,13, 16-H), 4.05-4.15 (4H, m, l'-H₂, 8'-H₂), 5.75 (IH, s, 2-H), 7.45 (IH, s, S-CH-C). Example 18: 6-(l,2-Dithiolo-[4,3-b]-5(4Η)-oxopyrrol-6-yl)carbamoyIhexyl monate C - The title compound was prepared as in Example 5c except that the reaction was stirred for 18h. The product was an orange gum (44mg, 27%); v_maχ (KBr) 3420, 3067, 1645, 1595, 1527, 1225, 1150 and 1050cm^{" 1}; λmax (EtOH) 216 (ε_m 21,049), 299.5 (3,437), and 389.5 (11,169); δ_H (CD3OD) 0.99 (3H, d, 7 6.9Hz, I7-H3), 1.09 (3H, d, 7 6.3Hz, 14-H₃), 1.37-1.46 (4H, m, 3'-, 4'-H₂), 1.6-1.83 (5H, m, 8-H, 2'-, 5'-H₂), 2.08-2.29 (7H, m, 4-H, 9-H₂, 12-H, 15-H₃), 2.39 (3H, t, 7

7.3Hz, 6'-H₂), 2.64 (IH, br.d, 7 16.8Hz, 4-H), 3.3 (6H, partially obscured by solvent peak), 3.50 (IH, d, 7 10.7Hz, 16-H), 3.60 (IH, m, 13-H), 3.72 (IH, dt, 7 2.4 and 9.4Hz, 5-H), 3.75 (IH, dd, 7 2.5 and 7.9Hz, 16-H), 3.83 (IH, t, 7 3Hz, 7-H), 4.08 (2H, t, 7 6.5Hz, l'-H₂), 5.4-5.5 (2H, m, 10H, 11H), 5.74 (IH, s, 2-H) and 7.05 (IH, s, 3"-H); mlz 610 (M⁺, 1%), 105 (62) and 213 (100). (Found +, 610.2380.

^C29^H42^N2°8^S2 requires 610.2383).

Example 19: 7-(l,2-Dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoylheptyl monate C - The title compound was prepared using the method described in Example 5c. The product was obtained in 56% yield as a yellow foam; λm^ (EtOH) 387 (ε_m 11,250) and 303nm (3,471); δπ (CD₃OD) 1.01 (3H, d, 7 6.9Hz, 17-H₃), 1.11 (3H, d, 7 6.4Hz, 14-H₃), 1.41 (6H, br.s, (CH₂) ), 1.60-1.85 (5H, , 12-H, (CH₂)₂), 2.1-2.3 (7H, m, 15-H₃, 8-H, 9-H₂, 4-H), 2.40 (2H, t, 7 7.4Hz, CH₂), 2.67 (lH, d, 7 14.2Hz, 4-H), 3.37 (lH, dd, 7 9.2 and 3.2Hz, 6-H), 3.52 (IH, d, 7 11.2Hz, 16-H), 3.57-3.86 (4H, m, 5-H, 7-H, 13-H, 16-H), 4.09 (2H, t, 7 6.5Hz, CH₂), 5.38- 5.53 (2H, m, 10-H, 11-H), 5.76 (IH, s, 2-H), 7.08 (IH, s,

₂O

₈S requires M, 624.2539).

Example 20: 7-(l,2-Dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yI)carbamoylheptyl monate A - The title compound was prepared using the method described in Example 5c. The product was obtained in 45% yield as a yellow foam; λ ^

(EtOH) 390nm (ε_m 8,326); δ_H (CD3OD) 0.96 (3H, d, 7 7.1Hz, 17-H₃), 1.21 (3H, d, J 6.4Hz, I4-H3), 1.41 (7H, bs, 12-H, (CH₂)₃), 1.60-1.77 (6H, m, 9-H₂, (CH₂)₂), 1.90-2.03 (IH, , 8-H), 2.16-2.30 (4H, s + , 15-H₃, 4-H), 2.40 (2H, t, J 7.5Hz, CH₂), 2.65 (lH, d, 7 14.3Hz, 4-H), 2.72 (IH, dd, 7 7.6 and 2.1Hz, 11-H), 2.74-2.88 (IH, m, 10-H), 3.37 (IH, dd, 7 8.9 and 3.1Hz, 6-H), 3.57 (IH, d, 7 11.4Hz, 16-H), 3.70-3.90 (4H, m, 5-H, 7-H, 13-H, 16-H), 4.09 (2H, t, 7 6.5Hz, CH₂), 5.75 (IH, br.s, 2-H), 7.09 (IH, s, -= ); (Found: M+, 640.2497. C₃₀H₄₄N O₉S₂ requires M, 640.2488).

Example 21 - Pharmaceutical Formulation Compound of formula (I) 2% polyethylene glycol 400 59 polyethylene glycol 4000 39