EP0699203A1 - Derives de thiomarinol, procede et intermediaires pour leur preparation et leur utilisation comme microbicides et herbicides - Google Patents

Derives de thiomarinol, procede et intermediaires pour leur preparation et leur utilisation comme microbicides et herbicides

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Publication number
EP0699203A1
EP0699203A1 EP94917636A EP94917636A EP0699203A1 EP 0699203 A1 EP0699203 A1 EP 0699203A1 EP 94917636 A EP94917636 A EP 94917636A EP 94917636 A EP94917636 A EP 94917636A EP 0699203 A1 EP0699203 A1 EP 0699203A1
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EP
European Patent Office
Prior art keywords
compound
formula
methyl
hydroxy
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94917636A
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German (de)
English (en)
Inventor
Keith Howard Baggaley
Nigel John Perryman Broom
Pamela Brown
Peter John O'hanlon
Neal Frederick Osborne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0699203A1 publication Critical patent/EP0699203A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • This invention relates to a novel class of compounds having antibacterial, antimycoplasmal and antifungal activity, to processes for their preparation and to 5 thpir 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.
  • microorganism Pseudomonas fluorescens 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):
  • 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
  • Pseudomonic acid C has the structure (C):
  • R is hydrogen or hydroxyl is produced by an Aheromonas 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 ⁇ -, based on spectroscopic studies of a cyclised derivative.
  • 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.
  • A* is a group of atoms for linking C(O)O with CONR ⁇ ;
  • Ri and R ⁇ which may be the same or different, is each selected from hydrogen or (C ⁇ _6)alkyl, (C3_7)cycloalkyl, (C2-6)alkenyl, ar yU aryl(C ⁇ _4)alkyl or heterocyclyl, each of which may be optionally substituted;
  • X is an epoxy moiety or an E-double bond moiety:
  • 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)(R )] m A2; [C(R3)(R4)] m A2 A 3 ; [C(R3)(R4)] mA 3; and [C(R3)(R4)] m A3 A 2; 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 (C 1 . 6 )al yl;
  • A- 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 (Cj.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: SO 2 NR; NRSO2; CONRSO 2 ; SO 2 NRCO and phenyloxy; in which R is hydrogen or (C ⁇ _6)alkyl.
  • R s hydrogen or (Cj.gjalkyl, preferably hydrogen.
  • R ⁇ is hydrogen or (C j .gialkyl, for instance methyl, preferably hydrogen.
  • A* is an optionally substituted polymethylene chain (CH 2 ) 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 ⁇ 6)alkyl, in particular on the ⁇ -carbon (carbon attached to carboxy).
  • the carbon adjacent to the tetrahydropyranyl ring and bearing a hydroxyl group is a chiral centre and may have either absolute configuration.
  • the present invention covers both possibilities.
  • the hydroxyl group has the same configuration as that in thiomarinol.
  • Suitable substituents for a (Cj.gjalkyl, (C3-7)cycloalkyl or (C 2 _6)alkenyl group or a polyalkylene chain include for example, halogen, cyano, azido, nitro, carboxy, (C ⁇ _6)alkoxycarbonyl, carbamoyl, mono- or di-(C ⁇ _6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C ⁇ _6)alkylsulphamoyl, amino, mono- or di-(C * .6)alkylamino, acylamino, ureido, (C]_6)alkoxycarbonylamino,
  • 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, (C ⁇ _5)alkyl, phenyl, (C ] _6)alkoxy, halo(C ⁇ _6)alkyl, hydroxy, amino, mono- or di-(C ⁇ _6)alkylamino, acylamino, nitro, carboxy, (C ⁇ _6)alkoxycarbonyl, (C i _6)-alkoxycarbonyl(C ⁇ .
  • 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.
  • 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.
  • 'halogen' refers to fluorine, chlorine, bromine or iodine.
  • 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.
  • solvent of crystallisation may be present in the crystalline product.
  • This invention includes within its scope such solvates.
  • 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.
  • compounds of formula (I) are esters of 4-hydroxy analogues 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,3S,4S,5S)-2,3-epoxy-5- hydroxy-4-methylhexylJ-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-[(4R,5S)-5- hydroxy-4-methylhex-2(E)-enyl]-3,4-dihydroxytetrahydropyran-2-yl ⁇ -3-methylbut-
  • compositions which comprise 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.
  • 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
  • almond oil fractionated coconut oil, oily esters, glycerine, propylene glyco
  • 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.
  • 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.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • 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 die sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.
  • 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.
  • a suitable liquid carrier such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.
  • 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 hypro ellose may also be included.
  • 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.
  • compositions for intramammary treatment of mammary disorders in animals 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.
  • 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.
  • the drug may be administered as part of the total dietary intake of a non-human animal.
  • 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 die 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.
  • a concentration of the drug in the drinking water of about 5-500 mg/ml, for example 5-200 mg/ml, is suitable.
  • the compounds of this invention are of use in therapy, in particular for treating bacterial, mycoplasma and/or fungal infections in animals, including humans.
  • the 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. influenzae 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 DCO, Legionella, for instance L. pneumophila; Pseudomonas, for instance P. aeruginosa Dalgleish and Enterobacter, for instance Ent.faecelis I.
  • Bacteroides for instance B.fragilis BC1, Haemophilus, for instance H. influenzae Ql
  • Moraxella for instance M. catarrhalis 1502
  • Streptococci for instance S. pyogenes CN10 and S. pneumoniae PU7
  • Staphylococci for
  • compounds of this invention are active against Staphylococci organisms such as S. aureus and coagulase negative strains of Staphylocci uch as S. epidermidis which are resistant (including multiply-resistant) to other anti-bacterial agents, for instance, ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides.
  • ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides.
  • Compounds of the present invention are therefore useful in the treatment of MRS A, MRCNS and MRSE. Fu ⁇ hermore, 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 catde, 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.
  • the 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 hypopneumoniae (pigs, enzootic pneumonia), Mycoplasma hyorhinis (pigs, arthritis) and Mycoplasma hyposinoviae (pigs, arthritis).
  • 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 hypopneumoniae pigs, enzootic pneumonia
  • Mycoplasma hyorhinis pigs, arthritis
  • Mycoplasma hyposinoviae
  • 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.
  • 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.
  • 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).
  • this method of treatment includes not only the novel compounds of formula, (I) but also thiomarinol.
  • the 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,
  • 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). It will be appreciated that this method of treatment includes not only the novel compounds of formula (I) but also thiomarinol.
  • 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).
  • 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) or thiomarinol.
  • 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 art; see, for instance, WO 93/19599 (Zeneca Ltd).
  • a suitable rate of application for herbicidal use 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 or thiomarinol 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) and thiomarinol 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.
  • the present invention provides a process for preparing a compound of formula (I) which process comprises esterifying an acid of formula (IV):
  • X is as hereinbefore defined and Z ⁇ , 7?-, 7? and Z4, 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):
  • Y' is a reactive esterifying leaving group
  • A*, Ri and R2 are as hereinbefore defined; under ester forming conditions; and thereafter, and if necessary, removing any hydroxyl protecting groups.
  • Y 1 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:
  • 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).
  • thiomarinol obtained by fermentation of the organism Aheromonas rava (EP 0 512 824-A, Sankyo Co Ltd), may be used to obtain 4-hydroxymonic acid C.
  • hydrolysis may be effected using enzymatic processes or whole cell processes.
  • 4-Hydroxymonic acid C may then be converted to the corresponding 4-hydroxymonic acid A by a suitable epoxidation procedure, using for instance m-chlorobenzoic acid in a solvent such as dichloromethane.
  • Y 2 is a protected hydroxyl group or Y (other than hydroxy); and A 1 is as hereinbefore defined; with an amine of formula (VII):
  • 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 wobutylcarbonic 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, triethylamine 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.
  • a suitable base such as a tertiary amine, for instance pyridine, 2, 6-lutidine, triethylamine or 4-dimethylaminopyridine
  • an aprotic solvent such as chloroform, dichloromethane or tetrahydrofuran
  • Compounds of formula (VI) 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.
  • 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.
  • a compound of formula (I) may be prepared by a process which compromises reacting an acid of formula (VIII):
  • Suitable amide forming conditions are well known in the art, as hereinbefore described.
  • 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 and P G M Wuts, Wiley-Interscience, New York, 2nd ed, 1991 and include lower alkyl, preferably methyl, allyl and tetrahydropyranyl.
  • 4-Hydroxyacids of formula (IV) may be obtained in a variety of ways. In a first process, a ketone of the formula (IX)
  • R ⁇ is lower alkyl, for instance methyl or .
  • ⁇ -propyl preferably wo-propyl
  • X, Z- , 7?- and 7? are as hereinbefore defined; for instance, by treatment thereof with an enolising agent, for instance a strong organic non-nucleophilic base such as a lithium dialkylamide, for example, lithium di-/sopropylamide, followed by trapping the enolate thus formed in situ with a suitable reagent such as tri-wo-propylsilyl triflate.
  • an enolising agent for instance a strong organic non-nucleophilic base such as a lithium dialkylamide, for example, lithium di-/sopropylamide
  • the enol ether (X) may then be reacted with a reagent capable of introducing an ⁇ -hydroxy group, for instance dimethyldioxirane, by analogy with the procedure described by Adams et al, Chem Ber, 1991,124, 2361 and references therein, to give a ⁇ -hydroxy ketone of formula
  • This ⁇ -hydroxyketone may then be converted into an ester derivative of an acid of formula (IV) by initial protection of the ⁇ -hydroxy group as, for instance, the trimethylsilylether, using for instance, trimethylsilyl chloride and triethylamine, followed by an olefination procedure such as those previously described for analogues lacking the ⁇ -hydroxy substituent in GB 1 587 058 (Beecham Group Ltd). Suitable such procedures include the following:
  • R7R8R9 P C HCO 2 R6 (XHI) in which R ⁇ , R8, R9 5 which may be the same or different, is each selected from (C ⁇ _6)alkyl, aryl or aryl (C ⁇ _4)alkyl, preferably phenyl, and R° is as hereinbefore defined; instead of the reagent derived from the compound of formula (XII) in a Wittig reaction; and
  • the ester derivative thus obtained may be converted into an acid of formula (IV) by suitable hydrolysis, for instance using mild base conditions such as sodium hydroxide in aqueous methanol, or a hydrolase enzyme, such as Subtilisin Carlsberg Protease.
  • suitable hydrolysis for instance using mild base conditions such as sodium hydroxide in aqueous methanol, or a hydrolase enzyme, such as Subtilisin Carlsberg Protease.
  • the ⁇ -hydroxyketone of formula (XI) may also be converted into a
  • the acid may then be obtained by suitable hydrolysis, as previously described for (IV) (ester— > acid).
  • ⁇ -hydroxyketones of formula (XI) are useful intermediates in the preparation of compounds of formula (I). Accordingly, in a further aspect, the present invention provides for a compound of formula (XI) as hereinbefore defined.
  • a ketone of the "A" series is readily obtaiTnable from methyl pseudomonate A, by the ozonolysis thereof, according to the procedure described in GB 1 587 059 (Beecham Group).
  • the corresponding ketone in the "C” series may be readily obtained from the corresponding "A” series ketone by a variety of methods, including treatment with sodium iodide/trifluoroacetic anhydride, potassium selenocyanate (Clayton et al, J Chem Soc Perkin Trans 1, 1981, 287), or a low valent tungsten halide derivative (Kozlkavski et al, J Amer Chem. Soc, 1980, 102, 6580 and Sharpless et al, J. Am Chem Soc, 1992, 94, 6538).
  • 4-hydroxy acids of formula (IV) may be obtained by a process which comprises treating an ester of formula (XV):
  • 4-hydroxy acids of formula (TV) may be obtained by a process which comprises treating a compound of formula (XVI):
  • Compounds of the formula (XVI) may be obtained by oxidation using, for instance, m-chloroperbenzoic acid in dichloromethane, of the corresponding thioether, itself obtainable by treating the corresponding ester of monic acid A or C with an appropriate non-nucleophilic base, such as lithium di-w ⁇ propylamide, followed by a sulphur electrophile such as diphenyl disulphide (to give R ⁇ as phenyl) (see Crimmin et al, J Chem Soc Perkin Trans 1, 1985, 549).
  • Acids of formula (IV) (in the "A” series) may also be obtained by a process which comprises treating an aldehyde of formula (XVII):
  • 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).
  • 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).
  • the various processes described herein also may be used to prepare the natural product thiomarinol which has previuosly only been available as a fermentation product. Accordingly, in a further aspect, the present invention provides processes for the preparation of thiomarinol, which processes are those hereinbefore described for compounds of formula (I).
  • '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 the compound of formulae (IV), (VIII), (IX), (X), (XI), (XV), (XVI), (XVII) and (XIX) 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 :
  • Me 3 Si- N N 'BuMe ⁇ -Si-N ⁇ N ⁇ . J in which Me denotes methyl, t-Bu denotes t-butyl, Y is halogen and each group L is independently selected from hydrogen, (Cj-gialkyl, (Cj-6)alkoxy, aryl or aryl(Ci"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.
  • (XI), (XV), (XVI), (XVII) and (XIX) may be protected by forming a cyclic derivative using a compound of formula (XX): RaC(OR b )(ORC)(ORd) (XX) in which R a is hydrogen or (C j - ⁇ alkyl and each of R* ⁇ R c and R ⁇ is (C ⁇ _6)alkyl such that in the cyclic derivative 7?- and Z together are a moiety R D C(OR c ).
  • R a is hydrogen, methyl, ethyl, n- or w ⁇ -propyl; most suitably it is hydrogen.
  • the groups R ⁇ , R c and R ⁇ are suitably methyl, ethyl, n- or w ⁇ -propyl, or n-, iso-, sec- or 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 1, 1979, 308.
  • the first fraction contained the less polar isomer of the title compound (19mg); ⁇ jj (CDCI3) 0.92 (3H, d, 77.1Hz, 17-H 3 ), 1.21 (3H, d, 76.3Hz, 14-H 3 ), 1.34 (IH, m, 12-H), 1.72 (2H, m, 9-H 2 ), 2.01 (IH, m, 8-H), 2.17 (3H, d, 7 1.2Hz, 15-H ), 2.52 (IH, br.
  • the first fraction contained the less polar isomer of the title compound (121mg); v max (KBr) 2956, 1730, 1251 and 1132cm- 1 ; ⁇ H (CDCI3) 0.02-0.22 (36H, m, SiCH 3 ), 0.89 (3H, d, 7 7.1Hz, I7-H3), 1.18 (3H, d, 7 6.3Hz, 14-H ), 1.35-1.46 (IH, m, 12-H), 1.48-1.58 (IH, m, 9-H), 1.58-1.7 (IH, m, 9-H), 1.75 (IH, b.s, 8-H), 2.16 (3H, d, 7 1.7Hz,
  • reaction mixture was heated slowly to 70°C and after lhr. 50min. the reaction was quenched with ammonium chloride solution (3ml), extracted into ethyl acetate and dried (anhyd. MgSO4). Evaporation yielded an oil (500mg) which was dissolved in THF (18ml), treated with 0.4M HC1 (4.2ml) for 2min. then quenched with saturated sodium bicarbonate solution (4.2ml). The solvents were removed under vacuum, methanol added, the solids filtered off and the filtrate evaporated.
  • the reaction mixture was allowed to warm to room temperature, stirred slowly under argon for 18hr. and then poured into 0.1M phosphate buffer at pH 7 containing a little ice.
  • the mixture was extracted with ethyl acetate (3 x 25ml), the combined extracts evaporated to a small volume and ethyl acetate added to the residue.
  • the water layer was removed, the organic layer evaporated and the residue dissolved in THF (15ml).
  • This solution was treated with 0.4M HC1 (3ml) for 2min. and then quenched with saturated sodium bicarbonate solution (3ml). After evaporation of the THF, ethyl acetate was added to the residue, the aqueous layer removed and the organic layer dried (anhyd.
  • the volume was reduced to ⁇ z.60ml, ethyl acetate added (20ml), and with vigorous stirring the pH of the aqueous layer was adjusted to 3 with 0.4M phosphoric acid.
  • the mixture was partitioned with MDC, filtered, the material on the filter washed with ethyl acetate and the aqueous filtrate washed with ethyl acetate (3 x 50ml).
  • the combined organics were dried (anhyd. MgSO4) to yield the title compound (78.6mg, 81%) as a colourless gum.
  • the stirred reaction mixture was maintained at pH 7 with 0.01M NaOH on a Metrohm Autotitration apparatus overnight.
  • the solution was concentrated to ca. 100ml, the pH adjusted to 3 witii 0.1M HC1 and the solution partitioned with MDC.
  • the mixture was filtered to remove an emulsion and the filter washed with ethyl acetate.
  • the aqueous filtrate was extracted further with ethyl acetate (2 x 30ml) and die combined organic fractions dried (anhyd. MgSO4) to yield the title compound (132.6mg, 85%) as a colourless gum.
  • Example 1 6-[4- ⁇ 5S-(2S,3S-Epoxy-5S-hydroxy-4S-methyl-hexyI)-3R,4R- dihydroxytetrahydropyran-2S-yl) ⁇ -4-hydroxy-3-methyl-but-2E-enoyl- oxyoctanoylamino]-l,2-dithiolo-[4 -b]pyrrol-5(4H)-one -
  • isobutyl- chloroformate (18.13mg, 17 ⁇ l, 0.134mmol was added and the solution stirred for 30min.
  • silica was placed on a column of silica gel (2.4g) made up in MDC and then eluted with 5-10% MeOH/MDC to yield the title product (20mg, 23%); v max ( KBr ) 3435 > 2865 ' 1645 > 1527 - 1212 and 1050cm " 1 ; ⁇ max (EtOH) 214.5 ( ⁇ m 28,544), 302.5 ( ⁇ m 7,111) and 391 ( ⁇ m 14.823)nm; ⁇ H (CD3OD) 0.94 (3H, d, 7 7Hz, I7-H3), 1.20 (3H, d, 7 6.4Hz, 14-H 3 ), 1.32-1.48 (7H, m, CH 2 and 12-H), 1.58- 1.72 (5H, m, CH 2 and 9- ⁇ 2 ), 1.78 (IH, m, 9-U), 1.92 (IH, m, 8-H), 2.12 (3H, s, 15- H 3 ), 2.39 (2H, t,
  • the - ⁇ H nmr of this material was identical to natural thiomarinol and both compounds co-eluted on hplc; Cjg column, eluant 64% MeOH in 0.05M ammonium acetate buffer pH 4.5, retention time 3.2min., detection at 390nm.
  • Example 3 4-Hydroxy-N-(4-methyI-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- y pseudomonamide A: isomer A a) 4-Hydroxymonic acid A : Isomer A - The less polar product of preparation le in trimethyl orthoformate is treated with a catalytic amount of toluene /j-sulphonic acid. After 0.5h the solvent is removed and the oil is immediately dissolved in IN sodium hydroxide. After 3h at 65°C the solution is cooled and the pH adjusted to 7.0 with concentrated hydrochloric acid. Methanol is added and the pH adjusted to 2.0 with 5N hydrochloric acid.
  • Example 4 4-Hydroxy-N-(4-methyI-l,2-dithiolo-[4,3-b]-5-(4H)-oxopyrrol-6- yOpseudomonamide A: Isomer B a) 4-Hydroxymonic acid A: Isomer B - Using the procedure described in example 3a the more polar product of preparation le is converted to the title compound. b) Sodium 4-hydroxymonate A: Isomer B - Using the procedure described in example 3b the product from example 4a is converted to the title compound.
  • Example 5 4-Hydroxy-N-(4-methyl-l,2-dithioIo-[4 -b]-5(4H)-oxopyrrol-6- yOpseudomonamide C: Isomer A a) Methyl 4-hydroxypseudomonate C: Isomer A -
  • the product from example 3c in dichloromethane and pyridine (5.5 equivalents) is treated dropwise with trichloroacetyl chloride (5 equivalents). After lh the mixture is washed with aqueous sodium bicarbonate, dilute citric acid and brine, then dried (MgSO4) and evaporated to crude acylated material.
  • Trifluoroacetic anhydride (1 equivalent) is added to a mixture of sodium iodide (3.3 equivalents) and acetonitrile at 20°C. After 5min. a solution of the above acylated material in acetonitrile is added and the mixture is stirred for 18h. Diethyl ether is added and the mixture washed with aqueous sodium hydrogen sulphite, aqueous sodium hydrogen carbonate and brine, then dried (MgSO4) and evaporated. The residue is then dissolved in ethanol and potassium carbonate (8 equivalents) is added. After 2h (tic monitoring) ethyl acetate is added and the mixture washed with water, brine then dried (MgSO4) and evaporated.
  • Example 6 4-Hydroxy-N-(4-methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yOpseudomonamide C: isomer B a) Methyl 4-hydroxypseudomonate C: Isomer B - Using the procedure described in example 5a, the product from example 4c is converted to the title compound. b) 4-Hydroxypseudomonate C: Isomer B - Using the procedure described in example 3d the product from example 6a is converted to the title compound.

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Abstract

L'invention concerne des dérivés ester de l'acide 4-hydroxymonique selon la formule (I) comportant une fraction terminale pyrrotine et possédant d'utiles propriétés anti-bactériennes, fongicides et herbicides. Plusieurs intermédiaires sont également revendiqués.
EP94917636A 1993-05-21 1994-05-16 Derives de thiomarinol, procede et intermediaires pour leur preparation et leur utilisation comme microbicides et herbicides Withdrawn EP0699203A1 (fr)

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GB939310485A GB9310485D0 (en) 1993-05-21 1993-05-21 Novel compounds
GB9310485 1993-05-21
PCT/EP1994/001582 WO1994028001A1 (fr) 1993-05-21 1994-05-16 Derives de thiomarinol, procede et intermediaires pour leur preparation et leur utilisation comme microbicides et herbicides

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AU4496996A (en) * 1995-01-31 1996-08-21 Sankyo Company Limited Pseudomonic acid derivatives
CA2217957A1 (fr) 1995-04-11 1996-10-17 Genhui Chen Xenorxides a proprietes antibacteriennes et antimycotiques
WO1997005126A1 (fr) * 1995-07-29 1997-02-13 Smithkline Beecham Plc Mupirocinsulfamates a activite antibacterienne
US6583171B1 (en) 1996-04-04 2003-06-24 Welichem Biotech Inc. Antineoplastic agents
GB9701597D0 (en) * 1997-01-27 1997-03-19 Smithkline Beecham Plc Novel compounds
WO2003080624A2 (fr) * 2002-03-26 2003-10-02 Welichem Biotech Inc. Nouveaux dithiolopyrrolones ayant une action therapeutique
CN109535174B (zh) * 2018-12-20 2020-06-12 桂林医学院 一种n-芳基二硫吡咯酮-吡喃酮杂合衍生物及其制备方法和应用

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GB2173499A (en) * 1985-02-04 1986-10-15 Ici Plc Fungicidal dithiolopyrrolones
IS1606B (is) * 1991-05-07 1996-10-18 Sankyo Company Limited Aðferð til framleiðslu nýs sýkladrepandi efnasambands Thiomarinol, fengið með ræktun Alteromanas rava SANK 73390

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