WO1994026750A1 - Deoxythiomarinol derivatives, process and intermediates for their preparation and their use as microbicides and herbicides - Google Patents
Deoxythiomarinol derivatives, process and intermediates for their preparation and their use as microbicides and herbicides Download PDFInfo
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- WO1994026750A1 WO1994026750A1 PCT/EP1994/001512 EP9401512W WO9426750A1 WO 1994026750 A1 WO1994026750 A1 WO 1994026750A1 EP 9401512 W EP9401512 W EP 9401512W WO 9426750 A1 WO9426750 A1 WO 9426750A1
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- 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
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- 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
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- 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
- A01N49/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group, wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group, wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof
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- 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
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- 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
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Definitions
- 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):
- 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
- inflnenzae and Moraxella catarrhalis acts as selective reversible inhibitor of bacterial is ⁇ -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.
- Pseudomonic acid C has the structure (C):
- 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 CONRl;
- R! and R which may be the same or different, is each selected from hydrogen or
- 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)(R4)] mA 2 ; [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 ⁇ _ 6 )al yl;
- A2 is a (C3_7)cycloalkylene group, an optionally substituted aryl group, preferably phenylene, or an optionally substituted heterocyclyl group;
- 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;
- R-* is hydrogen or (C ⁇ ._6)alkyl, preferably hydrogen.
- R2 is hydrogen or (Cj ⁇ alkyl, for instance methyl, preferably hydrogen.
- a 1 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 g)alkyl, in particular on the ⁇ -carbon (carbon attached to carboxy).
- a Ms preferably (CH 2 )7 or (CH 2 )g whilst in compounds of formula (I) in which X is a E-double bond (C series), A-* is preferably (CH 2 )6 or (CH 2 )7.
- Suitable substituents for a (C ⁇ 6)alkyl, (C3_7)cycloalkyl, (C 2 -6)alkenyl group or polymethylene 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 * j_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 ⁇ _6)alkyl, phenyl, (Cj_6)alkoxy, halo(C ⁇ _6)alkyl, hydroxy, amino, mono- or di-(C ⁇ _6)alkylamino, acylamino, nitro, carboxy, (C ⁇ _6)alkoxycarbonyl, (C ⁇ .6)-alkoxycarbonyl(C ⁇ _6)alkyl, (C ⁇ _6)alkylcarbonyloxy, (C _6)alkylthio, (C ⁇ .6)alkylsulphinyl, (C ⁇ _6)alkylsulphonyl, sulphamoyl, mono- or di-(C ⁇ .6)alkylsulphamoyl,
- 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.
- 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.
- '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 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-
- 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 the 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 hypromellose may also be included.
- 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.
- 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.
- 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
- 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.
- Gram positive organisms including Bacteroides, for instance B.fragilis BC1, Haemophilus, for instance H. influen ⁇ ae Ql ; Moraxella, for instance M. catarrhalis
- Streptococci for instance S. pyogenes CN10 and S. pneumoniae PU7;
- Staphylococci for instance S. aureus Oxford
- Escherichia for instance E. Coli DC0
- 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 MRSA, MRCNS and MRSE.
- 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.
- 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).
- 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
- 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).
- 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).
- 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.
- 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.
- 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 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.
- the present invention provides a process for preparing a compound of formula (I) which process comprises esterifying an acid of formula (IV):
- 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.
- 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);
- 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).
- 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.
- a suitable base such as a tertiary amine, for instance pyridine, 2, 6-lutidine or 4-dimethylaminopyridine
- an aprotic solvent such as chloroform, dichloromethane or tetrahydrofuran
- Acids of formula (VI) are ⁇ -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.
- 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 prep
- 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
- deoxygenation A ⁇ C
- C ⁇ A epoxidation
- EP 0 003 069-A Beecham Group pic
- Clayton J P et al JCS Perkin Trans I, 1982, 2827.
- 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 (V ⁇ i) 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 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.
- glycol function of monic acids A and C and the compound of formula (V ⁇ i) may be protected by forming a cyclic derivative using a compound of formula (IX):
- R a is hydrogen, methyl, ethyl, n- or w ⁇ -propyl; most suitably it is hydrogen.
- the groups R b , R c and R d are suitably methyl, ethyl, n- or w ⁇ -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.
- 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.
- 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.
- 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 j g 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.
- Example 2 6-[4- ⁇ 5S-(5S-Hydroxy-4R-methylhex-2E-e ⁇ yI)-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 ( ⁇ m /dn_ ⁇ mol " lcm ⁇ l 10659) and 314.5 (5329); ⁇ H (400MHz; CDCI3; Me Si) 0.99 (3H, d, J 7Hz,
- Example 6 (4-Methyl-l,2-dithioIo-[4,3-b]-5(4H)-oxopyrrol-6- y carbamoylmethyl monate
- 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%); ⁇ jj (CD3OD) (inter alia) 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H 3 ), 2.20 (3H, d, J 1.1Hz, I5-H3), 3.74 (3H, s, OMe), 4.64 (2H, s, l'-H 2 ), and 5.84 (IH, s, 2 r H); ⁇ C (CD3OD) 12.
- 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 ⁇ , and then evaporated in vacuo.
- 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 2 3 /£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 product was an orange foam (0.126g, 60%); ⁇ max (KBr) 3430, 3265, 2927, 1710, 1650, 1602, and 1228cm" l ; ⁇ ax (EtOH) 210 ( ⁇ 26,208), 312 (3,953), and 391nm (10,542); ⁇ H (CD3OD) 0.94 (3H, d, 77.1Hz, 17-H 3 ), 1.20 (3H, d, 76.5Hz, 14-H 3 ), 1.28-1.75 (19H, m, 12- H, 9-H 2 , 2'-9'-H 2 ), 1.91-2.00 (IH, m, 8-H), 2.18 (3H, d, 7 l.OHz, 15-H 3 ), 2.21 (IH, dd, 7 8.7, 14.5Hz, 4-H), 2.38 (2H, t, 77.5Hz, 10'-H 2 ), 2.64 (IH, brd, 7 14.3Hz, 4-H), 2.71 (lH,
- 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%); ⁇ H (CDCI3) ( ter alia) 0.95 (3H, d, 7 6.84Hz, I7-H3), 1.15 (3H, d, 76.25Hz, 14-H 3 ), 1.55-1.9 (8H, m, 9-H 2 , 2-H 2 , 3'-H 2 , 12-H, 18-H), 2.2( 3H, s, 15-H 3 ),
- 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.
- 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
- 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; ⁇ max (EtOH)/nm 387 ( ⁇ m 10,528) and 302.5 (3220); ⁇ H (250MHz; CD3OD; Me 4 Si) 0.94 (3H, d, 77Hz, 17-H 3 ), 1.19 (3H, d, 7 6.4Hz, M-H3), 1.37 (9H, m, 4 x CH 2 and 12-H), 1.68 (6H, m, 2 x CH 2 and 9-H 2 ), 1.94 (I
- 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; ⁇ max (KBrVcm " 1 , 3392 br, 2925, 1643; 7 ⁇ - ⁇ (EtOH)/nm 387 ( ⁇ m 11,009) and 305.5 (3290); ⁇ H (250MHz; CD3OD; Me 4 Si) 0.99 (3H, d, 77Hz, I7-H3), 1.09 (3H, d, 7 6.4Hz, 14-H 3 , 1.37 (9H, m, 4 x CH 2 , 12-H), 1.40- 1.85 (7H, m, 2 x CH 2 , 8-H, 9-H 2 ),
- 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%).
- the product was an orange solid (0.135g, 78%); ⁇ ma ⁇ (KBr) 3431, 1654, 1642, 1601, and 1228cm- 1 ; ⁇ max (EtOH) 213 ( ⁇ m 24,780), 312 (4,053), and 389nm (10,385); ⁇ H (CD 3 OD) 0.96 (3H, d, 77.1Hz, I7-H3), 1.22 (3H, d, 76.4Hz, 14-H 3 ), 1.37-1.49 (5H, m, 12-H, 3'-H 2 , 4'- H 2 ), 1.62-1.78 (6H, m, 9-H 2 , 2'-H 2 , 5'-H 2 ), 1.92-2.01 (IH, m, 8-H), 2.19 (3H, s, 15- H 3 ), 2.24 (IH, dd, 7 14.4, 9.7Hz, 4-H), 2.42 (2H, t, 77.4Hz, 6'-H 2 ), 2.
- 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%); ⁇ j j (CD 3 OD) ( ter alia) 0.95 (3H, d, 77.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H ), 2.18 (3H, d, 70.9Hz, 15-H
- the product was a pale yellow oil (1.380g, 93%); ⁇ ma ⁇ (KBr) 3459, 2930, 1737, 1715, and 1151cm" 1 ; ⁇ max (EtOH) 220nm ( ⁇ m 13,942); ⁇ H (CD3OD) (inter alia) 0.99 (3H, d, 76.9Hz, 17-H 3 ), 1.09 (3H, d, 76.4Hz, 14-H 3 ), 2.18 (3H, d, 70.7Hz, 15-H 3 ), 2.33 (2H, d, 77.4Hz, 6'-H 2 ), 2.66 (IH, br.d, 7 14.3Hz, 4-H), 3.65 (3H, s, CO 2 CH 3 ), 4.07 (2H, t, 76.5Hz, l'-H 2 ), 5.36-5.52 (2H, m, 10,11-H), and 5.74 (IH, s, 2-H); ⁇ C (CD3OD) 16.6 (C-17), 19.3 (
- the product was an orange foam (0.106g, 46%); ⁇ max (KBr) 3415, 2928, 1705, 1602, and 1229cm- 1 ; 7 ⁇ . ⁇ (EtOH) 206 ( ⁇ m 24,293), 311 (4,007), and 391nm (10,549); ⁇ H (CD3OD) 0.99 (3H, t, 76.9Hz, I7-H3), 1.09 (3H, t, 76.4Hz, 14-H 3 ), 1.36-1.48 (4H, m, 3'-H 2 , 4'-H 2 ), 1.61-1.82 (5H, m, 12-H, 2 * -H 2 , 5'-H 2 ), 2.08-2.28 (7H, m, 8-H, 9-H 2 , 4-H, 15-H 3 ), 2.39 (2H, t, 77.4Hz, 6'-H 2 ), 2.65 (IH, br.d, 7 14.4Hz, 4-H), 3.35 (3H, s,
- 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%).
- the product was an orange foam (0.202g, 74%); ⁇ max (KBr) 3422, 2926, 1708, 1648, 1603, and 1228cm" 1 ; ⁇ (EtOH) 214 ( ⁇ m 22,720), 31 1 (3,873), and 391nm (10,327); ⁇ H (CD3OD) 0.94 (3H, d, 7.0Hz, 17-H 3 ), 1.19 (3H, d, 76.5Hz, 14-H 3 ), 1.30-1.48 (HH, m, 12-H, 3'- 7'-H 2 ), 1.57-1.73 (6H, m, 9-H 2 , 2'-H 2 , 8'-H 2 ), 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'-H 2 ), 2.64 (I
- Example 16 9-(4-MethyM,2-dithiolo-[4,3-b]-5(4H)-oxopyrroI-6- yI)carbamoylnonyl monate
- C 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%); ⁇ H (CD3OD) (inter alia) 0.94 (3H, d, 77.1Hz, 17-H 3 ), 1.20 (3H, d, 76.5Hz, 14-H 3 ), 2.18 (3H, d, 7 1.1Hz, 15-H ), 2.31 (2H, t, 77.4Hz, 9'-H 2 ), 3.64 (3H, s, CO 2 CH 3 ), 4.06 (2H, t, 7
- the product was a pale yellow oil (1.400g, 96%); ⁇ H (CD 3 OD) (inter alia) 0.99 (3H, d, 7 6.9Hz, 17-H 3 ), 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'-H 2 ), 2.66 (IH, br.d, 7 14.4Hz, 4-H), 3.64 (3H, s, CO 2 CH 3 ), 4.07 (2H, d, 76.6Hz, l'-H 2 ), 5.36-5.52 (2H, m, 10-H, 11-H), and 5.74 (IH, s, 2-H); ⁇ 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 (
- the product was an orange foam (0.178g, 70%); ⁇ ma ⁇ (KBr) 3418, 2925, 1709, 1647, 1602, and 1228cm- 1 ; ⁇ max (EtOH) 204 ( ⁇ m 25,069), 214 (24,767), 312 (4,289), and 390nm (10,632); ⁇ H (CD3OD) 0.95 (3H, d, 76.9Hz, 17-H 3 ), 1.05 (3H, d, 76.3Hz, 14-H 3 ), 1.19-1.39 (10H, m, 3'-7 * -H 2 ), 1.50-1.64 (4H, m, 2'-H 2 , 8'-H 2 ), 1.66-1.76 (IH, m, 12-H), 2.03- 2.23 (7H, m, 8-H, 9-H 2 , 4-H, 15-H 3 ), 2.34 (2H, t, 77.4Hz, 9'-H 2 ), 2.62 (IH, br.d
- the mixture was heated at 40 2 C 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.
- Example 18 6-(l,2-Dithiolo-[4,3-b]-5(4 ⁇ )-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 m a ⁇ (KBr) 3420, 3067, 1645, 1595, 1527, 1225, 1150 and 1050cm " 1 ; ⁇ max (EtOH) 216 ( ⁇ m 21,049), 299.5 (3,437), and 389.5 (11,169); ⁇ H (CD3OD) 0.99 (3H, d, 7 6.9Hz, I7-H3), 1.09 (3H, d, 7 6.3Hz, 14-H 3 ), 1.37-1.46 (4H, m, 3'-, 4'-H 2 ), 1.6-1.83 (5H, m, 8-H, 2'-, 5'-H 2 ), 2.08-2.29 (7H, m, 4-H, 9-H 2 , 12-H, 15-H 3 ), 2.39 (3H, t, 7
- 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.
- 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; ⁇ ⁇
- Example 21 Pharmaceutical Formulation Compound of formula (I) 2% polyethylene glycol 400 59 polyethylene glycol 4000 39
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AU69270/94A AU6927094A (en) | 1993-05-13 | 1994-05-10 | Deoxythiomarinol derivatives, process and intermediates for their preparation and their use as microbicides and herbicides |
EP94917614A EP0698027A1 (en) | 1993-05-13 | 1994-05-10 | Deoxythiomarinol derivatives, process and intermediates for their preparation and their use as microbicides and herbicides |
JP6524955A JPH08510223A (en) | 1993-05-13 | 1994-05-10 | Deoxythiomarinol derivative, its production process and intermediates for its production, and its use as fungicides and herbicides |
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GB939309836A GB9309836D0 (en) | 1993-05-13 | 1993-05-13 | Novel compounds |
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GB9400591A GB9400591D0 (en) | 1994-01-14 | 1994-01-14 | Novel compounds |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1996023795A1 (en) * | 1995-01-31 | 1996-08-08 | Sankyo-Company, Limited | Pseudomonic acid derivatives |
WO1997005126A1 (en) * | 1995-07-29 | 1997-02-13 | Smithkline Beecham Plc | Mupirocinsulfamates with antibacterial activity |
US6316476B1 (en) | 1995-04-11 | 2001-11-13 | Welichem Biotech Inc. | Heterocyclic compounds with antibacterial and antimycotic properties |
US6583171B1 (en) | 1996-04-04 | 2003-06-24 | Welichem Biotech Inc. | Antineoplastic agents |
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JP5299926B2 (en) * | 2011-03-28 | 2013-09-25 | 学校法人東京薬科大学 | Antibacterial agent containing myxopyronine derivative |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3602148A1 (en) * | 1985-02-04 | 1986-08-07 | Imperial Chemical Industries Plc, London | HETEROCYCLIC COMPOUNDS |
EP0512824A1 (en) * | 1991-05-07 | 1992-11-11 | Sankyo Company Limited | Anti-bacterial compound |
EP0595458A1 (en) * | 1992-09-18 | 1994-05-04 | Sankyo Company Limited | Novel thiomarinol derivatives, and processes for their preparation |
-
1994
- 1994-05-10 AU AU69270/94A patent/AU6927094A/en not_active Abandoned
- 1994-05-10 WO PCT/EP1994/001512 patent/WO1994026750A1/en not_active Application Discontinuation
- 1994-05-10 EP EP94917614A patent/EP0698027A1/en not_active Withdrawn
- 1994-05-10 JP JP6524955A patent/JPH08510223A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3602148A1 (en) * | 1985-02-04 | 1986-08-07 | Imperial Chemical Industries Plc, London | HETEROCYCLIC COMPOUNDS |
EP0512824A1 (en) * | 1991-05-07 | 1992-11-11 | Sankyo Company Limited | Anti-bacterial compound |
EP0595458A1 (en) * | 1992-09-18 | 1994-05-04 | Sankyo Company Limited | Novel thiomarinol derivatives, and processes for their preparation |
Non-Patent Citations (2)
Title |
---|
H. SHIOZAWA ET AL: "Thiomarinol, a new hybrid antimicrobial antibiotic produced by a marine bacterium", JOURNAL OF ANTIBIOTICS., vol. 46, no. 12, December 1993 (1993-12-01), TOKYO JP, pages 1834 - 1842 * |
P. J. O'HANLON ET AL: "The chemistry of pseudomonic acid. Part 6. Structure ansd preparation of pseudomonic acid D", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, no. 11, 1983, LETCHWORTH GB, pages 2655 - 2657 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996023795A1 (en) * | 1995-01-31 | 1996-08-08 | Sankyo-Company, Limited | Pseudomonic acid derivatives |
US6316476B1 (en) | 1995-04-11 | 2001-11-13 | Welichem Biotech Inc. | Heterocyclic compounds with antibacterial and antimycotic properties |
WO1997005126A1 (en) * | 1995-07-29 | 1997-02-13 | Smithkline Beecham Plc | Mupirocinsulfamates with antibacterial activity |
US6583171B1 (en) | 1996-04-04 | 2003-06-24 | Welichem Biotech Inc. | Antineoplastic agents |
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AU6927094A (en) | 1994-12-12 |
JPH08510223A (en) | 1996-10-29 |
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