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WO1995005384A1 - Derives d'acides moniques a et c a activite antibacterienne, antimycoplasmique, antifongique et herbicide - Google Patents

Derives d'acides moniques a et c a activite antibacterienne, antimycoplasmique, antifongique et herbicide Download PDF

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Publication number
WO1995005384A1
WO1995005384A1 PCT/EP1994/002552 EP9402552W WO9505384A1 WO 1995005384 A1 WO1995005384 A1 WO 1995005384A1 EP 9402552 W EP9402552 W EP 9402552W WO 9505384 A1 WO9505384 A1 WO 9505384A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
dithiolo
oxopyrrol
methyl
Prior art date
Application number
PCT/EP1994/002552
Other languages
English (en)
Inventor
Nigel John Perryman Broom
Peter John O'hanlon
Neal Frederick Osborne
Donna Pengelly
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GB939316879A external-priority patent/GB9316879D0/en
Priority claimed from GB9400592A external-priority patent/GB9400592D0/en
Priority claimed from GB9401139A external-priority patent/GB9401139D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP7506705A priority Critical patent/JPH09504512A/ja
Priority to EP94924831A priority patent/EP0712405A1/fr
Priority to AU74975/94A priority patent/AU7497594A/en
Publication of WO1995005384A1 publication Critical patent/WO1995005384A1/fr

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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

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 fluorescens produces three closely related tetrahydropyranyl compounds known as pseudomonic acids A, B and C which are of 0 interest on account of their antibacterial properties.
  • Pseudomonic acid A (now known as mupirocin) has the structure (A):
  • Pseudomonic acid A exhibits good anti-bacterial activity, mainly against Gram- positive bacteria, but also against some Gram-negative bacteria such as Haemophilus 0 influenzae and Moraxella catarrhalis. It acts as selective reversible inhibitor of bacterial woleucyl 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 0251 434-A). The compound is marketed by Beecham Group pic under the trade mark Bactroban, as a topical formulation. 5 Systematic use is precluded by a rapid metabolism to monic acid, which is inactive. Pseudomonic acid C has the structure (C):
  • 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. It is expected that, for the thiomarinols, the presence of an ⁇ , ⁇ -unsaturated ester moiety will mean that the thiomarinols are susceptible to enzymatic hydrolysis.
  • B is selected from the following:
  • B 1 is a group X 1 , X 2 , Y 1 , NH or NHX 1 , in which:
  • X 1 is optionally substitued aryl, preferably phenylene; ⁇ 2 is (C ⁇ _ ⁇ o)alkylene, (C2-io)alkenylene, (C2-io) a lkynylene, (C3_7)cycloalkylene or aryl(Ci_4)alkylene. each of which may be optionally substituted; and Y-** is optionally substituted heterocyclyl, preferably heteroaryl;
  • B-2 is ⁇ 2, ⁇ 2. ⁇ l, ⁇ 2. ⁇ 2 or ⁇ 2. ⁇ 3 in which:
  • Y ⁇ is a 5- or 6- membered heteroaryl ring having from 1 to 4 heteroatoms, preferably 1 to 3, most preferably 1 or 2, each selected from oxygen, sulphur or nitrogen and optionally substituted by (C ⁇ _ ⁇ o)alkyl, (C2-io)alkenyl, (C2-io) a lkynyl, (C3_7)cycloalkyl, aryl(C ⁇ _4)alkyl, aryl or heterocyclyl; ⁇ 3 is an optionally substituted heterocyclic ring, preferably heteroaryl; and
  • X* and X 2 are as hereinbefore defined;
  • the linking group of atoms D comprises one or more carbon atoms which may 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.
  • D is a hydrocarbylene chain containing up to 20 carbon atoms, preferably a polymethylene chain having between between 1 and 20 carbon atoms, more preferably between 1 and 12 carbon atoms, which chain may be: (a) optionally substituted, for instance by a (C ⁇ 6)alkyl group, (b) optionally interrupted at one or more places by a moiety M,
  • a suitable linkage such as a direct bond, optionally substituted (C3_7)cycloalkylene, optionally substitued aryl, preferably phenylene, or optionally substituted heterocyclyl, preferably heteroaryl; and - in which M represents 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; NRSO 2 ; CONRSO ; SO 2 NRCO and phenyloxy; in which R is hydrogen or (C * ⁇ 6)alkyl.
  • Suitable heteroaryl groups for Y 1 include: furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, benzimidazole, oxadiazole, thiadiazole, triazole, tetrazole, thiatriazole, pyridine, quinoline, isoquinoline, pyrazine, pyrimidine, pyridazine and triazine; preferably thiophene, furan, pyrrole, thiazole, isothiazole, pyridine, pyrimidine, and quinoline.
  • Y * *- is:
  • Suitable heteroaryl groups for Y 2 include furan, thiophene, pyrrole, diazole, oxazole, thiazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole and tetrazole; preferably:
  • Suitable heteroaryl groups for Y-** * include:
  • Suitable aryl groups for B include phenylene.
  • Suitable combinations Y 2 - ⁇ l include:
  • Suitable combinations Y 2 - ⁇ 3 include:
  • the aryl ring of which Q forms a residue is benzene or naphthalene, preferably benzene, which may be unsubstituted or substituted by up to three, suitably up to one further substituent, in addition to D.
  • the heteroaryl ring of which Q forms a residue includes both single and fused rings, with each ring suitably comprising up to four heteroatoms each selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to two further substituents, in addition to D.
  • Each heteroaryl ring may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heteroaryl ring may include an aryl ring and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems.
  • the heteroaryl ring of which Q forms a residue is a monocyclic heteroaryl ring, for instance pyridine or furan.
  • the aryl or heteroaryl ring may be optionally substituted. It will be appreciated that in these instances, the aryl ring of which Q forms a residue is benzene and the heteroaryl ring of which Q forms a residue is furan or pyridine.
  • D is an oxyalkylene chain O(CH2) n or an alkylene chain (CH2) n in which n is an integer between 1 and 12.
  • Suitable values for B-D include:
  • Preferred values for B-D include:
  • R is hydrogen or (C ⁇ -.g)alkyl.
  • R ⁇ is hydrogen.
  • R 2 is hydrogen or (C ⁇ _6)alkyl, for instance methyl.
  • R 2 is hydrogen.
  • Suitable substituents for a (Cj.gjalkyl, (C3_7)cycloalkyl or (C2-6)alkenyl, group 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, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (C ⁇ _6)alkoxy, acyloxy, oxo, acyl, 2-thenoyl, (C ⁇ _6)alkylthio, (C ⁇ _6)alky
  • 'halogen' refers to fluorine, chlorine, bromine or iodine.
  • the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl.
  • an aryl group may have up to five, preferably up to three substituents. Suitable such substituents include, for example, halogen, cyano, (C . 6)alkyl, phenyl, (C ⁇ _6)alkoxy, halo(C ⁇ 6)alkyl, hydroxy, amino, mono- or di-(Cj_. 6)alkylamino, acylamino, nitro, carboxy, (C ⁇ _6)alkoxycarbonyl, (C ⁇ . ⁇ ).
  • heteroaryl' includes single and fused rings, each ring suitably comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems.
  • heterocyclyl' includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms 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.
  • a heteroaryl or a heterocyclyl group may have up to three substituents. Suitable such substituents include those previously mentioned for an aryl group as well as oxo.
  • the term 'hydrocarbylene' may include groups having up to 20 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms. Suitable groups include (C 6)alkylene, (C2-6)alkenylene, (C2-6)alkynylene, (C3_7)cycloalkylene, (C4_7)cycloalkenylene and aryl. 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.
  • 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. In such cases water of hydration may be formed.
  • 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 derivatives of either monic acid A or monic acid C and as such have the same absolute configurations at corresponding chiral centres.
  • 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- methylhexyl]-3,4-dihydroxytetrahydropyran-2-yl ⁇ -3-methylbut-2(E)-enoic acid.
  • 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. Accordingly, within the compounds of formula (I), there exists a first sub-set of compounds which are derivatives of monic acid A and which may be represented by formula (II):
  • 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 -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
  • preservatives for example methyl or propyl -hydroxybenzoate or sorbic acid
  • 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.
  • 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.
  • 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. 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.
  • 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.
  • 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 active against both Gram negative and Gram positive organisms, including Bacteroides, for instance B.fragilis BC1, Haemophilus, for instance H. influenzae Q 1 ; 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.
  • Bacteroides for instance B.fragilis BC1, Haemophilus, for instance H. influenzae Q 1 ; Moraxella, for instance M. catarrhalis 1502; Streptococci, for instance S. pyogenes CN10 and S. pneumoniae PU7; Staphylococci
  • 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, ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides.
  • 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, ⁇ -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
  • 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.
  • the compounds of this invention are also active against mycoplasma- induced infections, in particular infections caused by Mycoplasmafermentans, 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).
  • 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.
  • 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.
  • 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).
  • a suitable general process involves forming an amide bond between the terminal heterocyclic moiety and the remainder of the compound towards the end of the synthetic sequence. Accordingly, the present invention provides a process for preparing a compound of formula (I) which process comprises reacting an acid of formula (IV):
  • Particularly suitable amide forming conditions include reacting an activated derivative of an acid of formula (IV), for instance an acyl halide or a mixed anhydride such as an wo-butylcarbonic or methane sulphonic anhydride, with an amine of the formula (V) 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
  • Suitable compounds of formula (IV) for use in preparing the compounds of formula (I) may be prepared by analogy with the processes described in our own earlier patent applications for similar derivatives viz EP 0 001 914- A, EP 0029 665-A, WO 91/09855, WO 92/02518, WO 93/06118, EP 0 087 953-A, EP 0 123 378-A, EP 0 352 909-A, EP 0 399 645-A, WO 91/09856 and WO 94/02478 (Beecham Group or SmithKline Beecham), which are hereby incorporated herein by reference.
  • Such compounds of formula (IV) may usefully be regarded as novel examples of earlier derivatives having an appropriate substituent -DCO2H, in which D is as hereinbefore defined.
  • D represents an oxyalkylene chain O(CH2) n
  • a useful starting point will be a hydroxy substituted analogue of an earlier monic acid derivative with the other hydroxy groups (corresponding to 2 ⁇ , 7 - and Z3) suitably protected.
  • the isolated hydroxy group may then be alkylated with a suitable reagent R 3 (CH2) n COR 4 in which R 3 is a leaving group and R 4 is a carboxy protecting group.
  • the moiety -DCOOH in a suitably protected form, if need be
  • the moiety -DCOOH may be incorporated at an earlier stage of the sequence, by using an intermediate in which it is already present, prior to elaborating the spacer group B. It will be readily appreciated that, for other values of D, derivatives of monic acid with other functional groups may be used as a starting point.
  • 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 from pseudomonic acid C (Clayton J P et al, J Chem Soc Perkin Trans 1, 1982, 2827).
  • monic acid C may be obtained from monic acid A by the deoxygenation thereof, as described by Clayton J P et al, J Chem Soc Perkin Trans I, 1982, 2827 and in EP 0 003 069-A (Beecham Group).
  • Amines of formula (V) may be prepared 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.
  • '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, Greene and Wuts, Wiley-Interscience, New York, 2nd ed, 1991.
  • the hydroxyl groups of monic acids A and C, and compounds of formula (IV) 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.
  • Me denotes methyl
  • t-Bu denotes t-butyl
  • Y is halogen and each group L is independently selected from hydrogen, (C ⁇ -gJalkyl, (Cj ⁇ alkoxy, aryl or aryl(C j - 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 of the compounds of formula (IV) may be protected by forming a cyclic derivative using a compound of formula (VI):
  • R C C(OR d )(OR e )(OR f ) (VI) wherein R c is hydrogen or (Cj-6)alkyl and each of R d , R e and R ⁇ is (C ⁇ _6)alkyl such that in the cyclic derivative Z 2 and 7? together are a moiety R c C(OR d ).
  • R c is hydrogen, methyl, ethyl, n- or -_> ⁇ -propyl; most suitably it is hydrogen.
  • the groups R ⁇ , R e and R ⁇ are suitably methyl, ethyl, n- or wo-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.
  • 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.
  • 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.
  • Example 1 3R,4R-Dihydroxy-2S-[2,4-dioxo-4- ⁇ 4-(4-methyI-l,2-dithiolo-[4 -b]-
  • the title compound (7mg, 3%) was prepared from monic acid A (172mg) by the method described in example 1(f); ⁇ max (KBr) 3403, 2923, 1653, 1519, 1436cm- 1 ; ⁇ H (d 4 -MeOH) 0.96 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H ), 1.39 (IH, m, 12-H), 1.69 (2H, m, 9-H 2 ), 1.95 (IH, m, 8-H), 2.22 (3H, s, 15-H 3 ), 2.18- 2.83 (4H, m, 4-H 2 , 10-H, 11-H), 3.35 (3H, s, N-Me), 3.38-4.05 (6H, m, 5-H, 6-H, 7- H, 13-H, 16-H 2 ), 5.97 (IH, s, 2H), 7.23 (IH, s, 3'-H);
  • n-Butyllithium (1.6M in hexane) (29.24mmol, 19.5ml) was added dropwise to tris(methylthio)methane (24.37mmol, 3.24ml) in tetrahydrofuran (80ml) at -78°C. After 1.5 hours the above compound (24.37 mmol, 6.459g) in THF (20ml) was added and stirred for 1 hour at -65°C.
  • N-methoxy-N-methyl- 6,7,13- ⁇ -r (trimethylsilyl) monamide (WO 93/06118, SmithKline Beecham pic) (2mmol, 1.206g) in THF (10ml) was added dropwise. After 2 hours and warming to -50°C glacial acetic acid (4mmol, 0.2ml) was added followed by water (10ml). Extraction with diethyl ether, drying (MgSO4), evaporation to dryness under reduced pressure and purification by column chromatography over silica using ethyl acetate/hexane (0-20%) as eluent gave the title compound (0.442g, 25%); ⁇ j ⁇
  • Example 4 2- ⁇ 6-(4-Methyl-l,2-dithiolo-[4,3-b]-5-(4 ⁇ )-oxopyrrol-6- yl)carbamoylhexoxy ⁇ -thiazol-5-yl-l-normon-2-yl ketone - C series a) N-Methoxy-N-methyl-6,7,13-O-t (trimethylsilyl)monamide C - A solution of monic acid C (J.P. Clayton et.al, J.C.S.
  • Example 5 N- ⁇ 8-[(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yI)carbamoyl]octan-l-yl ⁇ monamide
  • CD 3 OD, Me 4 Si inter alia 0.95 (3H, d, / 7Hz, 17-H 3 ), 1.20 (3H, d, / 6.4Hz, 14-H 3 ), 1.33 (9H, t, / 6.4Hz, 3 x CH3), 1.35-1.72 (13H, m, 5 x CH 2 , 9-H 2 , 12-H), 1.95 (IH, m, 8-H), 2.13 (3H, s, 15-H 3 ), 2.10-2.68 (4H, m, CH 2 CO, 4-H 2 ), 2.68-2.86 (2H, m, 10-H, 11-H), 3.20 (6H, q, / 6.4Hz, 3 x NCH 2 ), 3.15-3.92 (8H, m, N-CH 2 , 5-H, 6-H, 7-H, 13-H, 16-H 2 ), 5.73 (IH, s, 2-H).
  • Example 6 N- ⁇ 8-[(4-Methyl-l,2-dithioIo-[4,3-b]-5(4H)-oxopyrrol-6- yI)carbamoyl]octan-l-yl ⁇ monamide
  • C - Prepared as described in Example 5(a) from the mixed anhydride of monic acid C and 8- aminocaprylic acid in 30% yield; ⁇ j-i (250MHz, CD3OD, Me4Si) inter alia 0.99 (3H, d, / 7Hz, 17-H 3 ), 1.09 (3H, d, / 6.4Hz, 14-H 3 ), 1.31 (9H, t, / 7.3Hz, 3 x CH 3 ), 1.25- 1.70 (13H, m, 5 x CH 2 , 9-H 2 , 12-H), 1.76 (IH, m, 8-H
  • This material was dissolved in ethanol (130ml), water (40ml) and 5N hydrochloric acid (25ml), and the mixture hydrogenated over 10% palladium on charcoal catalyst ( Og). Further portions of catalyst were added at intervals. After 3h hydrogenation the catalyst was filtered off, washed with water, and the solution evaporated to dryness.
  • the tetrahydropyranyl ester (0.185g, 0.29mmol) was dissolved in methanol (5ml) and water (4ml), and glacial acetic acid (1 drop) added. The mixture was stirred for 3%h, then diluted with aqueous sodium hydrogen carbonate and washed with diethyl ether. The aqueous phase was then layered with ethyl acetate and adjusted to pH 3.5 with 1.5M phosphoric acid. The phases were separated, and the aqueous extracted with ethyl acetate (x2).
  • Carboxyprop-l-oxy)phenyl]-2-(l-normon-2-yl)oxazole A (0.140g, 0.26mmol) was dissolved in dry tetrahydrofuran (10ml) and triethylamine (0.04ml, 0.29mmol), cooled in an ice-bath, and treated with isobutyl chloroformate (0.034ml, 0.26mmol). The mixture was stirred for Vih, then triethylamine (0.047ml, 0.34mmol) was added, followed by 6-amino-4-methyl-l,2-dithiolo-[4,3-b]-pyrrol-5(4H)-one hydrochloride (0.070g, 0.3 lmmol).
  • Example 8 5-[4-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yl)carbamoylmethyloxy-phenyl]-2-(l-normon-2-yl)oxazole A a) 5-(4-MethoxycarbonylmethyloxyphenyI)-2-(l-normon-2-yl)oxazole A - 5-
  • the product was an orange solid (0.24g, 78%); ⁇ max (KBr) 3372, 2922, 1653, 1616, and 1497cm" 1 ; ⁇ -ax (EtOH) 307 ( ⁇ m 31,503) and 393nm (11,405); ⁇ H (CD3OD/CDCI3) 0.93 (3H, d, / 7.1Hz, I7-H3), 1.19 (3H, d, / 6.5Hz, 14-H 3 ), 1.34-1.46 (IH, m, 12-H), 1.67-1.79 (2H, m, 9-H 2 ), 1.9-2.05 (IH, m, 8-H), 2.28 (3H, s, 15-H 3 ), 2.27-2.39 (IH, , 4-H), 2.67-2.84 (3H, m, 4-H, 10-H, 11-H), 3.37 (3H, s, NCH3), 3.35-3.45 (IH, m, 6-H), 3.57 (IH, br
  • Example 9 3R,4R-Dihydroxy-2-S-[2,4-dioxo-4- ⁇ 4-[3-(4-methyl-l,2-thiolo-[4,3- b]-5(4H)-oxopyrrol-6-yl)carbomoylprop-l-yloxy]phenyl ⁇ but-l-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methyIhexyl)tetrahydropyran a) 4-(3-carbomethoxyprop-l-yloxy)benzaldehyde - Using the method described in Example la, p-hydroxybenzaldehyde (1.22g, lOmmol) was reacted with methyl 4-bromobutyrate (1.81g, lOmmol) to give the title compound (1.37g, 61%) as a light yellow solid; ⁇ H (CDCI3) 2.16 (2H, m, 2'-H), 2.58 (2H
  • Example 9c Using the method described in Example Id, the product from Example 9c ( Og) was converted to the title compound (780mg); ⁇ fl (CDCI3) inter alia 0.92 (3H, d, J 7.0Hz, I7-H3), 1.22 (3H, d, / 6.2Hz, 14-H 3 ), 3.71 (3H, s, CO 2 Me), 6.21 (IH, s, 2- H), 6.93 (2H, d, / 9.0Hz, 3 * , 5'-H 2 ), 7.86 (2H, d, / 8.9Hz, 2", 6'-H 2 ).
  • the ⁇ spectrum indicated that the title compound was essentially in the enolic form.
  • Example 10 3R,4R-Dihydroxy-2S-[2,4-dioxo-4- ⁇ 4-[4-(l,2-dithiolo-[4,3-b]- 5(4H)-oxopyrrol-6-yl)carbamoylbut-l-yloxy)phenyl ⁇ but-l-yl]-5S-(2S,3S-epoxy- 5S-hydroxy-4S-methyIhexyl)tetrahydropyran - Using the method described in Example If, the product from Example le (180mg, 0.345mmol) was reacted with holothin hydrochloride (99mg, 0.474mmol) to give the title compound (41mg, 17%); v max (KB') 3404 , !636, 1599, 1506cm" 1 ; ⁇ max (EtOH) 387.5nm ( ⁇ m 10,154) 323.5 (22,970); ⁇ H (CDCl /d4-M
  • Example 11 3R,4R-Dihydroxy-2S-[2,4-dioxo-4- ⁇ 4-(3-l,2-dithiolo-[4 -b]-5(4H)- oxopyrrol-6-yl)carbamoylprop-l-yloxy]phenyl ⁇ but-l-yI]-5S-(2S,3S-epoxy-5S- hydroxy-4S-methylhexyl)tetrahydropyran - Using the method described in Example If, the product from Example 9e (577mg, 1.13mmol) was reacted with holothin hydrochloride (353mg, 1.69mmol) to give the title compound (206mg, 27%); v max (KBr) 3414, 1653, 1607cm" 1 ; ⁇ x (EtOH) 324.5nm ( ⁇ m 22,566), 385.
  • Example 12 2- ⁇ 4-(4-Methyl-l,2-dithioIo-[4,3-b]-5(4H)-oxopyrrol-6- yI)carbamoylbutoxy ⁇ thiazol-5-yl l-normon-2-yl ketone
  • n-Butyllithium (2.3M in hexane, 34.6ml, 79.7mmol) was added dropwise to tris(methylthio)methane (8.83ml, 66.3mmol) in dry tetrahydrofuran (120ml) at -78°C. After 1.5 hours the above compound (16.8g, 66.3mmol) in dry tetrahydrofuran (25ml) was added dropwise keeping the temperature below -60°C. The mixture was stirred at -60°C for 20 minutes, allowed to warm to -45°C and stirred for a further 2 hours.
  • the product was a white foam (0.301g, 57%); v max (KBr) 2921, 1736, 1456, 1258, 1186, and 1059cm" 1 ; ⁇ ma ⁇ (EtOH) 301.5nm ( ⁇ m 20,078); ⁇ H (CD3OD) (inter alia) 0.95 (3H, d, / 7.0Hz, 17-H ), 1.20 (3H, d, / 6.4Hz, M-H3), 1.70-2.08 (9H, m, 3 x H , 9-H 2 and 8-H), 2.25 (3H, s, 15- H3), 3.70 (3H, s, CO 2 CH 3 ), 4.50 (2H, t, / 5.9Hz, 1"-H 2 ), 6.23 (IH, s, 2-H), and 7.95 (IH, s, 4'-H); m/z 541 ( +, 14%) and 115 (100).
  • the product was a white gum (0.187g, 83%); ⁇ H (CD3OD) (inter alia) 0.96 (3H, d, / 7.0Hz, 17-H 3 ), 1.21 (3H, d, / 6.4Hz, 14-H 3 ), 2.25 (3H, s, 15-H 3 ), 2.39 (2H, t, / 7.1Hz, 4"-H 2 ), 4.51 (2H, t, / 6.1Hz, 1"-H 2 ), 6.74 (IH, s, 2-H), and 7.94 (IH, s, 4'-H); mlz 527 (M+, 0.5%), 128 (48), 100 (100), and 56 (94); mlz (NH3, DCI) 528 (MH+, 4%), 147 (100), and 91 (100).
  • Example 13 2- ⁇ l,2-Dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yI ⁇ carbamoyImethyloxythiazol-5-yl l-normon-2-yl ketone
  • Paraformaldehyde (3g) was heated in a flask and the formaldehyde generated was blown over the surface of the vigorously stirred reaction mixture with a stream of argon. Stirred at -50°C for a further 1.5 hours, then saturated ammonium chloride solution (50ml) was added.
  • the reaction was stirred for 2 ⁇ hours while warming to room temperature, then diluted with ethyl acetate and washed with sodium hydrogen carbonate solution and brine, dried and evaporated to give a pale yellow oil (1.27g).
  • the aqueous phases were saturated with sodium chloride, layered with ethyl acetate, and adjusted to pH 3.2 with 1.5M phosphoric acid. The layers were separated and the aqueous extracted with ethyl acetate.
  • the combined organic extracts (from pH 3.2) were washed with brine, dried and evaporated to give a second product (0.80g, ca. 39%).
  • the second product was shown by n.m.r. to be a mixture (ca. 2:1) of N-(8-carboxy-2- oxooct-l-yl)monamide A and monic acid A.
  • the first product was purified by column chromatography on silica (35g), eluting with 0-5% methanol in dichloromethane, to give the title compound as a colourless gum (0.715g, 34%); ⁇ H (CD3OD) (inter alia) 0.95 (3H, d, / 7.1Hz, 17-H 3 ), 1.20 (3H, d, / 6.4Hz, H-H3), 2.14 (3H, s, 15-H 3 ), 2.31 (2H, t, / 7.4Hz, 8'-H 2 ), 2.48 (2H, t, /7.3Hz, 3'-H 2 ), 3.64 (3H, s, CO 2 CH 3 ), 4.02 (2H, s, l'-H 2 ), and 5.82 (IH, s, 2-H); mlz 527 (M + , 1%), 509 (1), 283 (34), 111 (78), and 55 (100).
  • Example 16 5-[6-(l,2-Dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoylhexyl]-2- (l-normon-2-yl)oxazole A a) 5-(6-MethoxycarbonylhexyI)-2-(l-normon-2-yI)oxazoIe A - Using the method described in Example 15, N-(8-methoxycarbonyl-2-oxooct-l-yl)monamide A (from Example 14d, 0.695g, 1.32mmol) was cyclised to give the title compound as a colourless gum (0.106g, 16%); ⁇ (CD3OD) (inter alia) 0.96 (3H, d, /7.1Hz, 17- H3), 1.21 (3H, d, / 6.4Hz, 14-H 3 ), 2.20 (3H, s, 15-H 3 ), 2.34 (2H, t,
  • Example 17 5-[4-(l,2-DithioIo-[4,3-b]-5(4H)-oxopyrrol-6- yI)carbamoylmethyloxyphenyI]-2-(l-normon-2-yl)oxazole
  • the product of Example 8b (0.212g, 0.4 lmmol) was reacted to give the title compound as an orange foam (0.104g, 38%); v max (KBr) 3385, 1666, 1537, 1498, and 1245cm- 1 ; ⁇ m ax (EtOH) 306 ( ⁇ m 29,743) and 388nm (12,364); ⁇ H ((CD 3 ) 2 SO) 0.83 (3H, d, / 7.0Hz, 17-H 3 ), 1.06 (3H, d, / 6.4Hz, 14- H 3 ), 1.25-1.41 (IH, m, 12-H), 1.54-1.69 (2H,
  • Example 18 N- ⁇ 4-[3-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- ylaminocarbonyl)-propyloxy]phenyl ⁇ monamide
  • the mixed anhydride of monic acid A (688mg, 2mmol) was treated with 4-hydroxyaniline as described in Example 5a to give the title compound (641mg, 74%); v max (KBr) 3400 (br), 1663, 1637 and
  • Example 19 N- ⁇ 4-[4-(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yIaminocarbonyl)-butyloxy]benzyl ⁇ monamide
  • A Methyl 5-(4-methylphenoxy)pentanoate - A mixture of 4-methylphenol (2.66g), tetramethylguanidine (3.4ml) and methyl 5-bromopentanoate (3.5ml) in dry
  • Example 19b (526mg) in ethanol (30ml) was hydrogenated at room temperature and pressure over 5% Pd/C (lOOmg) for 30 minutes. The mixture was filtered and evaporated to give the title compound (476mg, 100%); v ma ⁇ (CH2CI2) 2952, 1733 and 1511cm- 1 ; ⁇ H [250MHz, (CD 3 ) 2 CO, Me Si] 1.79 and 1.95 (4H, 2 x m, 2 x CH 2 ), 2.41 (2H, m, CH 2 CO), 3.63 (3H, s, OMe), 4.01 (2H, m, OCH 2 ), 4.36 (2H, s, NCH 2 ), 6.85-7.31 (4H, m, Ar); mlz (EI + ) 237 (M + , 55%).
  • Example 20 N- ⁇ 8-[(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yl)carbamoyl]-octyl ⁇ monamide
  • a - A solution of monic acid A (820g) in THF (10ml) at -10°C under argon was treated sequentially with triethylamine (0.36ml) and isobutyl chloroformate (0.31ml). The mixture was stirred for
  • Example 21 N- ⁇ 9-[(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6- yl)carbamoyl]-nonyl ⁇ monamide
  • A Triethylammonium N-(9-carboxynonyl)monamide
  • the mixed anhydride of monic acid A (550mg) was reacted with 10-aminodecanoic acid (360mg) as described in Example 5a to give the title compound (800mg) as a mixture with triethylammonium monate A; ⁇ (250MHz, CD3OD, Me4Si) inter alia 0.96 (3H, d, / 7Hz, I7-H3), 1.22 (3H, d, / 6.5Hz, 14-H 3 ), 1.25-1.75 (
  • Example 21a N- ⁇ 9-[(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoyl]- nonyl ⁇ monamide
  • v m a ⁇ (KBr) 3373 (br), 2926, 1659, 1531 and 1435cm " 1 ; ⁇ max (EtOH) 392.5 ( ⁇ m 9,285), 315 ( ⁇ m 3,399), 214.5 ( ⁇ m 24,303); ⁇ H (250MHz, CD3OD, Me Si) 0.96 (3H, d, / 7.1Hz, I7-H3), 1.21 (3H, d, / 6.5Hz, 14-H 3 ), 1.27-1.75 (17H, m, 9-H 2 , 12-H, 7 x CH 2 ), 1.98 (IH
  • Example 22 N- ⁇ 10-[(4-Methyl-l,2-dithiolo-[43-b]-5(4H)-oxopyrrol-6- yl)carbamoyl]-decyi ⁇ monam ⁇ de A a) N-(10-Carboxydecyl)monamide A - The mixed anhydride of monic acid A (688mg, 2mmol) was reacted with 11-aminoundecanoic acid (474mg, 2mmol) as described in Example 20a to give the title compound (200mg, 19%); ⁇ jj (250MHz, CD3OD, Me4Si) 0.96 (3H, d, / 7Hz, I7-H3), 1.21 (3H, d, / 6.4Hz, 14-H 3 ), 1.26-1.75 (19H, m, 9-H 2 , 12-H, 8 x CH 2 ), 1.95 (IH, m, 8-H), 2.10-2.33 (6H,
  • Example 22a N- ⁇ 10-[(4-Methyl-l ⁇ -dithiolo-[4,3-b]-5(4H)-oxopyrroI-6-yl)carbamoyl]- decyljmonamide
  • Example 23 N ⁇ ll-[(4-Methyl-l,2-dithiolo-[4,3*.b]-5(4H)-oxopyrrol-5- yl)carbamoyI]-undecyl ⁇ monamide
  • A N-(ll-Carboxyundecyl)monamide
  • the mixed anhydride of monic acid A (688mg, 2mmol) was reacted with 12-aminododecanoic acid (504mg, 2mmol) as described in Example 20a to give the title compound (135mg, 12%); ⁇ jj (250MHz, CD3OD, Me4Si) 0.96 (3H, d, /7.1Hz, 17-H ), 1.22 (3H, d, / 6.4Hz, I4-H3), 1.26- 1.76 (21H, m, 9-H 2 , 12-H, 9 x CH 2 ), 1.96 (IH, m, 8-H), 2.06-2.85 (6H,
  • Example 23a N- ⁇ ll-[(4-Methyl-l,2-dithiolo-[4,3-b]-5(4H)-oxopyrrol-5-yl)carbamoyl]- undecyl ⁇ monamide
  • Example 5b The product from Example 23a was converted to the title compound by the method described in Example 5b (97mg, 60%); v m a ⁇ (KBr) 3404 (br), 2924, 1653 and 1538cm " 1 ; ⁇ max (EtOH) 391.5 ( ⁇ m 9,918), 315.5 (4,172), 212.5 (26,196); ⁇ H (250MHz, CD3OD, Me 4 Si) 0.96 (3H, d, / 7Hz, 17-H 3 ), 1.21 (3H, d, / 6.4Hz, H-H3), 1.24-1.75 (2H, m, 9-H , 12-H, 9 x CH 2 ), 1.96 (IH, m, 8- H), 2.08-2.23 (4
  • Example 21a The product from Example 21a (710mg) was converted, by the method described in Example 10 to a product containing the title compound; v m a ⁇ (KBr) inter alia 3393 (br), 2970, 1653 and 1537cm" l ; ⁇ fj (250MHz, CD3OD, Me4Si) inter alia 0.96 (3H, d, / 7Hz, I7-H3), 1.21 (3H, d, / 6.4Hz, 14-H 3 ), 1.25-1.75 (17H, m, 9-H 2 , 12-H, 7 x CH 2 ), 1.96 (IH, m, 8-H), 2.06-2.30 (4H, m, 4-H, 15-H 3 ), 2.40 (2H, t, / 7.3Hz, CH 2 CO), 2.55-2.88 (3H, m, 4-H, 10-H, 11-H), 3.13-3.95 (8H, m, 5-H, 6-H, 7-H, 13- H, 16-H 2
  • Example 25 E-2- ⁇ 2-[3R,4R-Dihydroxy-5S-(2S S-epoxy-5S-hydroxy-4S- methylhexyl)-tetrahydropyran-2S-yl]-l-methylethyIidene ⁇ -5[5-(4-methyl-l,2- dithiolo[4,3-b]-5-(4H)-oxopyrrol-6-yl)carbamoylpent-l-yloxy]indan-l-one a) 2-Bromo-5-t-butyldimethylsilyloxybenzyl bromide - 4-Bromo-3- methylphenol (4.49g, 24.0mmol), t-butyldimethylsilyl chloride (5.43g, 36.0mmol) and imidazole (4.90g, 22.0mmol) in N,N-dimethylformamide (30ml) were stirred at room temperature for 16h.
  • Ci3H 2 oBr 2 OS requires M, 377.9652.
  • Diisopropylamine (0.16ml, l.l ⁇ mmol) and t-butyllithium (1.7M in hexane, 3.88ml, 6.60mmol) were added dropwise sequentially to N-methoxy-N-methyl-6,7,13-O-tris(trimethylsilyl)monamide A (3.60g, ⁇ .OOmmol) in THF (30ml) maintaining the temperature below -65°C.
  • Methyl 6-iodohexanoate (0.3g, 1.15mmol) in THF (3ml) was added followed by DMF (5ml) and 15-crown-5 (O.lg, 0.58mmol). The resulting solution was stirred for 48 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water, dried (MgSU4), ancl evaporated.
  • Example 26 E-2- ⁇ 2-[3R,4R-Dihydroxy-5S-(2S S-epoxy-5S-hydroxy-4S- methylhexyl)-tetrahydropyran-2S-yl]-l-methylethylidene ⁇ -5-[3-(4-methyl-l,2- dithiolo[4,3-b]-5-(4H)-oxopyrrol-6-yl)carbamoylprop-l-yl]indan-l-one a) E-2- ⁇ 2-[3R,4R-Dihydroxy-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl]-l-methylethylidene ⁇ -5-(3-methoxycarbonylprop-l- yloxy)-indan-l-one - The product from Example 25c (0.53g, 1.22 x lO ' - ⁇ moles) was dissolved
  • methyl 4- iodobutanoate (0.27g, 1.22 x 10" ⁇ -'moles) was added in dry DMF (1ml). After lhour, a further portion of methyl-4-iodobutanoate (0.06g, 2.7 x 10 "4 moles, 0.2eq.) was added and the resulting solution stirred for 22hours. Water was added and the products extracted into ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulphate and evaporated to dryness.
  • Example 27 E-2- ⁇ 2-[3R,4R-Dihydroxy-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl) tetrahydropyran-2S-yl]-l-methylethylidene ⁇ -5-[l-(4-methyl-l,2- dithiolo[4 -b]-5-(4H)-oxopyrrol-6-yl)carbamoylmethoxy]indan-l-one a) E-2- ⁇ 2-[3R,4R-Dihydroxy-5S-(2S3S-epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl]-l-methylethylidene ⁇ -5-(methoxycarbonyl methoxy)indan-l-one - The product from Example 25c (0.56g, 1.29 x lO'- ⁇ moles) in dry DMF (5ml) was added slowly to a suspension of
  • methyl bromoacetate (0.23g, 1.58 x 10" ⁇ • ⁇ 'moles, 1.2eq.) was added and the resulting solution was stirred under an atmosphere of argon for 5hours. Water was added and the products extracted into ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulphate and evaporated to dryness.
  • Triethylamine hydrochloride was removed by trituration with dichloromethane, filtration gave the title compound as a yellow solid (70mg, 27%); ⁇ max (KBr) 3384, 1670, 1599, 1528cm " 1 ; ⁇ max (EtOH) 394.5nm ( ⁇ m 11,083), 302.0nm ( ⁇ m 25,132), 266.5nm ( ⁇ m 12,818); ⁇ [(CD 3 )2)SO] rer alia 0.85 (3H, d, /7.0Hz, I7-H3), 1.05 (3H, d, / 6.4Hz, 14-H 3 ), 1.30-1.40 (IH, m, 12-H), 1.48-1.70 (2H, m, 9-H 2 ), 1.75-1.85 (IH, m, 8-H), 2.28-2.38 (4H, m, 15-H 3 , 4-H), 2.55-2.8
  • Example 28 E-2- ⁇ 2-[3R,4R-Dihydroxy-5S(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)-tetrahydropyran-2S-yI]-l-methylethyIidene ⁇ 5-[l-(l,2-dithiolo[4,3- b]-5(4H)-oxopyrrol-6-yl)carbamoylmethoxy]indan-l-one - To the acid from Example 27b (160mg, 3.38 x 10" 4 mmol) in dry THF (10ml) under an atmosphere of argon, triethylamine (0.052ml, 3.7 x 10" moles) followed by isobutylchloroformate (0.044ml, 3.38 x 10" 4 moles) was added maintaining the external temperature below -20°C.
  • Example 29 E-2- ⁇ 2[5(5S-Hydroxy-4R-methylhex-2-enyl)-3R,4R- dihydroxytetrahydropyran-2S-yl]-l-methylethyIidene ⁇ 5-[l-(l,2-dithiolo[4 -b]- 5(4H)-oxopyrrol-6-yl)carbamoyl-methoxy]indan-l-one a) 2-Bromo-5-t-butyldimethyIsiIyloxybenzyl iodide - To 2-bromo-5-t- butyldimethylsilyoxybenzyl bromide from Example 25a (2g, 5.2mmol) in acetone (40ml), sodium iodide (7.9g, 52mmol) was added.
  • This mixture was treated with t-butyllithium (1.7M in pentane) (2.6ml, 4.4mmol) in dry THF (15ml) at -70°C for 2 hours. Saturated ammonium chloride solution (10ml) was added and the products were extracted into ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulphate, and evaporated to dryness, to give a complex mixture (1.4g). This mixture was treated with potassium t-butoxide (1M) (2.5ml, 2.5mmol) in dry THF (15ml) at -70°C for 2 hours. Acetic acid (0.16ml) followed by water was added.
  • Example 30 E-2- ⁇ 2(3R,4R-Dihydroxy-5S[2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydro-pyran-2S-yI]-l-methyIidene ⁇ 5-[3-(l,2-dithiolo[4,3-b]- 5(4 ⁇ )-oxopyrrol-6-yl)carbamoylpropyloxy]indan-l-one - To the acid from Example 26b (187mg, 0.36mmol) in dry THF (10ml), triethylamine (0.05ml, 0.36mmol) followed by isobutylchloroformate (0.064ml, 0.36mmol) were added at -20°C.
  • Example 31 5-[6-(l,2-Dithiolo-[4,3-b]-5(4H)-oxopyrroI-6-yl)carbamoylhexyl]-2- (l-normon-2-yl)-l,3,4-oxadiazole
  • Example 3 Id 5-[6-(l,2-Dithiolo-[4,3-b]-5(4H)-oxopyrrol-6-yl)carbamoylhexyl]-2-[l- normon-2-yl]-l,3,4-oxadiazole

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Abstract

Dérivés d'acides moniques A et C de la formule (I), dans laquelle A représente une fraction époxy ou une fraction à liaison double-E (i) ou (ii); B est choisi entre (a), (b), (c) et (d) (qui correspond à C(OH)=CHCO-B3), Q représentant le reste d'un noyau aryle ou hétéroaryle éventuellement substitué; D représente un groupe d'atomes liant B à -CONR1; ou B-D représentent (E)-C(CH¿3?)=CH; et R?1 et R2¿, qui peuvent être identiques ou différents, sont chacun choisis entre hydrogène ou (C¿1-6?)alkyle, (C3-7)cycloalkyle, (C2-6)alcényle, aryle, aryl(C1-4)alkyle, hétérocyclyle, (C1-6)alkylcarbonyle, (C3-7)cycloalkylcarbonyle, (C2-6)alcénylcarbonyle, arylcarbonyle, aryl(C1-4)alkylcarbonyle ou hétérocyclylcarbonyle, dont chacun peut éventuellement être substitué. Ces dérivés présentent une activité antibactérienne, antimycoplasmique, antifongique et herbicide.
PCT/EP1994/002552 1993-08-13 1994-08-02 Derives d'acides moniques a et c a activite antibacterienne, antimycoplasmique, antifongique et herbicide WO1995005384A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7506705A JPH09504512A (ja) 1993-08-13 1994-08-02 抗菌活性、抗マイコプラズマ活性、抗真菌類活性および除草活性を有するモン酸ａおよびｃの誘導体
EP94924831A EP0712405A1 (fr) 1993-08-13 1994-08-02 Derives d'acides moniques a et c a activite antibacterienne, antimycoplasmique, antifongique et herbicide
AU74975/94A AU7497594A (en) 1993-08-13 1994-08-02 Derivatives of monic acids a and c having antibacterial, antimycoplasmatical, antifungal and herbicidal activity

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GB939316879A GB9316879D0 (en) 1993-08-13 1993-08-13 Novel compounds
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GB9400592A GB9400592D0 (en) 1994-01-14 1994-01-14 Novel compounds
GB9401139A GB9401139D0 (en) 1994-01-21 1994-01-21 Novel compounds
GB9401139.2 1994-01-21

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023795A1 (fr) * 1995-01-31 1996-08-08 Sankyo-Company, Limited Derives d'acide pseudomonique
WO1997005126A1 (fr) * 1995-07-29 1997-02-13 Smithkline Beecham Plc Mupirocinsulfamates a activite antibacterienne
US5726195A (en) * 1995-07-28 1998-03-10 Cubist Pharmaceuticals, Inc. Aminoacyl adenylate mimics as novel antimicrobial and antiparasitic agents
WO2000021949A1 (fr) * 1998-10-12 2000-04-20 Smithkline Beecham Plc Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens
US6333344B1 (en) 1999-05-05 2001-12-25 Merck & Co. Prolines as antimicrobial agents
US6348482B1 (en) 1999-05-05 2002-02-19 Merck & Co., Inc. Catechols as antimicrobial agents
EP1884520A2 (fr) 1999-12-15 2008-02-06 Cubist Pharmaceuticals, Inc. Analogues de daptomycine en tant qu'agents antibactériens
EP1932853A1 (fr) 2001-08-06 2008-06-18 Cubist Pharmaceutical Inc. Nouveaux depsipeptides et leur procédé de préparation
EP2159229A1 (fr) 2000-01-20 2010-03-03 Cubist Pharmaceuticals, Inc. Lipopeptides à haute pureté, micelles de lipopeptides et procédés de préparation
WO2010075215A1 (fr) 2008-12-22 2010-07-01 Cubist Pharmaceuticals, Inc. Nouveaux agents antibactériens pour le traitement d'infections gram positives
EP2261237A2 (fr) 2000-12-18 2010-12-15 Cubist Pharmaceuticals, Inc. Daptomycine et analogues sous forme cristalline, leur préparation et utilisation
EP2332965A1 (fr) 2004-07-01 2011-06-15 BioSource Pharm, Inc. Antibiotiques peptidiques et leurs methodes de fabrication
US8071637B2 (en) 2006-09-29 2011-12-06 Welichem Biotech Inc. Dithiolopyrrolones compounds and their therapeutic applications
US8343912B2 (en) 2008-12-23 2013-01-01 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8415307B1 (en) 2010-06-23 2013-04-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
WO2013149121A1 (fr) 2012-03-30 2013-10-03 Cubist Pharmaceuticals, Inc. Inhibiteurs de la 1,3,4-oxadiazole et de la 1,3,4-thiadiazole bêta-lactamase
US9051330B2 (en) 2002-03-26 2015-06-09 Welichem Biotech Inc. Dithiolopyrrolones with therapeutic activity

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5299926B2 (ja) * 2011-03-28 2013-09-25 学校法人東京薬科大学 ミキソピロニン誘導体含有抗菌剤

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Publication number Priority date Publication date Assignee Title
EP0001914A2 (fr) * 1977-11-05 1979-05-16 Beecham Group Plc Amides possédant une activité antibactérienne, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0087953A2 (fr) * 1982-02-27 1983-09-07 Beecham Group Plc Composés 1-normon-2-yl-hétérocycliques antibactériens
EP0512824A1 (fr) * 1991-05-07 1992-11-11 Sankyo Company Limited Composé antibactérien
WO1993015072A1 (fr) * 1992-01-24 1993-08-05 Smithkline Beecham Plc Cetones de thiazolyle 1-normon-2-yl

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0001914A2 (fr) * 1977-11-05 1979-05-16 Beecham Group Plc Amides possédant une activité antibactérienne, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0087953A2 (fr) * 1982-02-27 1983-09-07 Beecham Group Plc Composés 1-normon-2-yl-hétérocycliques antibactériens
EP0512824A1 (fr) * 1991-05-07 1992-11-11 Sankyo Company Limited Composé antibactérien
WO1993015072A1 (fr) * 1992-01-24 1993-08-05 Smithkline Beecham Plc Cetones de thiazolyle 1-normon-2-yl

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J.P. CLAYTON ET AL., JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 1982, LETCHWORTH GB, pages 2827 - 2833 *
L.L. KLEIN ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 32, no. 1, 1989, WASHINGTON US, pages 151 - 160 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023795A1 (fr) * 1995-01-31 1996-08-08 Sankyo-Company, Limited Derives d'acide pseudomonique
US5726195A (en) * 1995-07-28 1998-03-10 Cubist Pharmaceuticals, Inc. Aminoacyl adenylate mimics as novel antimicrobial and antiparasitic agents
WO1997005126A1 (fr) * 1995-07-29 1997-02-13 Smithkline Beecham Plc Mupirocinsulfamates a activite antibacterienne
WO2000021949A1 (fr) * 1998-10-12 2000-04-20 Smithkline Beecham Plc Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens
US6333344B1 (en) 1999-05-05 2001-12-25 Merck & Co. Prolines as antimicrobial agents
US6348482B1 (en) 1999-05-05 2002-02-19 Merck & Co., Inc. Catechols as antimicrobial agents
US6417217B1 (en) 1999-05-05 2002-07-09 Merck & Co., Inc. Prolines as antimicrobial agents
US6545015B2 (en) 1999-05-05 2003-04-08 Merck & Co., Inc. Catechols as antimicrobial agents
US6579894B2 (en) 1999-05-05 2003-06-17 Merck & Co., Inc. Prolines as antimicrobial agents
EP1884520A2 (fr) 1999-12-15 2008-02-06 Cubist Pharmaceuticals, Inc. Analogues de daptomycine en tant qu'agents antibactériens
EP2298790A1 (fr) 1999-12-15 2011-03-23 Cubist Pharmaceuticals, Inc. Analogues de daptomycine en tant qu'agents antibactériens
EP2264047A1 (fr) 2000-01-20 2010-12-22 Cubist Pharmaceuticals, Inc. Lipopeptides à haute pureté, micelles de lipopeptides et procédés de préparation
EP2159229A1 (fr) 2000-01-20 2010-03-03 Cubist Pharmaceuticals, Inc. Lipopeptides à haute pureté, micelles de lipopeptides et procédés de préparation
EP2940034A1 (fr) 2000-01-20 2015-11-04 Cubist Pharmaceuticals, Inc. Procédé de purification de daptomycin
EP2940036A1 (fr) 2000-01-20 2015-11-04 Cubist Pharmaceuticals, Inc. Lipopeptides à haute pureté, micelles de lipopeptides et procédés de préparation
EP2261237A2 (fr) 2000-12-18 2010-12-15 Cubist Pharmaceuticals, Inc. Daptomycine et analogues sous forme cristalline, leur préparation et utilisation
EP1932853A1 (fr) 2001-08-06 2008-06-18 Cubist Pharmaceutical Inc. Nouveaux depsipeptides et leur procédé de préparation
US9051330B2 (en) 2002-03-26 2015-06-09 Welichem Biotech Inc. Dithiolopyrrolones with therapeutic activity
US8889826B2 (en) 2004-07-01 2014-11-18 Biosource Pharm, Inc. Peptide antibiotics and methods for making same
EP2332965A1 (fr) 2004-07-01 2011-06-15 BioSource Pharm, Inc. Antibiotiques peptidiques et leurs methodes de fabrication
US8071637B2 (en) 2006-09-29 2011-12-06 Welichem Biotech Inc. Dithiolopyrrolones compounds and their therapeutic applications
US8507647B2 (en) 2008-12-22 2013-08-13 Cubist Pharmaceuticals, Inc. Antibacterial agents for the treatment of gram positive infections
EP2674437A1 (fr) 2008-12-22 2013-12-18 Cubist Pharmaceuticals, Inc. Nouveaux agents antibactériens pour le traitement d'infections GRAM positives
WO2010075215A1 (fr) 2008-12-22 2010-07-01 Cubist Pharmaceuticals, Inc. Nouveaux agents antibactériens pour le traitement d'infections gram positives
US8937040B2 (en) 2008-12-23 2015-01-20 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8343912B2 (en) 2008-12-23 2013-01-01 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8906866B2 (en) 2010-06-23 2014-12-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8415307B1 (en) 2010-06-23 2013-04-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
WO2013149121A1 (fr) 2012-03-30 2013-10-03 Cubist Pharmaceuticals, Inc. Inhibiteurs de la 1,3,4-oxadiazole et de la 1,3,4-thiadiazole bêta-lactamase

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IL110620A0 (en) 1994-11-11
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MA23309A1 (fr) 1995-04-01
AP9400663A0 (en) 1996-02-10
EP0712405A1 (fr) 1996-05-22

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