EP0785937A1 - Derives de 2-(imidazol-4-yl)carbapeneme, leurs intermediaires ainsi que leur utilisation en tant qu'antibacteriens - Google Patents

Derives de 2-(imidazol-4-yl)carbapeneme, leurs intermediaires ainsi que leur utilisation en tant qu'antibacteriens

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Publication number
EP0785937A1
EP0785937A1 EP95934654A EP95934654A EP0785937A1 EP 0785937 A1 EP0785937 A1 EP 0785937A1 EP 95934654 A EP95934654 A EP 95934654A EP 95934654 A EP95934654 A EP 95934654A EP 0785937 A1 EP0785937 A1 EP 0785937A1
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EP
European Patent Office
Prior art keywords
group
compound
formula
preparation
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP95934654A
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German (de)
English (en)
Inventor
Eric Hunt
Steven Coulton
Jeremy David Hinks
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GB9420710A external-priority patent/GB9420710D0/en
Priority claimed from GB9424248A external-priority patent/GB9424248D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0785937A1 publication Critical patent/EP0785937A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a class of antibacterial compounds, in particular a class of carbapenems, processes for their preparation, pharmaceutical and veterinary compositions comprising such compounds, intermediates thereof, and their use in antibacterial therapy.
  • Carbapenems such as imipenem, the compound of formula (A):
  • Stability towards DHP-1 may also be imparted by chemical modification of the carbapenem nucleus, for instance by incorporating a 1 ⁇ -methyl substitutent, as in the compound meropenem, the compound of formula (B):
  • An alternative approach to imparting improved stability to DHP- 1 utilises 2- carbon substituted carbapenems, for instance, 2-aryl, 2-heteroaryl and 2- heteroaromatic carbapenems (US 4 543 257, US 4 260 627, US 4 962 101, US 4 978 659, EP 0 14 493, EP 0 414489, EP 0 010 316 and EP 0 030 032 Merck & Co) and 2-(substituted)methyl carbapenems (Schmidt et al, J.Amibiotics, 41, 1988, 780).
  • 2-aryl, 2-heteroaryl and 2- heteroaromatic carbapenems US 4 543 257, US 4 260 627, US 4 962 101, US 4 978 659, EP 0 14 493, EP 0 414489, EP 0 010 316 and EP 0 030 032 Merck & Co
  • 2-(substituted)methyl carbapenems
  • UK Patent 1 593 524, Merck & Co. discloses a number of C-2 substituted 5- me bered heteroaromatic carbapenem derivatives, including diazolyl and tetrazolyl compounds.
  • the heterocyclic ring is attached to the carbapenem nucleus through the C-2 position of the imidazole ring.
  • R a or R* 3 alone is hydrogen, optionally substituted (C ⁇ _6)alkyl or together form a 5 or
  • R! is (C ⁇ _6)alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a readily removable hydroxy protecting group, or by an amino group which is optionally protected by a readily removable amino protecting group; R is hydrogen or methyl and
  • -CO2R ⁇ is carboxy or a carboxylate anion or the group R3 is a readily removable carboxy protecting group.
  • Suitable (C j .g) alkyl groups for the substituent R a or R& include straight and branched chain alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl, n-propyl and wo-propyl, preferably methyl.
  • Suitable optional substituents for the (Cj_6) alkyl group in R a or R D include, for example, halogen, hydroxy, (C ⁇ alkoxy, carboxy and salt thereof, (C ⁇ -6)alkoxycarbonyl, carbamoyl, mono- or di(C ⁇ -6)alkylcarbamoyl, sulphamoyl, mono- and di(C ⁇ -6)alkylsulphamoyl, amino, mono- and di(C ⁇ -6)alkylamino, (C ⁇ -6)acylamino, ureido, (C ⁇ -6)alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, oxo, acyl, 2-thienyl, (C j -6)alkylthio, arylthio, (C i -6)alkane-sulphinyl, arylsulphinyl, (C i - ⁇ Jal
  • R a and/or R D is substituted with a (C j .6) alkyl, is when the substituent is methyl.
  • Suitable (Cj.g) alkyl groups for R* include straight and branched chain alkyl groups having from 1 to 6 carbon atoms.
  • Preferred alkyl groups include methyl, ethyl and is ⁇ -pr ⁇ pyl, of which ethyl is especially preferred.
  • the (Cj.g) alkyl group of R ⁇ has a hydroxy, fluoro or amino substituent which is suitably at position- 1 of the alkyl group.
  • R* is (R)- 1 -hydroxyethyl.
  • R ⁇ is hydrogen
  • aryl includes phenyl and naphthyl.
  • an aryl group including phenyl and naphthyl, may be optionally substituted by up to five, preferably up to three substituents.
  • Suitable substituents include halogen, (Ci.gjalkyl, aryl(C ⁇ _4)alkyl (C j .6)alkoxy, (C ⁇ 6)alkoxy(C ⁇ _6)alkyl, halo(C ⁇ _6)alkyl, hydroxy, amino, mono- and di-/V-(C ⁇ _6)alkylamino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C ⁇ 6)alkylcarbamoyl, (C ⁇ _6)alkoxycarbonyl, (C ⁇ -6)alkoxycarboxylate, aryloxycarbonyl, (C ⁇ _6)alkoxycarbonyl-(C ⁇ _6)alkyl aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (C ⁇ _6)alkylthio, (C ⁇ .
  • C ⁇ _6 alkyl sulphinyl
  • heterocyclyl heterocyclyl
  • C ⁇ _4 heterocyclyl
  • two adjacent ring carbon atoms may be linked by a (C3_5)alkyl or alkylene chain, to form a carbocyclic ring.
  • heteroaryl includes aromatic single and fused rings containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three substituents.
  • Each heteroaryl ring suitably has 5 or 6 ring atoms.
  • a fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring.
  • heterocyclyl and “heterocyclic” suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings ,may be unsubstituted or substituted by, for example, up to three substituents.
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • a substituent for a heteroaryl or a heterocyclyl group is selected from halogen, (C ⁇ _6)alkyl, aryl(C ⁇ _4)alkyl(C ⁇ _6)alkoxy, (C ⁇ 6)alkoxy(C ⁇ _6)alkyl, halo(Ci_6)alkyl, hydroxy, amino, mono- and di-N-(C ⁇ 6)alkyl-amino, acylamino,carboxy salts.carboxy esters, carbamoyl, mono- and di-N- (C ⁇ .6)alkylcarbonyl, (C ⁇ -6)alkoxycarboxylate, aryloxycarbonyl, (C ⁇ .
  • Suitable hydroxy and amino protecting groups for use in R* are those well known in the art and which may be removed under conventional conditions and without disrupting the remainder of the molecule.
  • a comprehensive discussion of the ways in which hydroxy and amino groups may be protected and methods for cleaving the resulting protected derivatives is given in for example "Protective Groups in
  • Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as, for instance, trialkylsilyl and also organooxycarbonyl groups such, as for instance, allyloxycarbonyl, trichloroethyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
  • Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
  • R ⁇ is hydrogen are primarily of use as intermediates in the preparation of compounds of formula (I) in which R ⁇ is hydrogen or a pharmaceutically acceptable salt thereof. Salts within compounds of formula (I) may be prepared by salt exchange in a conventional manner. Similarly, carboxy-protected derivatives of formula (I) i.e. those compounds of formula (I) in which R ⁇ is a readily removable carboxy protecting group, may be used in the preparation of a compound of formula (I) in which R ⁇ is hydrogen or a pharmaceutically acceptable salt thereof. Included within the scope of readily removable carboxy protecting groups for R ⁇ are ester groups including pharmaceutically acceptable in vivo hydrolysable ester groups.
  • Suitable readily removable carboxy protecting groups for the group -CO2R ⁇ include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters.
  • the derivative is preferably one which may readily be cleaved.
  • Suitable ester-forming carboxy-protecting groups are those which may be removed under conventional conditions.
  • a carboxy group may be regenerated from any of the above esters by the usual methods appropriate to the particular R3 group, for example, acid- and base-catalysed hydrolysis, enzymically-catalysed hydrolysis or photochemical methods, under conditions wherein the remainder of the molecule is substantially unaffected.
  • ester-forming carboxy-protecting group is 4-methoxybenzyl, which may be suitably be removed using aluminium chloride and anisole, 4-nitrobenzyl which may be suitably removed using iron powder and ammonium chloride (1M soln) or by hydrogenation using palladium on a carbon catalyst; or allyl which may be suitably removed using rerr ⁇ £w(triphenylphosphine)-palladium and triphenylphosphine.
  • the hydroxy, amino and carboxy-protecting groups when used, are selected so that they can be removed under the same conditions, in a single reaction step; for example allyloxycarbonyl (for hydroxy) and allyl (for carboxy) which may be both removed using tetr ⁇ &.s(triphenylphosphine)palladium and triphenylphosphine.
  • Another suitable combination is trialkylsilyl (for hydroxy) and 4- methoxybenzyl (for carboxy) which may both be removed using aluminium chloride and anisole.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
  • Suitable ester groups of this type include those of part formula (a), (b),
  • R a is hydrogen, (Cj-6)alkyl, (C3-7)cycloalkyl, methyl, or phenyl;
  • R D is (Cj- ⁇ alkyl, (C ⁇ -6)alkoxy, phenyl, benzyl, (C3-7)cycloalkyl, (C ⁇ -6)alkyl(C3-7)cycloalkyl, l-amino(C ⁇ -6)alkyl, or 1 -(Chalky l)amino(C ⁇ -6)alkyl; or
  • R a and R D together form a 1,2-phenylene group optionally substituted by one or two methoxy groups
  • R c is (C ⁇ -6)alkylene optionally substituted with a methyl or ethyl group; R and R e which may be the same or different is each (C ⁇ -6)alkyl;
  • R f is (C ⁇ -6)alkyl
  • R ⁇ is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C ⁇ -6)-alkyl, or (Cj-6)alkoxy;
  • Y is oxygen or NH.
  • suitable pharmaceutically acceptable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxy ethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl,
  • alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl
  • dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl
  • lactone groups such as phthalidyl and dimethoxyphthalidyl
  • esters linked to a second ⁇ -lactam antibiotic or to a ⁇ -lactamase inhibitor
  • a further suitable pharmaceutically acceptable in vivo hydrolysable ester group is that of the formula:
  • R n is hydrogen, (C ⁇ alkyl or phenyl.
  • Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (I) include metal salts, for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium; and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2- hydroxyethylamine, bw-(2-hydroxyethyl)-amine or tm-(2-hydroxyethyl)-amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, Nj - dibenzylethylenediamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N- benzyl-b-phenethylamine, dehydroabietylamine, N ⁇ V-bw-dehydro-abietylamine, ethylenediamine or N-
  • carbapenem compounds of the present invention are intended for use in pharmaceutical compositions, it will be further 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 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 readily be understood that the substantially pure form is preferred as for the carbapenem compounds. 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 present in the crystalline product.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • the carbapenem antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, according to techniques and procedures per se known in the an with reference to other antibiotics, and the invention therefore includes within its scope a pharmaceutical composition comprising an antibiotic compound according to the present invention such as, for example, a compound of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the compositions may be formulated for administration by any suitable route, such as oral, parenteral or topical application.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or 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 polyvinylpyrollidone; 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, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters, 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, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or aca
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound 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 compound.
  • the composition may contain from 0.1% to 99.5% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 100 mg to 12 g per day for an average adult patient (body weight 70 kg), for instance 1500 mg per day, depending on the route and frequency of administration. Such dosages correspond to approximately 1.5 to 170 mg/kg per day. Suitably the dosage is from 1 to 6g per day.
  • the daily dosage is suitably given by administering a compound of the invention several times in a 24-hour period. Typically, 250 mg is administered 4 times a day although, in practice, the dosage and frequency of administration which will be most suitable for an individual patient will vary with the age, weight and response of the patients, and there will be occasions when the physician will choose a higher or lower dosage and a different frequency of administration. Such dosage regimens are within the scope of this invention. No toxicological effects are indicated when a compound of the invention of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is administered in the above mentioned dosage range.
  • the present invention also includes a method of treating bacterial infections in humans and animals which method comprises administering a therapeutically effective amount of an antibiotic compound of the present invention of the formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • the present invention also provides for the use of a compound of formula (la) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof for the manufacture of a medicament for treating bacterial infection.
  • the compounds of the present invention of formula (la) or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof are active against a broad range of Gram-positive and Gram-negative bacteria, and may be used to treat a wide range of bacterial infections including those in immunocompromised patients.
  • the compounds of the invention of formula (la) or salts or pharmaceutically acceptable in vivo hydrolysable esters thereof are of value in the treatment of skin, soft tissue, respiratory tract and urinary tract infections in humans and may also be used to treat mastitis in cattle.
  • a particular advantage of the antibacterially active compounds of this invention is their stability to ⁇ -lactamase enzymes and they are therefore effective against ⁇ -lactamase producing organisms.
  • the present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula (II):
  • R3 is a readily removable carboxy protecting group
  • X is oxygen or a group PR ⁇ R5R6
  • R , R5 and R ⁇ which may be the same or different and is each an optionally substituted (C ⁇ .g)alkyl or an optionally substifuted aryl group, preferably an n-butyl or a phenyl group; under carbapenem ring forming conditions; and thereafter, and if necessary, carrying out any or all of the following steps: removing any protecting group(s); converting a first group R ⁇ comprising a hydroxyl substituent into a further group R* comprising an amino or fluoro group; and/or converting the product into a salt.
  • Suitable carbapenem ring forming conditions are well known in the art.
  • suitable ring forming conditions include treating the compound of formula (II) with a trivalent organic phosphorus compound of formula
  • R is (C ⁇ _4)alkyl, (C ⁇ _3)alkoxy or phenyl optionally substitued by (C ⁇ _3)alkyl;
  • R8 and R 9 which may be the same or different is each (C ⁇ _4)alkyl, allyl, benzyl or phenyl optionally substitued by (C]_3)alkyl or (Cj.3)alkoxy; by analogy with the process described in EP 0476649-A (Hoechst AG).
  • Suitable reagents of formula (III) include trimethyl phosphite, triethyl phosphite, dimethyl methylphosphonite and diethyl methylphosphonite.
  • the reaction is effected in an organic solvent such as tetrahydrofuran, ethyl acetate, an aromatic solvent such as benzene, toluene, xylene or mesitylene or a halogenated hydrocarbon solvent such as dichloromethane, trichloromethane or 1,1,2-trichloroethane, and at a temperature between 50 and 180° C, preferably between 70 and 165°C.
  • an organic solvent such as tetrahydrofuran, ethyl acetate, an aromatic solvent such as benzene, toluene, xylene or mesitylene or a halogenated hydrocarbon solvent such as dichloromethane, trichloromethane or 1,1,2-trichloroethane
  • R 4 , R and R > is each w-butyl
  • cyclisation may be effected at a lower temperature, for instance 50°C - 80°C, by analogy with the process described in WO 92/01695 (Beecham Group, for analogous penems).
  • a hydroxyl or an amino group may optionally be protected.
  • Suitable hydroxy protecting groups include organosilyl, for instance a trialkylsilyl group such as trimethylsilyl or t-butyl dimethylsilyl, or trichloroethyloxycarbonyl, 4-nitrobenzyloxy-carbonyl, 4-methoxybenzyloxy carbonyl and allyloxycarbonyl.
  • Suitable amino protecting groups include alloxycarbonyl, 4-methoxybenzyloxy carbonyl and 4-nitrobenzyloxycarbonyl.
  • Suitable values for the protecting group R ⁇ include allyl, 4-methoxybenzyl and 4-nitrobenzyl.
  • the conditions necessary for removing the protecting group will, of course, depend upon the precise nature of the protecting group. For instance, when of R is 4-methoxybenzyl, aluminium trichloride at -30 to -70°C may be used and when R is allyl (prop-2-en-l-yl), a combination of triphenylphosphine, sodium-2- ethylhexanoate in ethyl acetate/MDC and tetr ⁇ w-(triphenylphosphine)palladium (0) may be used and when R ⁇ is p-nitrobenzyl, hydrogenation in the presence of palladium on carbon catalyst in aqueous solvent eg, aqueous l,4,dioxan THF ethanol may be used.
  • aqueous solvent eg, aqueous l,4,dioxan THF
  • the present invention provides a compound of formula (II), as hereinbefore defined.
  • Compounds of formula (II) in which X is oxygen may be obtained by a process which comprises reacting a compound of formula (IV):
  • R 3 is a readily removable carboxy protecting group
  • R 3 is a readily removable carboxy protecting group; or a functional equivalent thereof; under dehydrating conditions, for instance azeotropic removal of water;
  • step (b) treating the intermediate formed in step (a) with a halogenating agent, for instance thionyl chloride, in the presence of a suitable base such as 2,6-lutidine; and (c) treating the intermediate formed in step (b) with a phosphorus reagent of the formula (VII):
  • a halogenating agent for instance thionyl chloride
  • R 4 , R ⁇ and R ⁇ are as hereinbefore defined, in the presence of a suitable base such as 2,6-lutidine.
  • R a , R D and R 2 are as hereinbefore defined and SiR3 ⁇ 4 is a trialkylsilyl such as trimethylsilyl or t-butyldimethylsilyl, with a compound of formula (IXa):
  • R 3 is either hydrogen or an aminoprotecting group, for instance, a trialkylsilyl group such as trimethylsilyl; in the presence of a Lewis acid, such as, for instance, zinc chloride or trimethylsilyl trifluoromethane sulphonate, in an inert organic solvent such a halogenated hydrocarbon solvent, for instance dichloromethane at ambient temperature:
  • a Lewis acid such as, for instance, zinc chloride or trimethylsilyl trifluoromethane sulphonate
  • Compounds of formula (Villa) may be prepared by treating compounds of formula (VIII) with trialkylsilyl chloride or trialkylsilyl triflate, and triethylamine in
  • aminoprotecting group R* 3 in (IXa) requires subsequent removal, this may be achieved by conventional means, such as mild acid treatment eg, methanol and hydrochloric acid or pyridinium p-toluenesulphonate, where R* 3 is trimethylsilyl.
  • R* and R 2 are as hereinbefore defined, R 3 is a readily removable carboxy protecting group and X* is a leaving group, with a compound of formula (XI):
  • Suitable hydroxy protecting groups include organosilyl, for instance a trialkylsilyl, group such as trimethylsilyl; 4-nitrobenzyloxycarbonyl and 4-methoxybenzyloxy carbonyl.
  • Suitable amino protecting groups include 4-methoxybenzyloxy carbonyl and 4-nitrobenzyloxycarbonyl.
  • Suitable values for the protecting group R 3 include 4-methoxybenzyl and 4-nitrobenzyl.
  • suitable leaving groups X * include for instance trifluoromethanesulphonyloxy, methanesulphonyloxy, 4-toluene sulphonyloxy, fluorosulphonyloxy, chloro, bromo, iodo and diphenoxyphosphoryloxy.
  • Suitable metals for use in the metallo group M are well known in the art and include tin, aluminium, zinc, boron, mercury and zirconium. Preferred examples of the metallo group M include for instance
  • Suitable cross-coupling catalysts are well known in the art and include palladium compounds, in particular palladium (0) and palladium (II) compounds, such as those described in "Palladium Reagents in Organic Synthesis", RF Heck, Academic Press Ltd, 1985.
  • Examples thereof include tr ⁇ (dibenzylideneacetone)dipalladium (0), tetr ⁇ £w(triphenylphosphine)palladium (0), trans dimethyl bw(triphenylphosphine)palladium (II), and palladium (II) acetate, benzyl bw(triphenylphosphine)palladium (II) chloride, b/.s(triphenylphosphine)palladium (II) dichloride.
  • Such palladium reagents are preferably used in combination with a halide source such as zinc chloride or lithum chloride and optionally in the presence of a phosphine ligand of palladium, for instance a compound such as a triarylphosphine, for example, rrw(4-methoxyphenyl)phosphine or trw(2,4,6-trimethoxyphenyl) phosphine; a tri-heteroarylphosphine, for example, trifurylphosphine, or a triarylarsine, for example triphenylarsine.
  • a phosphine ligand of palladium for instance a compound such as a triarylphosphine, for example, rrw(4-methoxyphenyl)phosphine or trw(2,4,6-trimethoxyphenyl) phosphine; a tri-heteroarylphosphine, for
  • a prefened catalyst system is trw(dibenzylideneacetone)dipalladium (0), in the presence of zinc chloride and a phosphine compound.
  • M is ClZn
  • a preferred catalyst is t (dibenzylideneacetone dipalladium (0), in the presence of a phosphine compound.
  • the reaction is effected in an inen aprotic polar coordinating solvent such as tetrahydrofuran, diethylether, dioxane, 2-dimethoxyethane, acetonitrile, dimethyl formamide, dimethyl sulphoxide and the like, and under a dry, inert atmosphere such as argon.
  • aprotic polar coordinating solvent such as tetrahydrofuran, diethylether, dioxane, 2-dimethoxyethane, acetonitrile, dimethyl formamide, dimethyl sulphoxide and the like
  • a dry, inert atmosphere such as argon.
  • the reaction is effected initially at a low temperature, for instance about -78°C, with the final phase of the reaction then being effected at ambient temperature.
  • 6-Acetylimidazo[2,l-b]thiazoline (0.504g; 3mM) was dissolved in dry THF (50ml) and cooled to -78°C under an atmosphere of argon.
  • a solution of lithium hexamethyldisilazide (IM solution in hexane; 3.0ml; 3.0mM) was added and stirring was continued at -78°C for 30min.
  • the diastercoisomeric mixture of hemiaminals was dissolved in dry THF (25ml) and cooled to -20°C under an atmosphere of argon. To the stined solution was added 2,6- lutidine (0.163ml), followed by thionyl chloride (0.151ml). Stirring was continued at - 20°C for 15min. The resulting suspension was then filtered, washing the precipitate with THF. The filtrate was evaporated to yield the diastereoisomeric chlorides as a pale yellow oil, v ⁇ (CH 2 C1 2 ) 1760, 1680cm " 1.
  • the t-butyldimethylsilyl ether from Preparation 3 (0.082g) was dissolved in dry THF (10ml) and stirred at room temperature for 64 hours with acetic acid (0.104g) and tetra-n-butyl ammonium fluoride (0.518ml of a IM solution in THF). The reaction solution was then diluted with ethyl acetate and washed with sat. sodium hydrogen carbonate solution and brine. The organic layer was dried (MgSO4) and evaporated at reduced pressure.
  • the product from Preparation 5 was convened to the title compound by the procedure of Example 1.
  • the white fluffy solid obtained after HP 20SS column chromatography was re-chromatographed over Biogel P-2, eluting with water, followed by further chromatography over HP 20SS eluting with a gradient of 0 to 10% ethanol-water.
  • the pure product was obtained as a white fluffy solid, v max (KBr), 3415 (broad), 1750, 1602 (shoulder) 1558cm" 1 ; ⁇ max (H 2 O) 31 lnm (e m 15,585).
  • Ethyl imidazole-2-thiol-4-carboxylate (30 g, 174.2 mM) was dissolved in DMF (100 ml) and iodomethane (11.93 ml, 27.2 g, 191.6 mM) was added. Triethylamine (26.7 ml, 19.4 g, 191.6 mM) was then added dropwise over 15 min. After stirring for 1 hour, the DMF was removed in vacuo and the residue diluted with EtOAc. The solid was removed by filtration and the filtrate evaporated to an oil, which solidified on standing to give crude ethyl 2-methylthioimidazole-4-carboxylate, suitable for further use.
  • Ethyl l-methyl-2-methylthioimidazole-4-carboxylate (7.0 g, 35 mM) was dissolved in EtOH (400 ml) and aqueous 2M NaOH (18.4 ml, 36.7 mM) was added. The mixture was heated to reflux for 2.5 h. The solvent was then removed by evaporation in vacua to give a white solid which was dried overnight at 40°C / 1 mmHg to give crude sodium l-methyl-2-methylthioimidazole-4-carboxylate suitable for further use.
  • N-Methoxy-l,N-dimethyl-2-methylthioimidazole-4-carboxamide (5.6 g, 26 mM) was dissolved in dry THF (90 ml) and the solution cooled in an ice bath under an atmosphere of argon. A solution of MeMgBr (3M in Et O) (10.4 ml, 31.2 mM) was added over 10 min. The cooling bath was then removed and the mixture stirred for 1.75 h. A mixture of EtOH (14 ml) and 5M hydrochloric acid (2.6 ml) was added and stirring continued for 30 min. The solvents were then removed by evaporation in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3.
  • the product from Preparation 8 (0.182 g; 0.42 mM) was dissolved in THF (10 ml) and treated with 0.05M hydrochloric acid (5 ml; 0.25 mM). The reaction mixture was stirred at ambient temperatures for 15 min. then neutralised by the addition of sat'd. aq. sodium hydrogen carbonate. The mixture was extracted with EtOAc, the extracts combined, washed with sat'd. brine, dried (MgSO4) and evaporated to dryness under reduced pressure.

Abstract

Composés de la formule générale (I) dans laquelle seul Ra ou Rb représente hydrogène, alkyle C¿1-6? éventuellement substitué, ou bien R?a ou Rb¿ forment ensemble un noyau hétérocyclique à 5 ou 6 chaînons qui peut contenir au moins un hétéroatome supplémentaire choisi parmi oxygène, azote ou soufre; R1 représente alkyle C¿1-6? non substitué ou substitué par fluoro, un groupe hydroxy éventuellement protégé par un groupe protecteur hydroxy pouvant être facilement enlevé ou par un groupe amino éventuellement protégé par un groupe protecteur amino pouvant être facilement enlevé; R?2¿ représente hydrogène ou méthyle et -CO¿2R?3 représente carboxy ou un anion carboxylate, ou le groupe R3 est un groupe protecteur carboxy que l'on peut facilement enlever. Ces composés sont utiles dans le traitement et la prophylaxie des infections bactériennes chez l'animal et chez l'homme.
EP95934654A 1994-10-14 1995-10-02 Derives de 2-(imidazol-4-yl)carbapeneme, leurs intermediaires ainsi que leur utilisation en tant qu'antibacteriens Withdrawn EP0785937A1 (fr)

Applications Claiming Priority (5)

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GB9420710 1994-10-14
GB9420710A GB9420710D0 (en) 1994-10-14 1994-10-14 Novel compounds
GB9424248A GB9424248D0 (en) 1994-12-01 1994-12-01 Novel compounds
GB9424248 1994-12-01
PCT/EP1995/003888 WO1996011932A1 (fr) 1994-10-14 1995-10-02 Derives de 2-(imidazol-4-yl)carbapeneme, leurs intermediaires ainsi que leur utilisation en tant qu'antibacteriens

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ATE223420T1 (de) 1997-01-28 2002-09-15 Meiji Seika Kaisha Carbapenemderivate
BR9912490A (pt) 1998-07-27 2001-06-05 Meiji Seika Kaisha Composto, composição farmacêutica, processo para tratar doenças infecciosas, e uso do composto
US20060281788A1 (en) 2005-06-10 2006-12-14 Baumann Christian A Synergistic modulation of flt3 kinase using a flt3 inhibitor and a farnesyl transferase inhibitor
JP2007039383A (ja) * 2005-08-03 2007-02-15 Dainippon Sumitomo Pharma Co Ltd アリールカルバペネム化合物の製造方法
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
SI2021335T1 (sl) 2006-04-20 2011-09-30 Janssen Pharmaceutica Nv Heterocikliäśne spojine kot zaviralci c-fms kinaze
EP2016074B1 (fr) 2006-04-20 2016-01-13 Janssen Pharmaceutica N.V. Inhibiteurs de la c-fms kinase
EP2021329B1 (fr) 2006-04-20 2016-04-13 Janssen Pharmaceutica N.V. Inhibiteurs de la c-fms kinase
JO3240B1 (ar) 2007-10-17 2018-03-08 Janssen Pharmaceutica Nv c-fms مثبطات كيناز
JOP20180012A1 (ar) 2012-08-07 2019-01-30 Janssen Pharmaceutica Nv عملية السلفنة باستخدام نونافلوروبوتانيسولفونيل فلوريد
IN2015DN00659A (fr) 2012-08-07 2015-06-26 Janssen Pharmaceutica Nv

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GB1593524A (en) * 1976-11-19 1981-07-15 Merck & Co Inc 1-carba-2-penem-3-carboxylic acids
US4260627A (en) * 1978-10-24 1981-04-07 Merck & Co., Inc. 1-, 6- And 2-substituted-1-carba-2-penem-3-carboxylic acids
DE69431919T2 (de) * 1993-10-29 2003-11-13 Smithkline Beecham Plc 2-(pyrazol-3-yl)carbapenemderivate

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