WO1996034869A1 - Esters de carbapenemes - Google Patents

Esters de carbapenemes Download PDF

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Publication number
WO1996034869A1
WO1996034869A1 PCT/EP1996/001882 EP9601882W WO9634869A1 WO 1996034869 A1 WO1996034869 A1 WO 1996034869A1 EP 9601882 W EP9601882 W EP 9601882W WO 9634869 A1 WO9634869 A1 WO 9634869A1
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WIPO (PCT)
Prior art keywords
group
formula
alkyl
compound
hydrogen
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PCT/EP1996/001882
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English (en)
Inventor
George Burton
Stephen Christopher Martin Fell
Alfred John Eglington
Stephen Frederick Moss
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Smithkline Beecham Plc
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Priority claimed from GBGB9508959.5A external-priority patent/GB9508959D0/en
Priority claimed from GBGB9508960.3A external-priority patent/GB9508960D0/en
Priority claimed from GBGB9508964.5A external-priority patent/GB9508964D0/en
Priority to PL96323148A priority Critical patent/PL323148A1/xx
Priority to BR9608318A priority patent/BR9608318A/pt
Priority to JP8533022A priority patent/JPH11504912A/ja
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to MX9708422A priority patent/MX9708422A/es
Priority to AU58141/96A priority patent/AU5814196A/en
Priority to EP96919680A priority patent/EP0823911A1/fr
Publication of WO1996034869A1 publication Critical patent/WO1996034869A1/fr
Priority to NO974995A priority patent/NO974995D0/no
Priority to US10/324,593 priority patent/US7045619B2/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • 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
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
    • 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):
  • DHP-1 renal dehydropeptidase- 1
  • Stability towards DHP-1 may also be imparted by chemical modification of the carbapenem nucleus, for instance by incorporating a l ⁇ -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 4543 257, US 4260627, US 4962 101,
  • UK Patent 1 593 524, Merck & Co. discloses a number of 5-membered heteroaromatic carbapenem derivatives including diazolyl and tetrazolyl compounds. However, in the case of the pyrazolyl derivatives the heterocyclic compound is attached to the carbapenem nucleus through the C-4 position.
  • R a is hydrogen or methyl and R5 is hydrogen or lower alkyl
  • R a and R5 are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower allcoxycarbonyl (EP 0430037, Banyu Pharmaceutical Co.).
  • R a is hydrogen or methyl
  • R5 is hydrogen or lower alkyl
  • R a and R5 are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower allcoxycarbonyl
  • R ⁇ is hydrogen, optionally substituted (C ⁇ _6)alkyl or optionally substituted aryl;
  • R ⁇ is hydrogen, optionally substituted (Cj. ⁇ alkyl or optionally substituted aryl; or R ⁇ and R ⁇ together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;
  • R c is (C ⁇ gjalkyl 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
  • -CO2R e is carboxy or a carboxylate anion or the group R e is a readily removable carboxy protecting group.
  • the present invention provides a compound of the general formula (I):
  • R ⁇ is hydrogen, optionally substituted (Cj.6)alkyl or optionally substituted aryl;
  • R ⁇ is hydrogen, optionally substituted (C ⁇ .g)alkyl or optionally substituted aryl; or
  • R ⁇ and R ⁇ together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;
  • 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;
  • R2 is hydrogen or methyl
  • R3 is selected from the group consisting of (a) a group of formula:
  • R is hydrogen or (Cj.6)alkyl
  • R2 is hydrogen, (C ⁇ _6)alkyl optionally substituted by halogen, (Cj.6)alkenyl, (Ci . 6)alkoxycarbonyl, aryl, or heteroaryl
  • R3 is hydrogen, (C ⁇ _6)alkyl, or (C ⁇ 6) a ⁇ co ⁇ car bonyl
  • R4 is a pharmaceutically acceptable ester forming group, and (b) a group of formula
  • R a is hydrogen, (C ⁇ -g)alkyl, (C3-7)cycloalkyl, methyl, or phenyl; and R D is (C ⁇ _6)alkyl(C3_7)cycloalkyloxy or (C ⁇ _6)alkoxy(C ⁇ 6) allc 1 -
  • Suitable (C . ) alkyl groups for R ⁇ and R ⁇ include straight and branched chain alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl, n- propyl and wopropyl, preferably ethyl and methyl.
  • Representative examples of R ⁇ and R ⁇ as (C ⁇ _6)alkyl are when both are methyl or ethyl.
  • a particularly preferred example is when R ⁇ is ethyl and R ⁇ is methyl .
  • Suitable optional substituents for the C ⁇ . alkyl group for R ⁇ and R ⁇ include, for example, halogen, hydroxy, (C ⁇ -g)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 j-6)alkoxycarbonylamino, aminocarbonyloxy and mono- and di(C ⁇ -6)alkylaminocarbonyloxy, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, oxo, acyl, heteroaryl, (Cj-6)alkylthio, arylthio.heterocyclythio, (C ⁇ -
  • Suitable (C ⁇ 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, w ⁇ -propyl, of which ethyl is especially preferred.
  • the (Cj_6) alkyl group of R ⁇ has a hydroxy, fluoro or amino substituent which is suitably at position- 1 of the alkyl group.
  • Rl is (R)- 1 -hydroxyethyl.
  • R 2 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.
  • R or R ⁇ being an aryl group is phenyl.
  • Suitable optional substituents for the aryl group include halogen, (Ci .6)alkyl, aryl(C ⁇ _4)alkyl, (C ⁇ 6)alkoxy, (C ⁇ 6)alkoxy(C ⁇ _6)alkyl, halo(C ⁇ 6)alkyl, hydroxy, amino, mono- and di-N-(C ⁇ _6)alkylamino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C ⁇ 6)alkylcarbamoyl, (C ⁇ _6)alkoxycarbonyl, (Cj.g) alkoxycarboxylate, aryloxycarbonyl, (C ⁇ _6)alkoxycarbonyl-(C ⁇ _6)alkyl aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (C
  • heteroatom includes one or more of the elements oxygen, nitrogen and sulphur.
  • 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(C ⁇ _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, (Cl-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 Organic Chemistry” (T.W. Greene, Wiley-Interscience, New York, 2nd edition, 1991).
  • 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
  • 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.
  • 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.
  • 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 art 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 , 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, although the oral route is preferred.
  • 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 prefera " bly 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.
  • 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.
  • 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.
  • the present invention also .provides for the use of a compound of formula (I) for the manufacture of a medicament for treating bacterial infection.
  • the compounds of the present invention 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 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 corresponding compound of formula (I), wherein R is an alkali metal cation, with a compound of formula (i) or (ii):
  • X is a leaving group such as halogen, more particularly bromine or iodine.
  • the reaction is typically carried out at between 0 and 60 C, for example at ambient temperature, under an inert, for example argon, atmosphere, in a suitable organic solvent , for example, N-methylpyrrolidin-2-one.
  • suitable solvent systems include N, N'-dimethylforma ide and N, N'-dimethylacetamide.
  • Compounds of formula (i) can be prepared as described by F. Ameer et al, J. Chem. Soc, (1983), 2293.
  • Compounds of formula ICH(R a )O.CO.R b can be prepared from the corresponding chloride via the Finkelstein reaction, which is well known to those skilled in the art.
  • Compounds of formula ClCH(R a )O.CO.R D can be prepared by esterifying an acid of formula R b COOH with chloromethyl chlorosulphate (Binderup et al., Synthetic Commun., 14(9), 857-864 (1984)), or by treating a compound of formula ClCH(R a )OCOCl with a compound of formula HR D in dichloromethane pyridine (Yoshimura et al., J. Antibiot., 1987, 40(1), 81-90).
  • a further process for the preparation of a compound of formula (I) comprises subjecting a compound of formula (LI):
  • R3 is a readily removable carboxy protecting group
  • X is oxygen or a group PR 4 R5R6,
  • R4, R-5 and R ⁇ may be the same or different and is each an optionally substituted (C ⁇ _6)alkyl or an optionally substituted aryl group, preferably an rc-butyl or a phenyl group; to 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 1 comprising a hydroxyl substituent into a further group R 1 comprising an amino * or fluoro group; converting the product into a salt; and esterifying the product as set out above.
  • Suitable carbapenem ring forming conditions are well known in the art.
  • suitable ring forming conditions include treating the compound of formula (11) 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 0 476 649-A (Hoechst AG).
  • (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.
  • compounds of formula (I) may be obtained by the well known Wittig cyclisation route to carbapenems (Guthikonda et al, J. Med. Chem., 1987, 30, 871).
  • R 4 , R 5 and R ⁇ is each phenyl
  • the process comprises the ring closing elimination of the elements of triphenylphosphine oxide.
  • R 4 , R5 and R ⁇ is each n-butyl
  • cyclisation may be effected at a lower temperature, for instance above 50°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 R3 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 R3 is 4-methoxybenzyl, aluminium trichloride and anisole in dichloromethane at -30 to -70°C may be used, when R ⁇ is allyl (prop-2-en-l-yl), a combination of triphenylphosphine, sodium-2-ethylhexanoate in ethyl acetate/MDC and tetrakis- (triphenylphosphine palladium (0) may be used and when R3 is p-nitrobenzyl hydrogenation in the presence of palladium on a carbon catalyst in aqueous solvent eg, aqueous l,4,dioxan THF ethanol may be used.
  • aqueous solvent eg, aqueous l,4,
  • 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 (VH):
  • 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* is as hereinbefore defined, and R 1 1 is an acyl group, for instance acetyl; in the presence of a base, such as, for instance, lithium hexamethyldisilazide (LHMDS); according to the procedures described in Tetrahedron_Lett., 1987, 28, 507, and Can. J. Chem, 1988, 66, 1537.
  • LHMDS lithium hexamethyldisilazide
  • R and R 2 are as hereinbefore defined and SiR3l 4 is a trialkylsilyl such as trimethylsilyl or t-butyldimethylsilyl, with a compound of formula (LXa):
  • 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 (V ⁇ i) with trialkylsilyl chloride or trialkylsilyl triflate, and triethylamine in MDC.
  • 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 I is an amino-substituted alkyl or cycloalkyl
  • R I is an amino-substituted alkyl or cycloalkyl
  • RI includes a hydroxy group by a Mitsunobu-type azide displacement of the hydroxy group thereof, followed by catalytic reduction, according to the procedure described in J Chem Soc, Perkin 1, 1982, 3011.
  • Compounds of formula (I) may also be prepared by a process which comprises reacting a compound of formula (X):
  • Rl 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):
  • M is a metallo group and R is as hereinbefore defined; in a cross-coupling reaction in the presence of a cross-coupling reaction catalyst selected according to the identity of M and thereafter and if necessary removing any protecting group and/or converting the product into a salt and/or esterifying the product as set out hereinabove.
  • Suitable values for the protecting group R 3 include 4-methoxybenzyl 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 R 14 R 15 R 16sn, B(OR)2 and ZnCl in which R 14 , R*5 and R 16 may the same or different and are each (Cj_6) alkyl.
  • 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 tra(dibenzylideneacetone)dipalladium (0), te/r ⁇ & «(triphenylphosphine)palladium (0), trans dimethyl bw(triphenylphosphine)palladium (II), and palladium (II) acetate, benzyl bw(triphenylphosphine)palladium (II) chloride, bw(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, trw(4-methoxyphenyl)phosphine or ⁇ ra(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, trw(4-methoxyphenyl)phosphine or ⁇ ra(2,4,6-trimethoxyphenyl) phosphine; a tri- heteroarylphosphine, for example, trifur
  • a preferred catalyst system is ⁇ rw(dibenzylideneacetone)dipalladium (0), in the presence of zinc chloride and a phosphine compound.
  • M is ZnCl
  • a preferred catalyst is rra(dibenzylideneacetone dipalladium (0), in the presence of a phosphine compound.
  • the reaction is effected in an inert 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.
  • N-Ethylhydrazine oxalate (12 g) in glacial acetic acid (100 ml) was cooled in an ice- bath and treated with ethyl 2,4-dioxovalerate (11.24 ml). After addition was complete the mixture was stirred at room temperature; after ca. 45 min the mixture was warmed to dissolve insoluble ethylhydrazine oxalate. The mixture was stirred for a further 2 h and then poured into water( ca. 300 ml) / ethyl acetate (ca. 700 ml) and solid K2CO3 was carefully added, with stirring, until the pH was neutral. After separation the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extracts were dried (M SO4), and the solvents removed to leave an oil.
  • M SO4 ethyl 2,4-dioxovalerate
  • Ethyl l-ethyl-5-methylpyrazole-3-carboxylate (10.93 g) in ethanol (70 ml) was treated with KOH (3.69 g), followed by water (30 ml), and the mixture was stirred and heated under reflux for 6 h.
  • the ethanol was removed using a rotary evaporator and ethyl acetate/water were added.
  • the pH of the mixture was adjusted to 3.0 and the layers were separated. The aqueous layer was re-extracted with ethyl acetate.
  • the phosphorane prepared above was taken up in 1,4-dioxan (60 ml) and treated with 5M HC1 (20 ml). After 1 h the mixture was carefully treated with ca. 40 ml saturated aqueous NaHCO3, followed by solid NaHCO3 until the pH was slightly alkaline. Saturated brine was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated.
  • the mixture was cooled and then loaded onto a column (4.5 x 12 cm) of silica gel (particle size 0.040 -0.063 mm), eluting with ethyl acetate/hexane mixtures; 1:1; 6:4; 7:3; 8:2; 9:1 (250 ml of each), followed by ethyl acetate.
  • the residual solid was dried under a stream of argon, and then in a desiccator.
  • the solid was then taken up in water containing sodium chloride and chromatographed on DIAION HP20SS resin, eluting with water, followed by water/THF mixtures; 1%, 2%, and 3%,THF.

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Abstract

L'invention porte sur un composé s'avérant utile pour le traitement d'affections bactériennes de formule générale (I) dans laquelle R est (a) et où Rα est hydrogène, C¿1-6? alkyle facultativement substitué ou aryle facultativement substitué; R?β¿ est hydrogène, C¿1-6? alkyle facultativement substitué ou aryle facultativement substitué; R?α et Rβ¿ forment ensemble un noyau hétérocyclique à 5 ou 6 éléments avec ou sans hétéroatomes additionnels, R1 est C¿1-6? alkyle substitué ou non par fluoro, un groupe hydroxy facultativement protégé par un groupe protecteur hydroxy facilement retirable ou un groupe amino facultativement protégé par un groupe protecteur amino facilement retirable, R?2¿ est hydrogène ou méthyle et R3 est sélectionné:(a) dans un groupe de formule (i) où R1 est hydrogène ou C¿1-6? alkyle, R?1¿ est hydrogène, C¿1-6? alkyle facultativement substitué par halogène, C1-6 alcényle, C1-6 alkoxycarbonyle, aryle ou hétéroaryle, R?3¿ est hydrogène, C¿1-6? alkyle, C1-6 alkoxycarbonyle; et R?4¿ est un groupe ester pharmacocompatible, et (b): un groupe CH(R?a)O.CO.Rb¿ dans lequel Ra est hydrogène, C¿1-6? alkyle, C3-7 cycloalkyle, méthyle ou phényle; et R?b¿ est C¿1-6? alkyle, C3-7 cycloalkyloxy ou C1-6 alkoxy C1-6 alkyle.
PCT/EP1996/001882 1993-10-29 1996-05-02 Esters de carbapenemes WO1996034869A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP96919680A EP0823911A1 (fr) 1995-05-03 1996-05-02 Esters de carbapenemes
AU58141/96A AU5814196A (en) 1995-05-03 1996-05-02 Esters of carbapenems
MX9708422A MX9708422A (es) 1995-05-03 1996-05-02 Esteres de carbapenemas.
BR9608318A BR9608318A (pt) 1995-05-03 1996-05-02 Esteres de carbapenems
JP8533022A JPH11504912A (ja) 1995-05-03 1996-05-02 カルバペネムのエステル
PL96323148A PL323148A1 (en) 1995-05-03 1996-05-02 Esters of crabapenemes
NO974995A NO974995D0 (no) 1995-05-03 1997-10-30 Estere av karbapenemer
US10/324,593 US7045619B2 (en) 1993-10-29 2002-12-19 2-(pyrazol-3-yl)carbapenem derivatives

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GBGB9508959.5A GB9508959D0 (en) 1995-05-03 1995-05-03 Novel compounds
GBGB9508964.5A GB9508964D0 (en) 1995-05-03 1995-05-03 Novel compounds
GB9508959.5 1995-05-03
GB9508964.5 1995-05-03
GBGB9508960.3A GB9508960D0 (en) 1995-05-03 1995-05-03 Novel compounds
GB9508960.3 1995-05-03

Related Parent Applications (2)

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PCT/EP1996/001880 Continuation-In-Part WO1996034868A1 (fr) 1993-10-29 1996-05-02 Ester de carbapenems
US08945524 Continuation-In-Part 1996-05-02

Related Child Applications (3)

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US08624624 Continuation-In-Part 1994-10-25
PCT/GB1994/002347 Continuation-In-Part WO1995011905A1 (fr) 1993-10-29 1994-10-25 Derives de 2-(pyrazol-3-yle)carbapenem
US08945521 A-371-Of-International 1996-05-02

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KR (1) KR19990008354A (fr)
CN (1) CN1184480A (fr)
AU (1) AU5814196A (fr)
BR (1) BR9608318A (fr)
CA (1) CA2217885A1 (fr)
CZ (1) CZ347697A3 (fr)
HU (1) HUP9801061A3 (fr)
MX (1) MX9708422A (fr)
NO (1) NO974995D0 (fr)
PL (1) PL323148A1 (fr)
TR (1) TR199701289T2 (fr)
WO (1) WO1996034869A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005066173A2 (fr) * 2004-01-08 2005-07-21 Glaxo Group Limited Nouveaux procedes
WO2005066175A2 (fr) * 2004-01-09 2005-07-21 Glaxo Group Limited Nouveaux procedes

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100771019B1 (ko) * 2002-03-20 2007-10-29 주식회사 만도 브레이크 액압제어장치
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

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1593524A (en) * 1976-11-19 1981-07-15 Merck & Co Inc 1-carba-2-penem-3-carboxylic acids
EP0318767A2 (fr) * 1987-11-24 1989-06-07 F. Hoffmann-La Roche Ag Esters d'acides carboxyliques pharmacologiquement actifs, clivables sous conditions physiologiques
EP0338824A2 (fr) * 1988-04-22 1989-10-25 Beecham Group Plc Esters de dérivés d'acide 6-bêta-(alpha-oxyimino)-acylamino-pénicillanique
WO1995011905A1 (fr) * 1993-10-29 1995-05-04 Smithkline Beecham Plc Derives de 2-(pyrazol-3-yle)carbapenem

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1593524A (en) * 1976-11-19 1981-07-15 Merck & Co Inc 1-carba-2-penem-3-carboxylic acids
EP0318767A2 (fr) * 1987-11-24 1989-06-07 F. Hoffmann-La Roche Ag Esters d'acides carboxyliques pharmacologiquement actifs, clivables sous conditions physiologiques
EP0338824A2 (fr) * 1988-04-22 1989-10-25 Beecham Group Plc Esters de dérivés d'acide 6-bêta-(alpha-oxyimino)-acylamino-pénicillanique
WO1995011905A1 (fr) * 1993-10-29 1995-05-04 Smithkline Beecham Plc Derives de 2-(pyrazol-3-yle)carbapenem

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005066173A2 (fr) * 2004-01-08 2005-07-21 Glaxo Group Limited Nouveaux procedes
WO2005066173A3 (fr) * 2004-01-08 2008-12-31 Glaxo Group Ltd Nouveaux procedes
WO2005066175A2 (fr) * 2004-01-09 2005-07-21 Glaxo Group Limited Nouveaux procedes
WO2005066175A3 (fr) * 2004-01-09 2006-01-12 Glaxo Group Ltd Nouveaux procedes

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KR19990008354A (ko) 1999-01-25
PL323148A1 (en) 1998-03-16
HUP9801061A3 (en) 1999-01-28
NO974995L (no) 1997-10-30
JPH11504912A (ja) 1999-05-11
HUP9801061A2 (hu) 1998-08-28
EP0823911A1 (fr) 1998-02-18
MX9708422A (es) 1998-02-28
CN1184480A (zh) 1998-06-10
AU5814196A (en) 1996-11-21
BR9608318A (pt) 1999-01-26
NO974995D0 (no) 1997-10-30
TR199701289T2 (xx) 1998-08-21
CZ347697A3 (cs) 1998-06-17
CA2217885A1 (fr) 1996-11-07

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