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
  • 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 novel antibacterial compounds, processes for their preparation, pharmaceutical and veterinary compositions comprising them, 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 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 4260 627, US 4962 101, US 4 978 659, EP 0 14493, EP 0414489, EP 0 010 316 and EP 0 030 032 Merck & Co) and 2-(substituted)methyl carbapenems (Schmidt et al, J.Antibiotics, 41, 1988, 780).
• 2-aryl, 2-heteroaryl and 2- heteroaromatic carbapenems US 4543 257, US 4260 627, US 4962 101, US 4 978 659, EP 0 14493, EP 0414489, EP 0 010 316 and EP 0 030 032 Merck & Co
• 2-(substituted)methyl carbapenems Schot al, J.Antibiotics, 41, 1988
• 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 R D is hydrogen or lower alkyl
• R a and R D are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower alkoxycarbonyl (EP 0430037, Banyu Pharmaceutical Co.).
• R a is hydrogen or methyl
• R D is hydrogen or lower alkyl
• R a and R D are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower alkoxycarbonyl
• R ⁇ is hydrogen, optionally substituted (C ⁇ _6)alkyl or optionally substituted aryl;
• RP is hydrogen, optionally substituted or optionally substituted aryl; or R ⁇ and RP together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;
• R c is (Ci _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;
• Rd is hydrogen or methyl
• R is selected from the group consisting of isobutyryloxymethyl, (5-methyl-2- oxo-l,3-dioxolen-4-yl)methyl, and benzoyloxymethyl.
• Particular compounds in accordance with the present invention are: isobutyryloxymethyl (5R, 6S)-2-[l-ethyl-5-methylpyrazol-3-yl]-6-[(lR)-l- hydroxyethyl]-carbapen-2-em-3-carboxylate,
• each carbapenem compound of the present invention is intended for use in pharmaceutical compositions, it will be understood that it is 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 compound may be used for preparing the more pure forms used in the pharmaceutical compositions. Preferably, whenever possible, each compound of the present invention is obtained in crystalline form
• solvent of crystallisation may be present in the crystalline product.
• This invention includes within its scope such solvates.
• 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 particularly 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 /7-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.
• 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 of formula (I) 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) wherein R is isobutyryloxymethyl or benzoyloxymethyl, which process comprises treating a corresponding compound of formula (I), wherein R is an alkali metal cation, with a compound of formula XCH2OCOCHMe2 or XCH2OCOC6H5, wherein 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.
• the present invention further provides a process for the preparation of a compound of formula (I) wherein R is (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl, which process comprises treating a corresponding compound of formula (I), wherein R is an alkali metal cation, with a ula:
• 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, in a suitable organic solvent , for example, N-methylpyrrolidin- 2-one, and in the presence of an acid-binding agent, such as 2,6-lutidine.
• suitable acid-binding agents include pyridine and diisopropylethylamine.
• suitable solvents include N, N'-dimethylformamide and N, N'-dimethylacetamide.
• ICH2 ⁇ COCHMe2 iodomethyl isobutyrate
• iodomethyl benzoate can be prepared from the corresponding chlorides via the Finkelstein reaction, which is well known to those skilled in the art.
• Chloromethyl isobutyrate and chloromethyl benzoate can be prepared by esterifying isobutyric acid or benzoic acid respectively with chloromethyl chlorosulphate (Binderup et al., Synthetic Commun., 14(9), 857-864 (1984)).
• the following Examples illustrate the present invention further:
• 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, untiLthe pH was neutral.
• 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 combined ethyl acetate layers were extracted with excess aqueous NaHCO3.
• the NaHCO3 extract was poured into excess acid, and the pH was then adjusted to 3, and NaCl was added to the solution.
• the resultant acid chloride was redissolved in dry dichloromethane and then treated with N,0- dimethylhydroxylamine hydrochloride (3.61 g). The mixture was cooled in an ice- bath and treated with pyridine (6.0 ml), the mixture was then allowed to stir at room temperature for 1.5 h and then diluted with ether (100 ml) and washed with brine. The organic layer was then dried (MgSO4) and evaporated to leave an oil.
• the mixture was diluted with ethyl acetate , washed with water, then with brine, and dried (MgSO4). After removal of the ethyl acetate the crude product was chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the phosphorane, which was used in the next stage.
• the phosphorane prepared above was taken up in 1,4-dioxan (60 ml) and treated with 5M HCl (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 (M SO4) and evaporated.
• 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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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1996
  • 1996-05-01 IL IL11809296A patent/IL118092A0/xx unknown
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  • 1996-05-02 MA MA24218A patent/MA23853A1/fr unknown
  • 1996-05-02 PL PL96323141A patent/PL323141A1/xx unknown
  • 1996-05-02 CN CN96194191A patent/CN1185783A/zh active Pending
  • 1996-05-02 EA EA199700293A patent/EA199700293A1/ru unknown
  • 1996-05-02 EP EP96919678A patent/EP0823910A1/en not_active Withdrawn
  • 1996-05-02 WO PCT/EP1996/001880 patent/WO1996034868A1/en not_active Application Discontinuation
  • 1996-05-02 JP JP8533020A patent/JPH11504910A/ja active Pending
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  • 1996-05-02 CA CA002217990A patent/CA2217990A1/en not_active Abandoned
  • 1996-05-03 PE PE1996000312A patent/PE50697A1/es not_active Application Discontinuation
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• 1997
  • 1997-10-30 NO NO974994A patent/NO974994D0/no not_active Application Discontinuation
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