WO1998023621A1 - Cephalosporin derivatives - Google Patents

Cephalosporin derivatives

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Publication number
WO1998023621A1
WO1998023621A1 PCT/US1997/021785 US9721785W WO9823621A1 WO 1998023621 A1 WO1998023621 A1 WO 1998023621A1 US 9721785 W US9721785 W US 9721785W WO 9823621 A1 WO9823621 A1 WO 9823621A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
hydrogen
compound
halogen
Prior art date
Application number
PCT/US1997/021785
Other languages
French (fr)
Inventor
Dane M. Springer
Bing Y. Luh
Stanley V. D'andrea
Thomas W. Hudyma
Oak K. Kim
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to EP97950724A priority Critical patent/EP0966472A1/en
Priority to IL12943797A priority patent/IL129437A0/en
Priority to NZ335892A priority patent/NZ335892A/en
Priority to BR9713350-7A priority patent/BR9713350A/en
Priority to CZ991853A priority patent/CZ185399A3/en
Priority to CA002272717A priority patent/CA2272717A1/en
Priority to JP52485698A priority patent/JP2001506607A/en
Priority to AU53652/98A priority patent/AU734948B2/en
Publication of WO1998023621A1 publication Critical patent/WO1998023621A1/en
Priority to NO992526A priority patent/NO992526D0/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • 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

  • the present invention is directed to new cephem derivatives represented by the general formula
  • Q is an optionally substituted pyridinium group connected to the sulfur atom via a ring carbon atom;
  • X is halogen;
  • Y is hydrogen or halogen;
  • A is C0 2 H, P0 3 H 2 , S0 3 H or tetrazole;
  • L 1 is a furan group, a thiophene group, a C 2 -C 10 alkyl group, or a C 2 -C 10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S0 2 , S0 2 NH,
  • n is 0 or 1; and R 1 is hydrogen or a carboxyl-protecting group; or pharmaceutically acceptable salts and /or prodrugs thereof.
  • the derivatives are gram-positive antibacterial agents especially useful in the treatment of diseases caused by methicillin-resistant Staphylococcus aureus (also referred to below as MRSA or methicillin-resistant S. aureus).
  • the literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents.
  • R j is hydrogen or chloro
  • R 2 is hydroxy or amino
  • Z is oxygen or sulfur
  • A is acetoxy or N-pyridinium
  • M is hydrogen, pharmaceutically acceptable non-toxic cations or an anionic charge when A is N-pyridinium.
  • EP 638,574 Al discloses cephem derivatives of the general formula
  • Z -H, halogen, -OH, -C 5 O-alkyl, -OCH 2 CONH 2 , -OCONH 2 , -OS0 2 NH 2 , -OCH 2 CN, -NH 2 either as such or
  • amides of benzene and toluene derivatives -N0 2 , -NO, -CHO, -CH 2 OH, -COOH, -SH, -SOH, -S0 2 H, -S0 3 H, -S-alkyl where the alkyl residue is -C 8 , -CF 3 ;
  • R -H, -OH, - -O-alkyl with the alkyl residue possibly containing halogens, acid functionalities either free or salified with alkaline or alkaline earth metals, basic functions such as -OCH 2 CH 2 NH 2 , -OCH 2 CH 2 NH-CH 3 , -
  • A -S-, -O-, -CH 2 -, -SO-, S0 2 -;
  • R 2 is an alkyl or aryl radical -CH 2 -OCOCH 3 , -CH 2 -S (CH 2 ) 2 -N-CH
  • C-3 substituents employed in the compounds of the present invention are known in the cephem art, but have not previously been combined with the C-7 substituents of the present invention. Applicants have discovered that the combination of C-3 and C-7 substituents provided in the compounds of the present invention unexpectedly gives the desired solubility, activity and toxicity profile needed for commercially viable anti-MRSA cephem products.
  • the present invention provides a novel series of cephem derivatives of the general formula
  • Q is an optionally substituted pyridinium group connected to the sulfur atom via a ring carbon atom;
  • X is halogen;
  • Y is hydrogen or halogen;
  • A is C0 2 H, P0 3 H 2 , S0 3 H or tetrazole;
  • L 1 is a furan group, a thiophene group, a C 2 -C 10 alkyl group, or a C 2 -C 10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S0 2 , S0 2 NH,
  • the compounds of formula I are antibacterial agents useful in the treatment of infections in humans and other animals caused by a variety of gram-positive bacteria, particularly methicillin-resistant S aureus.
  • the present invention provides novel cephem derivatives of general formula I above which are antibacterial agents useful in the treatment of infectious diseases in humans and other animals.
  • the compounds exhibit good activity against a wide variety of gram-positive microorganisms, e.g. S. pneumoniae, S. pyogenes, S. aureus. E. faecalis, S. epidermidis and S. hemolyticus. and are particularly useful against strains of methicillin-resistant S. aureus.
  • X is halogen
  • Y is hydrogen or halogen
  • A is C0 2 H, P0 3 H 2 , S0 3 H
  • L 1 is a furan group, a thiophene group, a C 2 -C 10 alkyl group, or a C 2 -C 10 alkyl group interrupted by one or more (preferably 1 or 2) groups
  • n 0 or 1.
  • X is halogen
  • Y is hydrogen or halogen
  • A is C0 2 H, P0 3 H 2 , S0 3 H or tetrazole
  • L 1 is a furan group, a thiophene group, a C 2 -C 10 alkyl group, or a C 2 -C 10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S0 2 , S0 2 NH, o H
  • n is 0 or 1;
  • R 3 and R 4 are each independently selected from hydrogen or - C 6 alkyl;
  • R 2 is hydrogen, NH 2 , pyrrolidinyl, C j -C 8 alkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkyl substituted by one or more substituents independently selected from OH, NR 5 R 6 in which R s and R 6 are each independently hydrogen or C ⁇ -C 6 alkyl, C0 2 H, morpholinyl, morpholinyl quaternized by a - alkyl
  • X is halogen
  • Y is hydrogen or halogen
  • A is C0 2 H, P0 3 H 2 , S0 3 H or tetrazole
  • L 1 is a furan group, a thiophene group, a C 2 -C 10 alkyl group or a C 2 -C 10 alkyl group interrupted by one or two groups independently
  • n 0 or 1;
  • R 3 and R 4 are each independently selected from hydrogen or -
  • R 2 is hydrogen, NH 2 , pyrrolidinyl, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkyl substituted by one or two substituents independently selected from OH,
  • R 5 and R 6 are each independently hydrogen or -Cg alkyl, C0 2 H, morpholinyl, morpholinyl quaternized by a C -C 6 alkyl group, oxo, halogen, S0 3 H, P0 3 H 2 , tetrazolyl,
  • R 7 is a furan or thiophene radical optionally substituted by a -C0 2 H or -S0 3 H group, phenyl or phenyl substituted by 1-2 substituents independently selected from OH, NR 5 R 6 in which R 5 and R 6 are as defined
  • R 1 is hydrogen or a carboxyl-protecting group
  • Halogen includes chloro, bromo, fluoro and iodo, and is preferably chloro or bromo and most preferably chloro.
  • the aliphatic "alkyl” groups may be straight or branched chains containing the specified number of carbon atoms.
  • salts as used herein is intended to include the nontoxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p- toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoracetic, hydroiodic, hydrobromic, and the like.
  • acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p- toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoracetic, hydroiodic, hydrobromic, and the like.
  • acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzo
  • alkali metal salts particularly sodium or potassium
  • alkaline earth metal salts particularly calcium or magnesium
  • suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris-(hydroxymethyl)amino- methane), or with bases such as piperidine or morpholine, are also intended to be encompassed by the term "pharmaceutically acceptable salt".
  • the counter anion X may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration.
  • the carboxyl-protecting group R 1 is intended to include readily removable ester groups which have been conventionally employed to block a carboxyl group during the reaction steps used to prepare the compounds of the present invention and which can be removed by methods which do not result in any appreciable destruction of the remaining portion of the molecule, e.g. by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation.
  • protecting groups include benzhydryl, p-nitrobenzyl, 2- naphthylmethyl, allyl, benzyl, p-methoxybenzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C j -Cg alkyl such as methyl, ethyl or t-butyl. Included within such protecting groups are those which are hydrolyzed under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl,
  • hydroxyl-protecting groups may be employed, for example, to increase the solubility of a cephem derivative.
  • ester "prodrugs" of this type are compounds wherein one or more hydroxy substituent groups are converted to sulfate (-OS0 3 H) or phosphate (-OP0 3 H 2 ) groups.
  • the compounds of the present invention can be made by conventional methods.
  • a suitable procedure is summarized by the following reaction scheme:
  • Acid intermediate VI is then coupled with a suitable cephem intermediate having a 3-substituent leaving group.
  • the leaving group may be acetoxy or halogen.
  • the cephem intermediate is the 3- chloromethyl cephem V, but other suitable cephem intermediates with equivalent leaving groups at the 3-position could also be employed.
  • the cephem intermediate V may be acylated with VI or a reactive derivative thereof by conventional acylation procedures well-known in the cephalosporin art to give N-acylated intermediate IV.
  • the free arylthioacetic acid e.g.
  • acylating agent VI may also be employed in the form of equivalent acylating derivatives such as an acid anhydride, mixed anhydride, activated ester, or acid halide.
  • the cephem intermediate preferably has the carboxyl group protected by a conventional carboxyl- protecting group which can be readily removed. Examples of such protecting groups are discussed above and include benzyl, 4-nitrobenzyl, 1,1 dimethylethyl, 4-methoxybenzyl, diphenylmethyl, allyl, and the like. Other examples of suitable protecting groups are disclosed in Protective Groups in Organic Synthesis, 2nd Ed., Theodora W.
  • intermediate V may be acylated with acid VI in the presence of dicyclohexylcarbodiimide and in an inert solvent such as tetrahydrofuran or dichloromethane.
  • the reaction temperature is typically between -20 °C and 50 °C.
  • insoluble material is removed by filtration, the filtrate is concentrated, and the residue is treated with a relatively non-polar solvent such as diethyl ether or ethyl acetate resulting in precipitation of the desired product.
  • acid VI may be
  • Cephem IV is typically isolated after aqueous work-up and evaporation of
  • cephem acid IV is obtained upon treatment of IV with trifluoroacetic acid neat or in an inert solvent such as methylene chloride.
  • a reagent such as anisole may also be employed to scavenge the liberated ester protecting group.
  • the reaction temperature is usually at or below room temperature.
  • the deprotection may also be carried out by treatment with other protic acids such as hydrochloric acid in a solvent such as methanol.
  • the final product is typically isolated by precipitation or crystallization.
  • the primary amine may be in the form of a zwitterion in examples where there is a free acid group present in the molecule.
  • a base such as sodium hydroxide, sodium bicarbonate, or pyridine is added to form the free amine in situ.
  • the product may be isolated as its sodium salt by evaporation of volatile solvents, followed by trituration with a solvent such as diethyl ether or ethyl acetate.
  • reaction mixture may be acidified and extracted with an organic solvent to afford the product as the free carboxylic acid.
  • carboxylate group is protected as an ester
  • the amine may be free or present as an acid salt.
  • a base such as sodium hydroxide, sodium bicarbonate, or pyridine is added to form the free amine in situ.
  • the product is typically isolated by precipitation or by reversed phase column chromatography following removal of volatile solvents.
  • thiopyridone intermediates of formula III may have an amine functional group protected as the t-butyloxycarbamate. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis, 2nd Ed., Theodora W. Greene (John Wiley & Sons, 1991). It is intended that such "protected" intermediates and end- products are included within the scope of the present disclosure and claims.
  • the desired end-product of formula I may be recovered either as the zwitterion or in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HC1, HI or methanesulfonic acid to the zwitterion.
  • R! is hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof, may be converted by conventional procedures to a corresponding
  • Rl is hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl-protecting group, or the
  • pharmaceutically acceptable salts or prodrugs thereof are potent antibiotics active against many gram-positive bacteria. While they may be used, for example, as animal feed additives for promotion of growth, as
  • preservatives for food as bactericides in industrial applications, for example in water-based paint and in the white water of paper mills to inhibit the growth of harmful bacteria, and as disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and dental equipment, they are especially useful in the treatment of infectious disease in humans and other animals caused by the gram-positive bacteria sensitive to the new derivatives. Because of their excellent activity against MRSA organisms, they are particularly useful in the treatment of infections resulting from such bacteria.
  • compositions comprising, in
  • the compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or
  • compositions may be in
  • compositions for injection the compositions for injection, the
  • preferred route of delivery may be prepared in unit dose form in ampules
  • compositions may be in ready-to- use form or in powder form for reconstitution at the time of delivery
  • a suitable vehicle such as sterile water.
  • the dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 50 mg/day to about 20 g/day. Administration is generally carried out in divided doses, e.g., three to four times a day, analogous to dosing with a cephalosporin such as cefotaxime.
  • MIC Minimum Inhibitory Concentrations
  • NCLS Mueller-Hinton medium
  • inoculate contained approximately 5 x 10 ⁇ cfu/ml and the plates were
  • the MIC was defined as the lowest drug concentration that prevented visible growth.
  • Organisms The test organism, MRSA strain A27223 used to generate systemic infection in mice, is grown on two large Brain Heart Infusion Agar plates. On each plate, 0.5 ml of frozen stock culture is plated out.
  • mice are infected
  • mice are used as controls.
  • Mice Mice used are male ICR mice. The average weight of the animals is
  • Drug preparation and treatment Compounds are tested at 4 dose levels, (25, 6.25, 1.56, and 0.39 mg/kg) and prepared in 5% cremophor, unless otherwise specified. Vancomycin is used as the control compound, and is dosed at 6.25, 1.56, 0.39, and 0.098 mg/kg. It is prepared in 0.1M phosphate buffer. There are five infected mice per dose level, and they are treated with 0.2 ml of the test compound, preferably by intramuscular injection. Treatment begins 15 minutes and 2 hours post-infection.
  • Test duration A PD50 (the dose of drug given which protects 50% of
  • mice from mortality experiment runs for 5 days. During this time, mortality of mice are checked every day and deaths are recorded. The cumulative mortality at each dose level is used to calculate a PD50 value
  • mice are sacrificed at the end of day 5 by
  • Ph 3 P triphenylphosphine
  • TMS tetramethylsilane
  • Analytical thin-layer chromatography was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors, and/or staining by heating with methanolic phosphomolybdic acid.
  • Column chromatography also referred to as flash chromatography, was performed in a glass column using finely divided silica gel at pressures somewhat above atmospheric pressure with the indicated solvents. Reversed-phase analytical thin-layer chromatography was
  • Reversed-phase column chromatography was performed in a glass column using Baker Octadecyl (Cis), 40 mm.
  • N-Methylmorpholine (3.90 mL, 0.036 mol) is added, and then the mixture is cooled to 0°C.
  • Ester 7 (1.03 g., 3.35 mmol) is dissolved in 200 mL CH2CI2 and 100
  • ester 10 as a pale yellow oil (2.56 g., 9.10 mmol; 70% yield) which solidifies overnight in the refrigerator to
  • ester 10 (2.5 g., 11.3 mmol) is converted to diester 11 (3.20 g., 9.12 mmol; 81% yield). Diester 11 was obtained as a white solid by chromatography on silica gel using 80% methylene chloride /hexane.
  • Dicyclohexylcarbodiimide (0.866 g., 4.20 mmol) is added, followed by tert- butyl glycine (0.550 g., 4.20 mmol), and the mixture stirred at room temperature for 2 hours.
  • Ether is added to the flask, and the solids removed by filtration. The filtrate is evaporated to yield 1.96 g. of crude material. Chromatography on silica using 80% CH2CI2 /hexane, followed
  • 2,4,5-Trichlorothiophenol (35.0 g., 0.166 mol) is dissolved in 500 mL methylene chloride and cooled to 0°C.
  • Triethylamine (22.0 g., 0.217 mol) is added, followed by a solution tert-butyl bromoacetate (35.1 g., 0.180 mol)
  • Ester 15 (51 g., 0.156 mol; 94%) as obtained is of suitable purity for subsequent reactions.
  • Ester 15 (50.0 g., 0.153 mol) is dissolved in 500 mL chloroform and cooled to 0°C.
  • m-Chloroperoxybenzoic acid 50-60% from Aldrich, 48.0 g., 0.140-0.168 mol
  • the ice bath is removed and stirring continued for 2.5 hours at room temperature.
  • the solids were removed by filtration, and the filtrate washed with dilute aqueous NaHS ⁇ 3, 5% aqueous Na2C ⁇ 3, saturated aqueous NaHC ⁇ 3, and
  • sulfoxide 16 (35.0 g., 105 mmol) is converted to diester 17 (32.5 g., 78.7 mmol; 75% yield).
  • diester 17 (32.5 g., 78.7 mmol; 75% yield).
  • the compound is isolated as a white solid after chromatography on silica using methylene chloride then 3% methanol /methylene chloride.
  • Diester 17 (28.0 g., 67.8 mmol) is dissolved in 500 mL acetone. Sodium iodide (48.7 g., 325 mmol) is added, followed by trifluoroacetic anhydride (40.0 g., 191 mmol) over 5 minutes. After stirring at room temperature for 1 hour, the solvents are evaporated. Methylene chloride is added and evaporated twice. The residue is taken up in methylene chloride and washed with aqueous NaHS ⁇ 3 solution (3X), water, and
  • Ester 15 (7.00 g., 21.4 mmol) is dissolved in 40 mL chloroform and treated with m-chloroperoxybenzoic acid (-60% from Aldrich, 12.0 g., -42 mmol). After stirring for 1 hour at room temperature, the solids are removed by filtration, and the filtrate is washed with dilute aqueous NaHS ⁇ 3, 5% aqueous Na2C ⁇ 3, saturated aqueous NaHC ⁇ 3, and then
  • 2,5-Dichlorophenol (20.4 g., 0.125 mol) is placed in a 1L round bottom flask equipped with a large egg-shaped stir bar and is dissolved in
  • reaction is diluted with CH2CI2 (-200 ml) and filtered through
  • Compound 26 is obtained as a yellow crystalline solid (13.0 g., 36.0 mmol; 33% yield from 2,5-dichlorophenol).
  • the solution is heated to reflux for 6 hours.
  • the mixture is diluted with
  • stannane 31 (1.70 g., 3.60 mmol) and aryl iodide 28 (1.03 g., 2.73 mmol) are converted to diester 32 (0.920 g., 2.13 mmol; 78% yield as a light yellow solid).
  • 2,4,5-Trichloroiodobenzene (25 g., 81.3 mmol) is dissolved in 80 mL DMF.
  • tert-Butyl acrylate (48 mL, 328 mmol), tributylamine (58 mL, 243 mmol), triphenylphosphine (4.08 g., 15.5 mmol), and palladium acetate (3.23 g., 14.4 mmol) are added, and the mixture heated to 80°C for three hours.
  • the solvents are evaporated and the residue is partitioned with EtOAc and water.
  • the aqueous phase is extracted with EtOAc, and the combined organic phase is washed with brine, dried (MgS ⁇ 4), and
  • the sodium salt of methyl mercaptoacetate is best made fresh before use. Approximately 30 mL of methyl mercaptoacetate is dissolved in -250 mL THF. One equivalent of 5 N NaOH is added slowly in pipetfulls, and the mixture allowed to stir for 5 minutes. The solvents are removed in vacuo (including water) and the sticky solid is co-evaporated with ether (-200 mLs) and then dry THF (2 x 200 mLs). The solid is
  • Diester 3 (4.40 g., 0.012 mol) is dissolved in 30 mL THF. To this
  • Acid 1 is obtained as a tan solid (3.80
  • Cephem amine V (15.04 g., 0.035 mmol) is suspended under a nitrogen atmosphere in 65 mL THF. A solution of DCC in methylene chloride (1M, 36.2 mL, 0.036 mmol) is added, and the mixture allowed to stir for 5 minutes. Acid 1 (13.15 g., 0.035 mmol) is added and the mixture is stirred for 1.5 hours. Ether (-30 mL) is added, and the solids (mostly DCU) are filtered off. The red-colored filtrate is evaporated to -25-30 mL and ether and pentane are added to precipitate the cephem product. The solid cephem is collected, washed with ether, and dried under vacuum to afford diester IV" (14.2 g., 0.019 mmol; 54% yield).
  • Diester IV (0.760 g., 1.00 mmol) is dissolved in 4 mL CH2CI2 and
  • Diacid IV is obtained (0.420 g., 0.780 mmol; 78% yield) as a light yellow solid.
  • Diacid IV (0.780 g., 1.45 mmol) is dissolved in 3 mL methanol and 8 mL CH2O2.
  • Thiopyridone III' (0.395 g., 1.45 mmol) is added, and the mixture is
  • Cephem IA' (0.605 g., 0.747 mmol) is suspended in 3 mL CH2C12,

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Abstract

Provided are cephem derivatives represented by general formula (I) wherein Q is an optionally substituted pyridinium group connected to the sulfur atom via a ring carbon atom; X is halogen; Y is hydrogen or halogen; L1 is a furan group, a thiophene group, a C¿2?-C10 alkyl group, or a C2-C10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, SO2, SO2NH, (IIa), (IIb); n is 0 or 1; A is CO2H, PO3H2, SO3H or tetrazole; and R?1¿ is hydrogen or a carboxyl-protecting group; and pharmaceutically acceptable salts and/or prodrugs thereof. The derivatives are gram-positive antibacterial agents especially useful in the treatment of diseases caused by methicilin-resistant Staphylococcus aureus (MRSA).

Description

CEPHALOSPORIN DERIVATIVES
1. Field of the Invention
The present invention is directed to new cephem derivatives represented by the general formula
Figure imgf000003_0001
wherein Q is an optionally substituted pyridinium group connected to the sulfur atom via a ring carbon atom; X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group, or a C2-C10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH,
Figure imgf000003_0002
n is 0 or 1; and R1 is hydrogen or a carboxyl-protecting group; or pharmaceutically acceptable salts and /or prodrugs thereof. The derivatives are gram-positive antibacterial agents especially useful in the treatment of diseases caused by methicillin-resistant Staphylococcus aureus (also referred to below as MRSA or methicillin-resistant S. aureus). 2. Description of the Prior Art
The literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents.
With respect to the C-7 substituents of the present invention, U.S. Patent 3,345,366 discloses cephem derivatives of the type
Figure imgf000004_0001
co2M
wherein Rj is hydrogen or chloro, R2 is hydroxy or amino, Z is oxygen or sulfur, A is acetoxy or N-pyridinium and M is hydrogen, pharmaceutically acceptable non-toxic cations or an anionic charge when A is N-pyridinium. This approach was also discussed in Antimicrob. Ag. Chemother. Meeting. 1968, pgs 109-114 (Hobby, G.L.) and JP 50083383.
EP 638,574 Al discloses cephem derivatives of the general formula
Y^ R
/CH
Figure imgf000004_0002
COOH wherein X = absent, -O-, -S-, -SO-, -S02-, -NH-; Y = -CH, N-;
Z = -H, halogen, -OH, -C5 O-alkyl, -OCH2CONH2, -OCONH2, -OS02NH2, -OCH2CN, -NH2 either as such or
substituted with C C6 alkyl radicals, -NHCOCH3, - NHS02CH3,
— NHSO2 — P - CH3
\=X amides of - linear acids,
amides of benzene and toluene derivatives, -N02, -NO, -CHO, -CH2OH, -COOH, -SH, -SOH, -S02H, -S03H, -S-alkyl where the alkyl residue is -C8, -CF3;
R = -H, -OH, - -O-alkyl with the alkyl residue possibly containing halogens, acid functionalities either free or salified with alkaline or alkaline earth metals, basic functions such as -OCH2CH2NH2, -OCH2CH2NH-CH3, -
OCH2(o, m, p)-pyridinyl, -OCH2CN, -OCH2CONH2, -
OCH2S02NH2; n = 0 to 4;
A = -S-, -O-, -CH2-, -SO-, S02-; Rj = a structural group characteristic of cephalosporins such as -Cl, -H, -OCH3, -CH2OCH2NH2, -CH2OCH3, -CH3, -CH=CH-
CH3, -CF3, -C02R2, -S02R where R2 is an alkyl or aryl radical -CH2-OCOCH3 , -CH2-S
Figure imgf000006_0001
(CH2)2-N-CH
Figure imgf000006_0002
Figure imgf000006_0003
CH2COOH
NH. N.
A
-CH2-S N - N -CH,-S A. N
-CH2-S s. '/ N -CH2-S A s
ΓH. l N
CH •3
their pharmaceutically acceptable salts and their C6 and C7 epimers.
The C-3 substituents employed in the compounds of the present invention are known in the cephem art, but have not previously been combined with the C-7 substituents of the present invention. Applicants have discovered that the combination of C-3 and C-7 substituents provided in the compounds of the present invention unexpectedly gives the desired solubility, activity and toxicity profile needed for commercially viable anti-MRSA cephem products.
SUMMARY OF THE INVENTION
The present invention provides a novel series of cephem derivatives of the general formula
Figure imgf000007_0001
I wherein Q is an optionally substituted pyridinium group connected to the sulfur atom via a ring carbon atom; X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group, or a C2-C10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH,
Figure imgf000007_0002
n is 0 or 1; and R1 is hydrogen or a carboxyl-protecting group; or pharmaceutically acceptable salts and /or a prodrugs thereof.
The compounds of formula I are antibacterial agents useful in the treatment of infections in humans and other animals caused by a variety of gram-positive bacteria, particularly methicillin-resistant S aureus.
Also included in the invention are processes for preparing the compounds of formula I and pharmaceutical compositions containing
said compounds in combination with pharmaceutically acceptable carriers
or excipients. DETAILED DESCRIPTION
The present invention provides novel cephem derivatives of general formula I above which are antibacterial agents useful in the treatment of infectious diseases in humans and other animals. The compounds exhibit good activity against a wide variety of gram-positive microorganisms, e.g. S. pneumoniae, S. pyogenes, S. aureus. E. faecalis, S. epidermidis and S. hemolyticus. and are particularly useful against strains of methicillin-resistant S. aureus.
The compounds of formula I are characterized by an optionally substituted pyridinium thiomethyl group of the type
Figure imgf000008_0001
at the 3-position of the cephem ring and a 7-substituent of the type
Figure imgf000008_0002
wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H
or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group, or a C2-C10 alkyl group interrupted by one or more (preferably 1 or 2) groups
independently selected from vinyl, S, SO, S02, S02NH, O
Λ y or
N H Y '■
O
and n is 0 or 1.
A preferred embodiment of the present invention comprises a compound of the formula
Figure imgf000009_0001
IA wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group, or a C2-C10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH, o H
'N H Y o
n is 0 or 1; R3 and R4 are each independently selected from hydrogen or - C6 alkyl; R2 is hydrogen, NH2, pyrrolidinyl, Cj-C8 alkyl, C3-C6 cycloalkyl, C2- C6 alkyl substituted by one or more substituents independently selected from OH, NR5R6 in which Rs and R6 are each independently hydrogen or Cα-C6 alkyl, C02H, morpholinyl, morpholinyl quaternized by a - alkyl
O
II group, oxo (C), halogen, S03H, P03H2, imidazolyl, imidazolyl substituted by 1-2 Cj- alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 - alkyl groups or N=CR7 in which R7 is a furan or thiophene ring optionally substituted by either -C02H or -S03H, phenyl or phenyl substituted by 1-3
substituents independently selected from OH, NR5R6 in which R5 and R6 are as defined above, C02H, morpholinyl, morpholinyl quaternized by a Cj-C6 alkyl group, oxo, halogen, S03H, P03H2, imidazolyl, imidazolyl substituted by 1-2 - alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 Cα-C6 alkyl groups or N=CR7 in which R7 is as defined above; and R1 is hydrogen or a carboxyl-protecting group, or a pharmaceutically acceptable salt and /or a prodrug thereof.
Another preferred embodiment comprises a compound of the formula
Figure imgf000010_0001
IA wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group or a C2-C10 alkyl group interrupted by one or two groups independently
selected from vinyl, S, SO, S02, S02NH,
Figure imgf000010_0002
'• n is 0 or 1; R3 and R4 are each independently selected from hydrogen or -
C6 alkyl; R2 is hydrogen, NH2, pyrrolidinyl, Cα-C6 alkyl, Cα-C6 alkyl substituted by one or two substituents independently selected from OH,
NR5R6 in which R5 and R6 are each independently hydrogen or -Cg alkyl, C02H, morpholinyl, morpholinyl quaternized by a C -C6 alkyl group, oxo, halogen, S03H, P03H2, tetrazolyl,
Figure imgf000011_0001
in which R7 is a furan or thiophene radical optionally substituted by a -C02H or -S03H group, phenyl or phenyl substituted by 1-2 substituents independently selected from OH, NR5R6 in which R5 and R6 are as defined
above, COzH, S03H, P03H2, tetrazolyl, or
Figure imgf000011_0002
halogen; and R1 is hydrogen or a carboxyl-protecting group; or a pharmaceutically acceptable salt and /or a prodrug thereof.
Particularly preferred groups of the formula
Figure imgf000011_0003
in the above-described compounds of formula I and formula IA include
Figure imgf000012_0001
Particularly preferred groups of the formula
Figure imgf000012_0002
include
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
Specific preferred embodiments of the present invention include the following:
Figure imgf000014_0001
wherein R1 is hydrogen or a carboxyl-protecting group
Figure imgf000014_0002
Figure imgf000014_0003
l-[3-[N-(N-methyl) morpholino)]-prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo- 7-[(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000014_0004
C02H 2,6-dimethyl-l-[amino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-
carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yl]methylthio]pyridinium inner salt
Figure imgf000015_0001
C02H
l-[amino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2- carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt
Figure imgf000015_0002
CO2H
l-[N-pyrrolidino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2-
carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt
Figure imgf000016_0001
C02H
l-[methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2- carboxyethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt
Figure imgf000016_0002
2,6 dimethyl-l-[2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichloro-4-(2-[[(lS)-(carboxy-l-ethyl(amino)carbonyl)phenylthio) acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio] pyridinium inner salt
Figure imgf000017_0001
,χι
C02H
1 -[amino]-4- [ [(6R)-trans-2-carboxy-8-oxo-7- [ (2,5-dichloro-4-(carboxymethyl
thio)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt
Figure imgf000017_0002
'-
C02H
l-[aminocarbonyl methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4- (carboxymethylthio)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2- en-3-yl]methylthio]pyridinium inner salt
Figure imgf000017_0003
C02H l-[2-hydroxy-3-amino-prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000018_0001
C02H
1 - [3-hy droxy-4-carboxypheny 1] -4- [ [ (6R)-trans-2-carboxy-8-oxo-7- [ (2,5- dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000018_0002
C02H
l-[5-(sulfonylfuran-2-yl)-methylimine]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichloro-4-(2-carboxyethenyl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000019_0001
C02H
2,6-dimethyl-l-[2-hydroxy-3-amino-prop-l-yl]-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichloro-4-(2-carboxyeth-l-yl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000019_0002
C02H
l-[3-(l,2 dimethyl-lH-imidazol-3)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo- 7-[(2,5-dichloro-4-carboxyphenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]- oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000019_0003
C02H l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4- (carboxymethysulfonyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]- oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000020_0001
C02H
2,6-dimethyl-l-[3-(3-(l,2 dimethyl-lH-imidazol-3)prop-l~yl]-4-[[(6R)-trans- 2-carboxy-8-oxo-7-[(2,5-dichloro-4-
(carboxymethysulfonyl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000020_0002
l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-((( carboxymethyl)amino)carbonyl)acetamido)phenylthio)acetamido]-5-thia- l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000021_0001
l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2- (((carboxymethyl)amino)carbonyl)ethenyl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000021_0002
l-[3-(3-(l,2 dimethyl-lH-imidazol-3-yl)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-
oxo-7-[(2,5-dichloro-4-(5-carboxy-2-thiophene)phenylthio)acetamido]-5- thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000021_0003
2,6-dimethyl-l-[amino]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(2- (((carboxymethyl)amino)carbonyl)ethenyl)phenylthio)acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt
Figure imgf000022_0001
2,6-dimethyl-l-[ N-(N-methyl) morpholino]-4-[[(6R)-trans-2-carboxy-8-oxo-
7-[(2,5-dichloro-4-(2-(((carbonylmethyl)amino) carbonylethenyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en- 3-yl]methylthio]pyridinium inner salt
Figure imgf000022_0002
2,6-dimethyl-l-[ l,2-dimethyl-lH-imidazol-3-yl)prop-l-yl]-4-[[(6R)-trans-2-
carboxy-8-oxo-7-[(2,5-dichloro-4-(N-carboxymethyl
aminosulfonyl)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or
Figure imgf000023_0001
l-[2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-(5- carboxy-2-furan)phenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en- 3-yl]methylthio]pyridinium inner salt; or pharmaceutically acceptable salts and /or prodrugs thereof.
To elaborate on the definitions for substituents of the formula I and formula IA compounds:
(a) "Halogen" includes chloro, bromo, fluoro and iodo, and is preferably chloro or bromo and most preferably chloro.
(b) The aliphatic "alkyl" groups may be straight or branched chains containing the specified number of carbon atoms.
The term "pharmaceutically acceptable salt" as used herein is intended to include the nontoxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p- toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoracetic, hydroiodic, hydrobromic, and the like. Some of the compounds of the present invention have an acidic hydrogen and can, therefore, be converted with bases in a conventional manner into pharmaceutically acceptable salts. Such salts, e.g. ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris-(hydroxymethyl)amino- methane), or with bases such as piperidine or morpholine, are also intended to be encompassed by the term "pharmaceutically acceptable salt".
Compounds of the present invention in the form of acid addition salts may be written as
Figure imgf000024_0001
where X represents an acid anion and R1 is hydrogen or a carboxyl-
protecting group. The counter anion X may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration. The carboxyl-protecting group R1 is intended to include readily removable ester groups which have been conventionally employed to block a carboxyl group during the reaction steps used to prepare the compounds of the present invention and which can be removed by methods which do not result in any appreciable destruction of the remaining portion of the molecule, e.g. by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation. Examples of such protecting groups include benzhydryl, p-nitrobenzyl, 2- naphthylmethyl, allyl, benzyl, p-methoxybenzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and Cj-Cg alkyl such as methyl, ethyl or t-butyl. Included within such protecting groups are those which are hydrolyzed under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl,
indanyl, α-acetoxyethyl, -pivaloyloxyethyl and methoxy methyl.
Compounds of the present invention with such physiologically hydrolyzable carboxyl protecting groups are also referred to herein as "prodrugs". Compounds of the present invention where R1 is a
physiologically removable protecting group are useful directly as
antibacterial agents. Compounds where an R1 protecting group is not physiologically removable are useful intermediates which can be easily
converted to the bioactive form by conventional deblocking procedures
well-known to those skilled in the art. Compounds of the present invention wherein a hydroxyl substituent is esterified with a group hydrolyzable under physiological conditions are also included within the scope of the term "prodrug" as used herein. Such hydroxyl-protecting groups may be employed, for example, to increase the solubility of a cephem derivative. Illustrative of suitable ester "prodrugs" of this type are compounds wherein one or more hydroxy substituent groups are converted to sulfate (-OS03H) or phosphate (-OP03H2) groups.
The compounds of the present invention can be made by conventional methods. A suitable procedure is summarized by the following reaction scheme:
Figure imgf000027_0001
τv deprotection
Figure imgf000027_0002
IV
Figure imgf000027_0003
III
Figure imgf000027_0004
IA
To elaborate on the above process, intermediates of type VI are first prepared, for example, analogous to the process illustrated below:
Figure imgf000028_0001
Figure imgf000028_0002
Acid intermediate VI is then coupled with a suitable cephem intermediate having a 3-substituent leaving group. For example, the leaving group may be acetoxy or halogen. In the preferred embodiment illustrated by the reaction scheme, the cephem intermediate is the 3- chloromethyl cephem V, but other suitable cephem intermediates with equivalent leaving groups at the 3-position could also be employed. The cephem intermediate V may be acylated with VI or a reactive derivative thereof by conventional acylation procedures well-known in the cephalosporin art to give N-acylated intermediate IV. In addition to using the free arylthioacetic acid, e.g. with a suitable condensing agent such as dicyclohexylcarbodiimide, acylating agent VI may also be employed in the form of equivalent acylating derivatives such as an acid anhydride, mixed anhydride, activated ester, or acid halide. The cephem intermediate preferably has the carboxyl group protected by a conventional carboxyl- protecting group which can be readily removed. Examples of such protecting groups are discussed above and include benzyl, 4-nitrobenzyl, 1,1 dimethylethyl, 4-methoxybenzyl, diphenylmethyl, allyl, and the like. Other examples of suitable protecting groups are disclosed in Protective Groups in Organic Synthesis, 2nd Ed., Theodora W. Greene (John Wiley & Sons, 1991), Chapter 5. In one embodiment, intermediate V may be acylated with acid VI in the presence of dicyclohexylcarbodiimide and in an inert solvent such as tetrahydrofuran or dichloromethane. The reaction temperature is typically between -20 °C and 50 °C. Upon completion of the reaction, insoluble material is removed by filtration, the filtrate is concentrated, and the residue is treated with a relatively non-polar solvent such as diethyl ether or ethyl acetate resulting in precipitation of the desired product. Alternatively, acid VI may be
converted to the corresponding acid chloride, for example by treatment with thionyl chloride with or without a solvent such as dichloromethane,
followed by coupling with cephem amine V in the presence of a base such
as triethylamine or N-methylmorpholine to give intermediate IV.
Cephem IV is typically isolated after aqueous work-up and evaporation of
volatile solvents followed by trituration of the compound with a
relatively non-polar solvent such as diethyl ether or ethyl acetate. This intermediate may be used in the next reaction step as the X = chloride derivative, or can be converted to the X = bromide or X = iodide derivative by treatment with the appropriate metal halide in a solvent such as acetone.
To prepare the quaternary cephem intermediate IV is deprotected under acidic conditions, followed by reaction of the resulting intermediate IV with a thiopyridone derivative HI. For example, when R is diphenylmethyl or 4-methoxybenzyl, cephem acid IV is obtained upon treatment of IV with trifluoroacetic acid neat or in an inert solvent such as methylene chloride. A reagent such as anisole may also be employed to scavenge the liberated ester protecting group. The reaction temperature is usually at or below room temperature. The deprotection may also be carried out by treatment with other protic acids such as hydrochloric acid in a solvent such as methanol. The final product is typically isolated by precipitation or crystallization. Reaction of IV with a thiopyridone
derivative ffl in a solvent such as dimethylformamide, dimethyl sulfoxide, ethanol, methanol, or other appropriate solvents at a temperature between -20 °C and 100 °C affords target quaternary cephem I.
The final product is isolated as described above. Thiopyridones in are typically prepared according to a method analogous to that described in T. Takahashi et al., European Patent Application No. 209751 and in I.E. El-
Kholy et al., J. Heterocyclic Chem. Vol. 11, p. 487 (1974). This procedure
entails reaction of 4-thiopyrone (European Patent No. 209751) with an appropriate primary amine in a solvent such as aqueous methanol or ethanol at a temperature ranging between 0 °C and 78 ° C. The primary amine may be in the form of a zwitterion in examples where there is a free acid group present in the molecule. In these cases, a base such as sodium hydroxide, sodium bicarbonate, or pyridine is added to form the free amine in situ. The product may be isolated as its sodium salt by evaporation of volatile solvents, followed by trituration with a solvent such as diethyl ether or ethyl acetate. Alternatively, the reaction mixture may be acidified and extracted with an organic solvent to afford the product as the free carboxylic acid. If the carboxylate group is protected as an ester, the amine may be free or present as an acid salt. In the latter case, a base such as sodium hydroxide, sodium bicarbonate, or pyridine is added to form the free amine in situ. The product is typically isolated by precipitation or by reversed phase column chromatography following removal of volatile solvents.
Other representative intermediate VI groups may be prepared as described in the preparation of starting materials section below.
It will be understood that where the substituent groups used in the
above reactions contain certain reaction-sensitive functional groups such
as amino or carboxylate groups which might result in undesirable side-
reactions, such groups may be protected by conventional protecting
groups known to those skilled in the art. For example, thiopyridone intermediates of formula III may have an amine functional group protected as the t-butyloxycarbamate. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis, 2nd Ed., Theodora W. Greene (John Wiley & Sons, 1991). It is intended that such "protected" intermediates and end- products are included within the scope of the present disclosure and claims.
The desired end-product of formula I may be recovered either as the zwitterion or in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HC1, HI or methanesulfonic acid to the zwitterion. Compounds of formula I where
R! is hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof, may be converted by conventional procedures to a corresponding
compound where R! is a physiologically hydrolyzable ester group.
It will be appreciated that certain products within the scope of formula I may have a C-3 substituent group which can result in formation of optical isomers. It is intended that the present invention
include within its scope all such optical isomers as well as epimeric
mixtures thereof, i.e. R- or S- or racemic forms.
The novel cephalosporin derivatives of general formula I
(including the IA compounds) wherein Rl is hydrogen, an anionic charge or a physiologically hydrolyzable carboxyl-protecting group, or the
pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against many gram-positive bacteria. While they may be used, for example, as animal feed additives for promotion of growth, as
preservatives for food, as bactericides in industrial applications, for example in water-based paint and in the white water of paper mills to inhibit the growth of harmful bacteria, and as disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and dental equipment, they are especially useful in the treatment of infectious disease in humans and other animals caused by the gram-positive bacteria sensitive to the new derivatives. Because of their excellent activity against MRSA organisms, they are particularly useful in the treatment of infections resulting from such bacteria.
The pharmaceutically active compounds of this invention may be used alone or formulated as pharmaceutical compositions comprising, in
addition to the active cephem ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or
intramuscular injection). The pharmaceutical compositions may be in
solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection, the
preferred route of delivery, may be prepared in unit dose form in ampules
or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to- use form or in powder form for reconstitution at the time of delivery
with a suitable vehicle such as sterile water.
The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 50 mg/day to about 20 g/day. Administration is generally carried out in divided doses, e.g., three to four times a day, analogous to dosing with a cephalosporin such as cefotaxime.
IN VITRO ACTIVITY
Samples of the compounds prepared below in Examples 1 - 22 after solution in water and dilution with Nutrient Broth were found to exhibit
the following Minimum Inhibitory Concentrations (MIC) values versus the indicated microorganisms as determined by tube dilution. The MICs
were determined using a broth micro dilution assay in accordance with
that recommended by the National Committee for Clinical Laboratory
Standards (NCCLS). Mueller-Hinton medium was used except for Streptococci which was tested in Todd Hewitt broth. The final bacterial
inoculate contained approximately 5 x 10^ cfu/ml and the plates were
incubated at 35°C for 18 hours in ambient air (Streptococci in 5% Cθ2)-
The MIC was defined as the lowest drug concentration that prevented visible growth.
Microorganism MIC value in ug/ml
S. aureus methicillin resistant A27223 <8 S. pneumoniae A9585 <2
S. pyogenes A9604 <2
E. faecalis A20688 <8
S. aureus A9537, penicillinase negative <1
5. aureus A15090, penicillinase positive <1 S. epidermidis A24548 <1
S. epidermidis A25783, methicillin resistant <2
5. hemolyticus A21638 <8
TN VIVO ACTIVITY
The in vivo therapeutic efficacy of the compounds prepared in Examples 1 - 22 below after intramuscular injection to mice
experimentally infected with the representative MRSA strain A27223 was also measured.
The determination of the effectiveness of antimicrobial agents in Staphylococcus aureus systemic infection in mice
Organisms: The test organism, MRSA strain A27223 used to generate systemic infection in mice, is grown on two large Brain Heart Infusion Agar plates. On each plate, 0.5 ml of frozen stock culture is plated out.
Plates are then incubated for 18 hours at 30°C. The next day each plate is
washed with 20 ml of Brain Heart Infusion Broth and then pooled together. A microscopic direct count of microorganism is done using a
1:1000 dilution of plate wash. After a direct count is obtained, the number of organisms per milliliter is calculated. The count is adjusted to the desired amount of inoculum by diluting in 4% hog mucin. The desired
challenge (amount of organisms given to mice) is 2.4 x 10^ cfu/0.5 ml /mouse for MRSA strain A27223. The mice are infected
intraperitoneally with 0.5 ml of challenge. Ten non-treated infected mice
are used as controls. Mice: Mice used are male ICR mice. The average weight of the animals is
from 20 to 26 grams.
Drug preparation and treatment: Compounds are tested at 4 dose levels, (25, 6.25, 1.56, and 0.39 mg/kg) and prepared in 5% cremophor, unless otherwise specified. Vancomycin is used as the control compound, and is dosed at 6.25, 1.56, 0.39, and 0.098 mg/kg. It is prepared in 0.1M phosphate buffer. There are five infected mice per dose level, and they are treated with 0.2 ml of the test compound, preferably by intramuscular injection. Treatment begins 15 minutes and 2 hours post-infection.
Test duration: A PD50 (the dose of drug given which protects 50% of
mice from mortality) experiment runs for 5 days. During this time, mortality of mice are checked every day and deaths are recorded. The cumulative mortality at each dose level is used to calculate a PD50 value
for each compound. Surviving mice are sacrificed at the end of day 5 by
CO2 inhalation.
Calculation: Actual calculation of PD50 is performed with a computer
program using the Spearman-Karber procedure.
Results: The in vivo efficacy, expressed as the PD50 value, ranged from
about 0.8 to 22.0 mg/kg (for certain compounds, more than one test was carried out; the indicated range is for at least one test result when
multiple tests were done).
ILLUSTRATIVE EXAMPLES
The following examples illustrate the invention, but are not intended as a limitation thereof. The abbreviations used in the examples are conventional abbreviations well-known to those skilled in the art. Some of the abbreviations used are as follows:
h = hour(s) mol = mole(s) mmol = mmole(s)
S = gram(s)
THF = tetrahydrofuran
L = liter(s) mL = milliliter(s)
Et20 = diethyl ether
EtOAc = ethyl acetate
BOC = butoxycarbonyl
DCC = dicyclohexylcarbodiimide
DPM = diphenylmethyl
Ph3P = triphenylphosphine
t-Bu = tertiary-butyl
EtOH = ethanol Bu3N = tributylamine
MeOH = methanol
DMF = dimethylformamide
DABCO = l,4-diazabicyclo[2.2.2]octane
TFA = trifluoroacetic acid
DMS = dimethylsulfide m-CPBA = meta-chloroperoxybenzoic acid
TFAA = trifluoroacetic anhydride
TEA = triethylamine
In the following examples, all temperatures are given in degrees
Centigrade. Proton nuclear magnetic resonance ( H NMR) spectra were recorded on a Bruker AM-300 or a Varian Gemini 300 spectrometer. All spectra were determined in CDCI3, DMSO-d6, CD3OD, or D2O unless
otherwise indicated. Chemical shifts are reported in δ units relative to
tetramethylsilane (TMS) or a reference solvent peak and interproton
coupling constants are reported in Hertz (Hz). Splitting patterns are
designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublets; dt, doublet of triplets;
and app d, apparent doublet, etc. Mass spectra were recorded on a Kratos
MS-50 or a Finnegan 4500 instrument utilizing direct chemical ionization
(DCI, isobutene), fast atom bombardment (FAB), or electron ion spray
(ESI). Analytical thin-layer chromatography (TLC) was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors, and/or staining by heating with methanolic phosphomolybdic acid. Column chromatography, also referred to as flash chromatography, was performed in a glass column using finely divided silica gel at pressures somewhat above atmospheric pressure with the indicated solvents. Reversed-phase analytical thin-layer chromatography was
carried out on precoated reverse phase plates and visualized using UV light or iodine vapors. Reversed-phase column chromatography was performed in a glass column using Baker Octadecyl (Cis), 40 mm.
Preparation of Starting Materials
scheme 2
Figure imgf000041_0001
scheme 3
Figure imgf000041_0002
Figure imgf000041_0003
11 scheme 5
Figure imgf000042_0001
scheme 6
Figure imgf000042_0002
scheme 7
Figure imgf000042_0003
22 23
scheme 8
Figure imgf000043_0001
32
A. Synthesis of acid 2
Acid 1 (2.00 g., 0.006 mol) is dissolved in 50 mL EtOH, and Ptθ2 (1.00
g., 0.004 mol) is added. The mixture is hydrogenated at 20 psi for 18 hours.
1H-NMR analysis indicates that the reaction has only proceeded to 30% conversion. More Ptθ2 (0.400 g., 0.002 mol) is added, and hydrogenation
at 20 psi is continued another 6 hours. At this time the reaction is only 50% complete. The solids are filtered, and the filtrate is treated with fresh Ptθ2 (1.00 g., 0.004 mol) and hydrogenated at 20 psi for another 20 hours.
The reaction still shows some starting olefin. At this point the mixture is filtered, and the filtrate is concentrated. The residue is chromatographed
on silica using CH2CI2 as eluant, followed by a gradient elution with methanol/CH2Cl2 (up to 15% MeOH). Acid 2 is obtained (0.750 g., 0.002
mol; 33% yield) as a white solid.
ΪH-NMR (300 MHz, CDCI3): δ 7.40 (s, 1H, ArH), 7.30 (s, 1H, ArH), 3.72 (s,
2H, SCH2), 2.96 (t, 2H, J = 8 Hz, ArCH2), 2.54 (t, 2H, J = 8 Hz, CH2CO2R),
1.43 (s, 9H, C(CH3)3).
B. Synthesis of acid 4
Diester 3 (7.00 g., 0.019 mol) is suspended in 40 mL CH2CI2. Anisole
(1 mL) is added, followed by 15 mL of trifluoroacetic acid. The mixture is stirred for 1 hour at room temperature. The solvents are concentrated to -15 mL, and excess ether is added to precipitate a white solid. The solid is collected, washed with ether, and dried under vacuum to yield acid 4 (4.85 g., 0.015 mol; 79% yield).
iH-NMR (300 MHz, DMSO-d6): δ 8.08 (s, 1H, ArH), 7.71 (d, 1H, J = 16 Hz,
ArCH=C), 7.43 (s, 1H, ArH), 6.69 (d, 1H, J = 16 Hz, C=CHCθ2), 4.19 (s, 2H,
SCH2), 3.66 (s, 3H, OCH3). C. Synthesis of hydroxysuccinimide ester 5
Acid 4 (8.75 g., 0.027 mol) is suspended in 55 mL THF under an atmosphere of nitrogen. Dicyclohexylcarbodiimide (1M in CH2CI2, 28.7
mL, 0.029 mol) is added, followed by N-hydroxysuccinimide (3.14 g., 0.027 mol). The reaction is allowed to stir for 3 hours at room temperature. The mixture is diluted with -30 mL acetone, filtered to remove dicyclohexylurea, and concentrated to -25 mL. A solid forms which is filtered off, and the filtrate is evaporated to dryness. Crude 5 is obtained as a white solid (12.3 g.) which is of sufficient purity for use in subsequent reactions.
iH-NMR (300 MHz, DMSO-dό): δ 8.27 (s, 1H, ArH), 8.01 (d, 1H, J = 16 Hz,
ArCH=C), 7.50 (s, 1H, ArH), 7.17 (d, 1H, J = 16 Hz, C=CHCθ2), 4.23 (s, 2H,
SCH2), 3.68 (s, 3H, OCH3), 2.84 (m, 4H, CH2CH2).
D. Synthesis of amide 6
tert-Butylglycine hydrochloride (5.19 g., 0.031 mol) is suspended
under a nitrogen atmosphere in 60 mL dry DMF. N-Methylmorpholine (3.90 mL, 0.036 mol) is added, and then the mixture is cooled to 0°C.
Crude hydroxysuccinimide ester 5 (12.3 g.) is added, and the mixture
allowed to stir for 10 minutes at 0°C. The cooling bath is removed and the
reaction is stirred for 1 hour. The mixture is concentrated, and the residue dissolved in ethyl acetate and placed in a separatory funnel. The
solution is washed with 0.4 N aqueous HC1, 0.1 N aqueous NaHCθ3, water and then brine. The organic phase is dried (MgSθ4) and evaporated
to afford clean amide 6 as a light yellow solid (10.4 g., 0.024 mol; 89% yield from acid 4).
iH-NMR (300 MHz, DMSO-dό): δ 8.42 (t, IH, J = 8 Hz, NH), 7.81 (s, IH,
ArH), 7.59 (d, IH, J = 16 Hz, ArCH=C), 7.47 (s, IH, ArH), 6.80 (d, IH, J = 16 Hz, C=CHCONH), 4.20 (s, 2H, SCH2), 3.85 (d, 2H, J = 8 Hz, NCH2C02), 3.67
(s, 3H, OCH3), 1.41 (s, 9H, C(CH3)3).
E. Synthesis of 2,4,5-trichlorobenzaldehyde 8
Ester 7 (1.03 g., 3.35 mmol) is dissolved in 200 mL CH2CI2 and 100
mL methanol. The mixture is cooled to -78°C, and ozone is bubbled through the solution until it turns blue. The mixture is purged with oxygen, and then 1.3 mL of methyl sulfide is added. The mixture is allowed to warm to room temperature, and the solvents are evaporated. The crude residue is partitioned between ether and water. The ether layer is washed with water and brine, and then dried (MgSθ4). Concentration
of the ether layer, followed by chromatography on silica using 25% CH2θ2/hexane as eluant, affords 8 (0.55 g., 2.63 mmol; 79% yield) as a
white solid.
iH-NMR (300 MHz, CDCI3): δ 10.34 (s, IH, CHO), 7.98 (s, IH, ArH), 7.58 (s,
IH, ArH). F. Synthesis of 2,4,5-trichlorobenzoic acid 9
2,4,5-Trichlorobenzaldehyde (0.275 g., 1.31 mmol) is dissolved in 8 mL acetone. A slight excess of Jones Reagent is added, and the mixture stirred at room temperature for 1 hour. Methanol (-6 mL) is added, and
after 5 minutes the mixture is partitioned between methylene chloride and water. The aqueous phase is extracted with chloroform (2X), and the combined organic extracts are washed with water, then brine. The organic phase is dried (MgSθ4), and concentrated to afford pure 2,4,5-
trichlorobenzoic acid 9 (0.285 g., 1.26 mmol; 96% yield) as a white solid.
iH-NMR (300 MHz, CDCI3): δ 8.01 (s, IH, ArH), 7.61 (s, IH, ArH).
G. Synthesis of 2,4,5-trichlorobenzoic acid, tert-butyl ester 10
Acid 9 (2.93 g., 13.0 mmol) placed in a Parr hydrogenation bottle (under an atmosphere of nitrogen) is dissolved in 55 mL of dioxane. The
bottle is cooled to -78°C, and 5 mL cone, sulfuric acid is added cautiously, followed by -50 mL liquid isobutylene (cooled to -78°C). The bottle is
sealed and agitated on a Parr shaker overnight (-19.5 hours). The sealed bottled is vented, and the solution slowly added to a separatory funnel containing half-saturated aqueous NaHCθ3 and ether. The aqueous layer
is extracted with ether, and the combined organic phase was dried (MgSθ4) and concentrated. Chromatography on silica using hexane,
followed by 25% CH2CI2 /hexane, affords ester 10 as a pale yellow oil (2.56 g., 9.10 mmol; 70% yield) which solidifies overnight in the refrigerator to
an off-white solid.
iH-NMR (300 MHz, CDCI3): δ 7.81 (s, IH, ArH), 7.53 (s, IH, ArH), 1.58 (s,
9H, C(CH3)3).
H. Synthesis of diester 11
Using the method described below for the synthesis of diester 3, ester 10 (2.5 g., 11.3 mmol) is converted to diester 11 (3.20 g., 9.12 mmol; 81% yield). Diester 11 was obtained as a white solid by chromatography on silica gel using 80% methylene chloride /hexane.
!H-NMR (300 MHz, CDCI3): δ 7.75 (s, IH, ArH), 7.30 (s, IH, ArH), 3.75 (s,
3H, OCH3), 3.72 (s, 2H, SCH2), 1.58 (s, 9H, C(CH3)3).
I. Synthesis of acid 12
Diester 11 (1.60 g., 4.56 mmol) is dissolved in 5 mL methylene chloride. Trifluoroacetic acid (2 mL) is added, and the mixture stirred for
4 hours at room temperature. The solvents are evaporated to provide 12 (1.24 g., 4.20 mmol; 92% yield) as a tan solid of sufficient purity for use in
the next reaction. IH-NMR (300 MHz, DMSO-d6): δ 7.87 (s, IH, ArH), 7.46 (s, IH, ArH), 4.23
(s, 2H, SCH2), 3.68 (s, 3H, OCH3).
J. Synthesis of amide 13 Acid 12 (1.24 g., 4.20 mmol) is dissolved in 14 mL dry THF.
Dicyclohexylcarbodiimide (0.866 g., 4.20 mmol) is added, followed by tert- butyl glycine (0.550 g., 4.20 mmol), and the mixture stirred at room temperature for 2 hours. Ether is added to the flask, and the solids removed by filtration. The filtrate is evaporated to yield 1.96 g. of crude material. Chromatography on silica using 80% CH2CI2 /hexane, followed
by a second chromatography using 20% ethyl acetate /hexane affords amide 13 (0.844 g., 2.07 mmol; 49% yield) as a white solid.
!H-NMR (300 MHz, CDCI3): δ 7.78 (s, IH, ArH), 7.31 (s, IH, ArH), 4.12 (d,
2H, J = 6 Hz, NCH2CO2), 3.77 (s, 3H, OCH3), 3.72 (s, 2H, SCH2), 1.48 (s, 9H,
C(CH3)3).
K. Synthesis of ester 15
2,4,5-Trichlorothiophenol (35.0 g., 0.166 mol) is dissolved in 500 mL methylene chloride and cooled to 0°C. Triethylamine (22.0 g., 0.217 mol) is added, followed by a solution tert-butyl bromoacetate (35.1 g., 0.180 mol)
in 100 mL methylene chloride (over 5 minutes). After stirring for 20
minutes at 0°C, the ice-bath is removed, and stirring continued for another hour. The mixture is placed in a separatory funnel and washed with water (2X), 10% aqueous H3PO4, and then brine. The organic phase
is dried (MgSθ4), and evaporated to afford a white solid, which is washed
with hexane. Ester 15 (51 g., 0.156 mol; 94%) as obtained is of suitable purity for subsequent reactions.
iH-NMR (300 MHz, CDCI3): δ 7.47 (s, IH, ArH), 7.45 (s, IH, ArH), 3.66 (s,
2H, SCH2), 1.43 (s, 9H, C(CH3)3).
L. Synthesis of sulfoxide 16
Ester 15 (50.0 g., 0.153 mol) is dissolved in 500 mL chloroform and cooled to 0°C. m-Chloroperoxybenzoic acid (50-60% from Aldrich, 48.0 g., 0.140-0.168 mol) is added in small portions over 30 minutes. The ice bath is removed and stirring continued for 2.5 hours at room temperature. The solids were removed by filtration, and the filtrate washed with dilute aqueous NaHSθ3, 5% aqueous Na2Cθ3, saturated aqueous NaHCθ3, and
then brine. The organic phase is dried (MgSθ4), and evaporated. The
crude material is chromatographed twice on silica gel using methylene
chloride and then 3% methanol /methylene chloride to afford sulfoxide 16
(35.0 g., 0.102 mol; 67% yield) as a white solid. iH-NMR (300 MHz, CDCI3): δ 7.95 (s, IH, ArH), 7.53 (s, IH, ArH), 4.05 (d,
IH, J = 14 Hz, CH2S(0)), 3.70 (d, IH, J = 14 Hz, CH2S(0)), 1.43 (s, 9H,
C(CH3)3).
M. Synthesis of diester 17
Using the procedure described below for the synthesis of diester 3, sulfoxide 16 (35.0 g., 105 mmol) is converted to diester 17 (32.5 g., 78.7 mmol; 75% yield). The compound is isolated as a white solid after chromatography on silica using methylene chloride then 3% methanol /methylene chloride.
ΪH-NMR (300 MHz, CDCI3): δ 7.83 (s, IH, ArH), 7.28 (s, IH, ArH), 3.92 (d,
IH, J = 14 Hz, CH2S(0)), 3.77 (s, 3H, OCH3), 3.71 (s, 2H, SCH2), 3.57 (d, IH, J
= 14 Hz, CH2S(0)).
N. Synthesis of diester 20
Diester 17 (28.0 g., 67.8 mmol) is dissolved in 500 mL acetone. Sodium iodide (48.7 g., 325 mmol) is added, followed by trifluoroacetic anhydride (40.0 g., 191 mmol) over 5 minutes. After stirring at room temperature for 1 hour, the solvents are evaporated. Methylene chloride is added and evaporated twice. The residue is taken up in methylene chloride and washed with aqueous NaHSθ3 solution (3X), water, and
then brine. The organic phase is dried (MgSθ4), and evaporated. Chromatography of the residue on silica using methylene chloride affords diester 20 (23.5 g., 59.2 mmol; 87 % yield) as a white solid.
iH-NMR (300 MHz, CDCI3): δ 7.38 (s, IH, ArH), 7.35 (s, IH, ArH), 3.74 (s,
3H, OCH3), 3.66 (s, 2H, SCH2), 3.60 (s, 2H, SCH2).
O. Synthesis of sulfone 18
Ester 15 (7.00 g., 21.4 mmol) is dissolved in 40 mL chloroform and treated with m-chloroperoxybenzoic acid (-60% from Aldrich, 12.0 g., -42 mmol). After stirring for 1 hour at room temperature, the solids are removed by filtration, and the filtrate is washed with dilute aqueous NaHSθ3, 5% aqueous Na2Cθ3, saturated aqueous NaHCθ3, and then
brine. The organic phase is dried (MgSθ4), and evaporated.
Chromatography of the residue on silica using methylene chloride then 3% methanol /methylene chloride affords sulfone 18 (7.00 g., 19.5 mmol; 93% yield) as a white solid.
IH-NMR (300 MHz, CDCI3): δ 8.17 (s, IH, ArH), 7.67 (s, IH, ArH), 4.32 (s,
2H, SCH2), 1.33 (s, 9H, C(CH3)3).
P. Synthesis of diester 19
Using the procedure described below for the synthesis of diester 3,
sulfone 18 (7.20 g., 20.0 mmol) is converted to diester 19 (8.05 g., 18.8 mmol; 94% yield). The compound is isolated as a white solid after chromatography on silica using methylene chloride then 3%
methanol /methylene chloride.
!H~NMR (300 MHz, CDCI3): δ 8.05 (s, IH, ArH), 7.40 (s, IH, ArH), 4.28 (s,
2H, SO2CH2), 3.78 (s, 3H, OCH3), 3.77 (s, 2H, SCH2).
Q. Synthesis of sulfonamide 22 tert-Butyl glycine (2.62 g., 20.0 mmol) and triethylamine (2.50 g., 25.0 mmol) are dissolved in 20 mL chloroform under a nitrogen atmosphere.
The solution is cooled with an ice-bath, and 2,4,5-
trichlorobenzenesulfonyl chloride (5.60 g., 20.0 mmol) dissolved in 30 mL chloroform is added over 5 minutes. The cooling bath is removed and the mixture allowed to stir at room temperature for 1 hour. The solution is washed with 10% aqueous H3PO4, water, and then brine. The organic
phase is dried (MgSθ4), and evaporated to afford clean sulfonamide 22
(7.00 g., 18.8 mmol; 94% yield) as a white solid.
!H-NMR (300 MHz, CDCI3): δ 8.10 (s, IH, ArH), 7.63 (s, IH, ArH), 3.72 (s,
2H, NCH2CO2), 1.33 (s, 9H, C(CH3)3).
R. Synthesis of diester 23
Using the procedure described above, sulfonamide 22 (3.70 g., 10.0
mmol) is converted to diester 23 (2.37 g., 7.40 mmol; 74% yield). The compound is isolated as a white solid after chromatography on silica using methylene chloride then 5% methanol /methylene chloride.
iH-NMR (300 MHz, CDCI3): δ 7.96 (s, IH, ArH), 7.36 (s, IH, ArH), 5.65 (t,
IH, J = 5 Hz, NH), 3.85 (s, 3H, OCH3), 3.78 (s, 2H, SCH2), 3.71 (d, 2H, J = 5
Hz, NCH2CO2), 1.34 (s, 9H, C(CH3)3).
S. Synthesis of 2,5-dichloro-4-iodophenol 24
2,5-Dichlorophenol (20.4 g., 0.125 mol) is placed in a 1L round bottom flask equipped with a large egg-shaped stir bar and is dissolved in
307 mL CH2CI2. With rapid stirring, iodine (46.6 g., 0.183 mol) is added,
followed by silver sulfate (42.3 g., 0.136 mol). The purple solution is stirred 1 day, at which point NMR analysis of an aliquot indicates the reaction is complete.
The reaction is diluted with CH2CI2 (-200 ml) and filtered through
a fritted Buchner funnel to remove silver salts. The salts are washed with additional CH2CI2 (-100 mL). The organic filtrate is transferred to a
separatory funnel and is washed first with a solution of sodium
thiosulfate (-40 g. in -200 mL water; this removes excess I2), and then
brine. The organic phase is dried (MgSθ4), and evaporated to give 24
(34.59 g., 0.108 mol; 86% yield) as a pale pink/yellow solid. The material is
sufficiently pure to carry forward. iH-NMR (300 MHz, CDCI3): δ 7.75 (s, IH, ArH), 7.14 (s, IH, ArH), 5.62 (br,
IH, OH).
T. Synthesis of thiocarbamate 25 Iodophenol 24 (34.59 g., 0.108 mol) is placed into a 500 mL round bottom flask equipped with septa, N2 inlet, and a stir bar. The phenol is
then dissolved in 130 mL DMF. DABCO (24.2 g., 0.216 mol) is added followed by dimethylthiocarbamyl chloride (21.6 g., 0.175 mol). The mixture is stirred at room temperature for - 1 hour, then diluted with EtOAc (-400 mL) and poured into a separatory funnel containing - 300 mL of ice-water. The phases are separated, and the aqueous extracted twice with - 200 mL of EtOAc. The combined organic extracts are washed twice with water (~ 100 mL), and then brine. The organic phase is dried (MgSθ4), and evaporated to afford 25 as a dark oil. This material is
dissolved in CH2CI2 and dried again (MgSθ4). After evaporation a yellow
solid (-35 g.) is obtained. The compound was of sufficient purity to be used in the next reaction.
!H-NMR (300 MHz, CDCI3): δ 7.90 (s, IH, ArH), 7.24 (s, IH, ArH), 3.46 (s,
3H, CH3), 3.37 (s, 3H, CH3). U. Synthesis of 26
The crude material obtained above (-35 g.) was heated neat under N2 at 220 °C for two hours. After cooling, the material was dissolved in
CH2CI2 and filtered through a plug of silica gel. The fractions containing
the product are evaporated to afford 30.2 g. of a brown solid. This material was chromatographed on silica (in portions) using a gradient elution
starting with 1:1 CH2Cl2/hexane (material dissolved in a minimum
amount of CH2CI2 for column loading), and then -70% CH2θ2/hexane.
Compound 26 is obtained as a yellow crystalline solid (13.0 g., 36.0 mmol; 33% yield from 2,5-dichlorophenol).
!H-NMR (300 MHz, CDCI3): δ 7.95 (s, IH, ArH), 7.62 (s, IH, ArH), 3.10 (br
s, 3H, CH3), 3.00 (br s, 3H, CH3).
V. Synthesis of 2,5-dichloro-4-iodothiophenol 27
Carbamate 26 (9.80 g., 0.026 mol) is dissolved in 40 mL EtOH and
treated with 30 mL 3N aqueous KOH. The mixture is heated to reflux with stirring under nitrogen for 3 hours. The solution is allowed to cool
and is then acidified with 3 N HC1 until pH -3. The mixture is extracted
with CH2CI2 (thrice), and the combined organic phase washed with water
and then brine. The extracts are dried (MgSθ4) and evaporated. The
crude material is chromatographed on silica using 1:1 CH2CI2 /hexane.
Thiol 27 (6.43 g., 0.021 mol; 81% yield) is obtained as a white solid. !H-NMR (300 MHz, CDCI3): δ 7.83 (s, IH, ArH), 7.56 (s, IH, ArH).
W . Synthesis of ester 28
Thiol 27 (6.43 g., 0.021 mol) is dissolved in 50 mL CH2CI2 and
triethylamine (2.52 g., 0.025 mol) is added. Methyl bromoacetate (3.82 g., 0.025 mol) is then added over 5 minutes. The resultant mixture is stirred
at room temperature for 1.5 hours, at which time ^H-NMR analysis indicated the reaction was complete. The mixture was diluted with CH2CI2 (-200 mL) and was washed with water, IN HCl, water, and then
brine. The organic layer was dried (MgSθ4) and evaporated. The crude
material is chromatographed on silica using 70% CH2CI2 /hexane. Ester
28 is obtained as a white solid (7.20 g., 0.019 mol; 90% yield).
iH-NMR (300 MHz, CDCI3): δ 7.82 (s, IH, ArH), 7.42 (s, IH, ArH), 3.75 (s,
3H, OCH3), 3.68 (s, 2H, SCH2).
X. Synthesis of stannane 29
Bis(tributyltin) (29.5 g., 50.9 mmol) is dissolved under a nitrogen atmosphere in 70 mL dry THF. The solution is cooled to -20°C, and
butyllithium (1.6 M in hexane, 31.2 mL, 49.9 mmol) is added dropwise over 20 minutes, maintaining the temperature of the bath at -20°C. The
solution is then cooled to -50°C, and then copper(I) bromide methylsulfide complex (5.10 g., 24.8 mmol) is added. The mixture is allowed to stir at -40°C for 15 minutes, and is then cooled to -78°C. 5- Bromofuroic acid tert-butyl ester (4.10 g., 16.6 mmol) dissolved in 15 mL THF is added, and the mixture allowed to stir for 3 hours at -78°C. The reaction mixture is poured into 1 L of ether and -300 mL half-saturated aqueous ammonium chloride solution. After stirring for 5 minutes the ether layer is decanted onto another -300 mL of half-saturated aqueous ammonium chloride solution. After 5 minutes the biphasic mixture is separated, and the organic phase is washed with brine, dried (MgSθ4) and
evaporated. Chromatography on silica using hexane, then 25% methylene chloride /hexane affords stannane 29 (5.05 g., 11.1 mmol; 67% yield) as a clear oil.
!H-NMR (300 MHz, CDCI3): δ 7.04 (d, IH, J = 4 Hz, HetArH), 6.56 (d, IH, J
= 4 Hz, HetArH), 1.59-1.47 (m, 3 H, SnBu3), 1.37-1.24 (m, 9 H, SnBu3), 1.13-
1.05 (m, 6 H, SnBu3), 0.89 (t, 9H, J = 6 Hz, SnBu3).
Y. Synthesis of diester 30
Stannane 29 (1.50 g., 3.28 mmol) is dissolved in 8 mL dry THF. Aryl
iodide 28 (0.928 g., 2.46 mmol) is added, followed by
bis(triphenylphosphine)-palladium(II) chloride (0.160 g., 0.228 mmol).
The solution is heated to reflux for 6 hours. The mixture is diluted with
-15 mL THF, 4 mL cone, aqueous KF is added, and the mixture is stirred
for 20 minutes. Ether is added, and the mixture is then filtered to remove insoluble tin solids. The biphasic filtrate is separated, and the aqueous layer is extracted with ether. The combined organic phases are washed with brine, dried (MgSθ4) and evaporated. During evaporation crystals
began to form, and when only -5 mL of liquid remains it is decanted. The solids are washed with hexane and then pumped dry. Diester 30 (0.793 g., 1.91 mmol; 78% yield) is obtained as a white solid.
!H-NMR (300 MHz, CDCI3): δ 7.99 (br s, IH, ArH), 7.40 (br s, IH, ArH),
7.19 (d, IH, J = 2 Hz, HetArH), 7.13 (d, IH, J = 2 Hz, HetArH), 3.75 (s, 3H, OCH3), 3.71 (s, 2H, SCH2), 1.60 (s, 9H, C(CH3)3).
Z. Synthesis of stannane 31
Using the method described above, 5-bromo-2-thiophenecarboxylic
acid, tert-butyl ester (4.52 g., 17.2 mmol) is converted to stannane 31 (4.33 g., 9.16 mmol; 53% yield). The compound is isolated as a light yellow oil after chromatography on silica using 25% methylene chloride/hexane.
iH-NMR (300 MHz, CDCI3): δ 7.80 (d, IH, J = 3 Hz, HetArH), 7.12 (d, IH, J
= 3 Hz, HetArH), 1.58 (m, 15H, SnBu3), 0.92 (t, 9H, J = 6 Hz, SnBu3), 0.85-
0.80 (m, 3H, SnBu3). A A. Synthesis of diester 32
Using the method described above for the synthesis of diester 30,
stannane 31 (1.70 g., 3.60 mmol) and aryl iodide 28 (1.03 g., 2.73 mmol) are converted to diester 32 (0.920 g., 2.13 mmol; 78% yield as a light yellow solid).
iH-NMR (300 MHz, CDCI3): δ 7.66 (d, IH, J = 3 Hz, HetArH), 7.55 (s, IH,
ArH), 7.44 (s, IH, ArH), 7.27 (d, IH, J = 3 Hz, HetArH), 3.78 (s, 3H, OCH3),
3.73 (s, 2H, SCH2), 1.58 (s, 9H, C(CH3)3).
Example 1
l-[2-hydroxy-3-amino-prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichloro-4-(2-carboxyethenyl)phenylthio acetamido]-5-thia-l- azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt.
scheme 1
Figure imgf000061_0001
A. Synthesis of olefin 7
2,4,5-Trichloroiodobenzene (25 g., 81.3 mmol) is dissolved in 80 mL DMF. tert-Butyl acrylate (48 mL, 328 mmol), tributylamine (58 mL, 243 mmol), triphenylphosphine (4.08 g., 15.5 mmol), and palladium acetate (3.23 g., 14.4 mmol) are added, and the mixture heated to 80°C for three hours. The solvents are evaporated and the residue is partitioned with EtOAc and water. The aqueous phase is extracted with EtOAc, and the combined organic phase is washed with brine, dried (MgSθ4), and
evaporated. The dark red-brown oil is chromatographed on silica in a fritted Buchner funnel using vacuum filtration, with 30%
CH2CI2 /hexane followed by 50% CH2CI2 /hexane as eluant. Acrylate 7 is
obtained (18.7 g., 60.8 mmol; 75% yield) as a mauve solid.
iH-NMR (300 MHz, CDCI3): δ 7.82 (d, IH, J = 16 Hz, ArCH=C), 7.67 (s, IH,
ArH), 7.51 (s, IH, ArH), 6.34 (d, IH, J = 16 Hz, C=CHCθ2t-Bu), 1.51 (s, 9H,
C(CH3)3).
B. Synthesis of diester 3
Acrylate 7 (21.23 g., 69 mmol) is dissolved in 131 mL DMF. The sodium salt of methyl mercaptoacetate (17.7 g., crude: see note below) is added and the mixture stirred at room temperature for one hour. The mixture is partitioned with EtOAc and water. The aqueous phase is extracted with EtOAc, and the combined organic phase is washed with
brine, dried (MgSθ4), and evaporated. Chromatography on silica in a
fritted Buchner funnel (vacuum filtration) using 50% CH2CI2 /hexane
followed by 90% CH2Cl2/hexane as eluant affords diester 3 (19.6 g., 52.0
mmol; 75% yield). iH-NMR (300 MHz, CDCI3): δ 7.86 (d, IH, J = 16 Hz, ArCH=C), 7.60 (s, IH,
ArH), 7.36 (s, IH, ArH), 6.35 (d, IH, J = 16 Hz, C=CHCθ2t-Bu), 3.77 (s, 3H,
OCH3), 3.72 (s, 2H, SCH2), 1.51 (s, 9H, C(CH3)3).
Note: The sodium salt of methyl mercaptoacetate is best made fresh before use. Approximately 30 mL of methyl mercaptoacetate is dissolved in -250 mL THF. One equivalent of 5 N NaOH is added slowly in pipetfulls, and the mixture allowed to stir for 5 minutes. The solvents are removed in vacuo (including water) and the sticky solid is co-evaporated with ether (-200 mLs) and then dry THF (2 x 200 mLs). The solid is
pumped dry for several hours under high vacuum until the flask is no longer cool due to evaporation. The freely mobile white solid is used as obtained. Excess of this reagent (1.5 to 2 equivalents) is generally used.
C. Synthesis of acid 1
Diester 3 (4.40 g., 0.012 mol) is dissolved in 30 mL THF. To this
solution is added 13 mL of IN NaOH, and the mixture is allowed to stir at
room temperature for 1.5 hours. At this time ^H-NMR analysis of an
aliquot indicates that the reaction is complete. The THF is removed
under vacuum, and the concentrate is diluted with water and extracted with EtOAc. The aqueous layer is then acidified with IN HCl to pH 4, and
then extracted with CH2CI2. The organic phase is washed with brine,
dried (MgSθ4), and then evaporated. Acid 1 is obtained as a tan solid (3.80
g., 0.011 mol; 92% yield). iH-NMR (300 MHz, CDCI3): δ 7.82 (d, IH, J = 16 Hz, ArCH=C), 7.56 (s, IH,
ArH), 7.33 (s, IH, ArH), 6.29 (d, IH, J = 16 Hz, C=CHCθ2t-Bu), 3.72 (s, 2H,
SCH2), 1.51 (s, 9H, C(CH3)3).
D. Synthesis of cephem IV"
Cephem amine V (15.04 g., 0.035 mmol) is suspended under a nitrogen atmosphere in 65 mL THF. A solution of DCC in methylene chloride (1M, 36.2 mL, 0.036 mmol) is added, and the mixture allowed to stir for 5 minutes. Acid 1 (13.15 g., 0.035 mmol) is added and the mixture is stirred for 1.5 hours. Ether (-30 mL) is added, and the solids (mostly DCU) are filtered off. The red-colored filtrate is evaporated to -25-30 mL and ether and pentane are added to precipitate the cephem product. The solid cephem is collected, washed with ether, and dried under vacuum to afford diester IV" (14.2 g., 0.019 mmol; 54% yield).
iH-NMR (300 MHz, CDCI3): δ 7.53 (d, IH, J = 16 Hz, ArCH=C), 7.45-7.20
(m, 12H, ArH), 6.98 (s, IH, Ph2CH), 6.35 (d, IH, J = 16 Hz, C=CHCθ2t-Bu),
5.82 (dd, IH, J = 5, 8 Hz, R1R2CHNR3), 4.97 (d, IH, J = 5 Hz, CH(NR)(SR)),
4.37 (m, 2H, CH2CI), 3.76 (d, IH, J = 16 Hz, ArSCH2), 3.55 (d, IH, J = 16 Hz,
ArSCH2), 3.40 (d, IH, J = 16 Hz, RSCH2R), 1.54 (s, 9H, C(CH3)3). E. Synthesis of diacid IV
Diester IV" (0.760 g., 1.00 mmol) is dissolved in 4 mL CH2CI2 and
0.8 mL anisole. Trifluoroacetic acid (2 mL) is added, and the mixture is stirred for 4 hours. The solvents are evaporated, and the residue triturated with CH2CI2/ ether. The solid is collected, washed with EtOAc
and then dried under vacuum. Diacid IV" is obtained (0.420 g., 0.780 mmol; 78% yield) as a light yellow solid.
iH-NMR (300 MHz, DMSO): δ 9.30 (d, IH, J = 8 Hz, RC(O)NH), 8.07 (s, IH,
ArH), 7.72 (d, IH, J = 16 Hz, ArCH=C), 7.54 (s, IH, ArH), 6.68 (d, IH, J = 16 Hz, C=CHCθ2H), 5.71 (dd, IH, J = 5, 8 Hz, R1R2CHNR3), 5.13 (d, IH, J = 5
Hz, CH(NR)(SR)), 4.55 (m, 2H, CH2CI), 3.97 (m, 2H, ArSCH2), 3.70 (d, IH, J
= 16 Hz, RSCH2R), 3.53 (d, IH, J = 16 Hz, RSCH2R).
F. Synthesis of cephem IA'
Diacid IV" (0.780 g., 1.45 mmol) is dissolved in 3 mL methanol and 8 mL CH2O2. Thiopyridone III' (0.395 g., 1.45 mmol) is added, and the mixture is
stirred at room temperature for 4 hours. The flask is then placed in a refrigerator at 4°C overnight. The solvents are concentrated, and the product precipitated with ether. The solid is filtered, then suspended in EtOAc and stirred for 30 minutes. The product is then filtered, and the solid dried under vacuum. Cephem IA' is obtained as a tan solid (0.690 g., 0.850 mmol; 59% yield
of a mixture of two diastereomers). iH-NMR (300 MHz, DMSO, partial): δ 9.31 (d, IH, J = 8 Hz, RC(O)NH),
8.67 (d, 2H, J = 7 Hz, SpyrH), 7.98 (d, 2H, J = 7 Hz, SpyrH), 8.07 (s, IH, ArH), 7.72 (d, IH, J = 16 Hz, ArCH=C), 7.54 (s, IH, ArH), 6.69 (d, IH, J = 16 Hz, C=CHCθ2H), 5.70 (dd, IH, J = 5, 8 Hz, R1R2CHNR3), 5.14 (d, IH, J = 5 Hz,
CH(NR)(SR)), 4.59-4.45 (m, 2H, CH2Spyr), 4.40-4.32 (m, 2H, pyrCH2R), 4.05-
3.95 (m, 2H, ArCH2S), 1.38 (s, 9H, C(CH3)3).
G. Synthesis of cephem IA"
Cephem IA' (0.605 g., 0.747 mmol) is suspended in 3 mL CH2C12,
and 1 mL of trifluoroacetic acid is added. The solution is stirred for two hours and the solvents evaporated. The crude material is dissolved in CH2CI2 and precipitated with ether. The solids are collected, suspended
in EtOAc and stirred for 30 minutes. The solids are collected and dried under vacuum (P2O5). Cephem IA" is obtained (0.410 g., 0.609 mmol; 82%
yield).
iH-NMR (300 MHz, DMSO, partial): d 9.40-9.35 (m, IH, RC(O)NH), 8.77- 8.72 (m, 2H, SpyrH), 8.23-8.18 (m, 2H, SpyrH), 8.12 (s, IH, ArH), 7.77 (d, IH, J = 16 Hz, ArCH=C), 7.62 (s, IH, ArH), 6.75 (d, IH, J = 16 Hz, C=CHCθ2H),
5.68-5.61 (m, IH, R1R2CHNR3), 5.11 (d, IH, J = 5 Hz, CH(NR)(SR)), 4.07-
3.97 (m, 2H, ArSCH2). Following the general procedures and using the appropriate starting materials described above, the following additional compounds were prepared:
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
TABLE: NMRDATA
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0001
t
Figure imgf000074_0003
Figure imgf000074_0002
Figure imgf000075_0001

Claims

CLAIMSWe claim:
1. A compound of the formula
Figure imgf000076_0001
wherein Q is an optionally substituted pyridinium group connected to the sulfur atom via a ring carbon atom; X is halogen; Y is hydrogen or halogen; A is COzH, P03H2, S03H or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group, or a C2-C10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH,
~.N^ °r -N H Y o : n is 0 or 1; and R1 is hydrogen or a carboxyl-protecting group; or a pharmaceutically acceptable salt and/or a prodrug thereof.
2. A compound of the formula
Figure imgf000077_0001
IA
wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group, or
a C2-C10 alkyl group interrupted by one or more groups independently selected from vinyl, S, SO, S02, S02NH, o
Figure imgf000077_0002
n is 0 or 1; R3 and R4 are each independently selected from hydrogen or - C6 alkyl; R2 is hydrogen, NH2, pyrrolidinyl, C3-C6 cycloalkyl, C C6 alkyl, C2- C6 alkyl substituted by one or more substituents independently selected from OH, NR5R6 in which R5 and R6 are each independently hydrogen or Cα-C6 alkyl, C02H, morpholinyl, morpholinyl quaternized by a - alkyl group, oxo, halogen, S03H, P03H2, imidazolyl, imidazolyl substituted by 1- 2 C C6 alkyl groups, tetrazolyl, tetrazolyl substituted by 1-2 C C6 alkyl groups or N=CR7 in which R7 is a furan or thiophene ring optionally substituted by either -C02H or -S03H, phenyl or phenyl substituted by 1-3 substituents independently selected from OH, NR5R6 in which R5 and R6 are as defined above, C02H, morpholinyl, morpholinyl quaternized by a Cj-C6 alkyl group, oxo, halogen, S03H, P03H2, imidazolyl, imidazolyl substituted by 1-2 - alkyl groups, tetrazolyl, tetrazolyl substituted by 1- 2 Cα-C6 alkyl groups or N=CR7 in which R7 is as defined above; and R1 is hydrogen or a carboxyl-protecting group, or a pharmaceutically acceptable i salt and /or a prodrug thereof.
3. A compound of the formula
Figure imgf000078_0001
IA
wherein X is halogen; Y is hydrogen or halogen; A is C02H, P03H2, S03H or tetrazole; L1 is a furan group, a thiophene group, a C2-C10 alkyl group or a C2-C10 alkyl group interrupted by one or two groups independently selected from vinyl, S, SO, S02, S02NH, o
Λ H or Y o n is 0 or 1; R3 and R4 are each independently selected from hydrogen or - C6 alkyl; R2 is hydrogen, NH2, pyrrolidinyl, - alkyl, C C6 alkyl substituted by one or two substituents independently selected from OH, NR5R6 in which R5 and R6 are each independently hydrogen or Cj-C6 alkyl, C02H, morpholinyl, morpholinyl quaternized by a -C6 alkyl group, oxo, halogen, S03H, P03H2, tetrazolyl,
Figure imgf000079_0001
in which R7 is a furan or thiophene radical optionally substituted by a -C02H or -S03H group, phenyl or phenyl substituted by 1-2 substituents independently selected from OH, NR5R6 in which R5 and R6 are as defined
above, C02H, S03H, P03H2, tetrazolyl, or
Figure imgf000079_0002
halogen; and R1 is hydrogen or a carboxyl-protecting group; or a pharmaceutically acceptable salt and /or a prodrug thereof.
4. A compound of claim 3 wherein is
Figure imgf000079_0003
-
Figure imgf000080_0001
5. A compound of claim 3 or claim 4 wherein
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000081_0002
Figure imgf000081_0003
6. A compound of the formula
Figure imgf000081_0004
wherein A „ s and Q are as defined below:
Figure imgf000082_0001
Figure imgf000082_0002
C02H
C02H
Figure imgf000082_0004
C02H
Figure imgf000083_0001
C02H
Figure imgf000083_0002
C02H
Figure imgf000083_0003
Figure imgf000083_0004
"I C02H
Figure imgf000083_0005
"l
C02H
Figure imgf000084_0001
C02H
Figure imgf000084_0002
C02H
Figure imgf000084_0003
C02H
Figure imgf000084_0004
C02H
Figure imgf000084_0005
C02H
Figure imgf000085_0001
o , ι
C02H
Figure imgf000085_0002
C02H
Figure imgf000085_0003
Figure imgf000085_0004
Figure imgf000085_0005
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000086_0003
C02H
or
Figure imgf000086_0004
C02H and R1 is hydrogen or a carboxyl-protecting group; or a pharmaceutically acceptable salt and/or a prodrug thereof.
7. The compound of the formula
Figure imgf000087_0001
or a pharmaceutically acceptable salt and /or a prodrug thereof.
8. The compound of the formula
Figure imgf000087_0002
or a pharmaceutically acceptable salt and /or a prodrug thereof.
9. The compound of the formula
Figure imgf000087_0003
or a pharmaceutically acceptable salt and /or a prodrug thereof.
10. The compound of the formula
Figure imgf000088_0001
or a pharmaceutically acceptable salt and /or a prodrug thereof.
11. The compound of the formula
Figure imgf000088_0002
or a pharmaceutically acceptable salt and /or a prodrug thereof.
12. The compound of the formula
Figure imgf000089_0001
or a pharmaceutically acceptable salt and /or a prodrug thereof.
13. A pharmaceutical composition comprising an effective antibacterial amount of a compound of Claim 1 and a pharmaceutically acceptable carrier or excipient.
14. A method of treating a bacterial infection which comprises administering to a host afflicted with such infection an effective antibacterial amount of a compound of Claim 1.
15. A method of treating a bacterial infection caused by a strain of methicillin-resistant Staphylococcus aureus which comprises
administering to a host afflicted with such infection an effective
antibacterial amount of a compound of Claim 1.
PCT/US1997/021785 1996-11-27 1997-11-21 Cephalosporin derivatives WO1998023621A1 (en)

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NZ335892A NZ335892A (en) 1996-11-27 1997-11-21 Cephalosporin derivatives for treating bacterial infections
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US8895587B2 (en) * 2011-05-18 2014-11-25 Syngenta Participations Ag Insecticidal compounds based on arylthioacetamide derivatives
CN105131018B (en) * 2015-09-23 2017-12-26 浙江华方药业股份有限公司 A kind of preparation method of ceftezole acid
CN114957056A (en) * 2021-02-20 2022-08-30 帕潘纳(北京)科技有限公司 Process for preparing methyl 3-methyl-2-chloro-4-methylsulfonylbenzoate and intermediates thereof

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