WO1997037997A1 - Derives de cephalosporine - Google Patents

Derives de cephalosporine Download PDF

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Publication number
WO1997037997A1
WO1997037997A1 PCT/US1997/005271 US9705271W WO9737997A1 WO 1997037997 A1 WO1997037997 A1 WO 1997037997A1 US 9705271 W US9705271 W US 9705271W WO 9737997 A1 WO9737997 A1 WO 9737997A1
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WIPO (PCT)
Prior art keywords
carboxy
oxo
thia
trans
oct
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PCT/US1997/005271
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English (en)
Inventor
John D. Matiskella
Stanley V. D'andrea
Thomas W. Hudyma
Yasutsugu Ueda
Oak K. Kim
Raymond F. Miller
Shelley E. Hoeft
Joanne J. Bronson
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Brystol-Myers Squibb Company
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Priority to AU24291/97A priority Critical patent/AU2429197A/en
Publication of WO1997037997A1 publication Critical patent/WO1997037997A1/fr

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    • 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

Definitions

  • the present invention is directed to new cephem derivatives represented by the general formula
  • Ar is an optionally substituted lipophilic phenyl, naphthyl or pyridyl group
  • R 1 represents C C 10 alkyl or C 3 -C 6 cycloalkyl linked by a carbon atom to the quaternary nitrogen, said alkyl or cycloalkyl group having a carboxy, -S0 3 H or tetrazolyl substituent and said alkyl group being optionally interrupted by -S- or
  • R 2 , R 3 , R 9 and R 10 are each independently hydrogen, (C 1 -C 10 )alkyl or ( -C ⁇ alkyl substituted by one or more, preferably one or two, substituents independently selected from C0 2 H, hydroxy and NR ⁇ R 12 in which R 11 and R 12 are each independently hydrogen or (C 1 -C 6 )alkyl, and R 2 and R 9 or R 3 and R 10 can optionally be joined in a
  • the literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents. Applicants are not aware, however, of any literature disclosing compounds with the combination of C-3 and C-7 substituents found by applicants to give the desired activity, solubility and toxicity profile needed for a commercially viable anti-MRSA cephalosporin product.
  • the present invention provides a novel series of cephem derivatives of the general formula
  • R 4 , R 5 and R 6 are each independently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy (C ⁇ -C 6 )alkyl, (C ⁇ -C 6 )alkyl, - (CH 2 ) n R 7 or -(CH 2 ) n SR 7 ; n is an integer of from 1 to 6; R 7 is hydrogen or(C ⁇ - C 6 )alkyl; R 1 represents alkyl having from 1 to 10 carbons or cycloalkyl having from 3 to 6 carbons, said alkyl or cycloalkyl group being linked by a carbon atom to the quaternary nitrogen and having a carboxy, -SO 3 H or tetrazolyl substituent, and said alkyl group being optionally interrupted by -S- or
  • R 7 is as defined above;
  • R 2 , R 3 , R 9 and R 10 are each independently hydrogen, (C C 10 )alkyl or (C C 10 )alkyl substituted by one or more, preferably one or two, substituents independently selected from C0 2 H, hydroxy and NR n R 12 in which R 11 and R 12 are each independently hydrogen or (C C 6 )alkyl, and R 2 and R 9 or R 3 and R 10 can optionally substituted by one or more of (C ⁇ -C 6 )alkylthio, hydroxy, ( - C6)alkylsulfinyl, (C ⁇ -C6)alkylsulfonyl, carbamoyl, ureido, C 2 -C 6 alkenyl, halo, oxo, hydroxyimino, heteroaryl or phenyl in which the phenyl or heteroaryl group is optionally substituted by up to three hydroxy or (C ⁇ -C 6 )alkoxy groups;
  • 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 variety of gram-positive microorganisms, e.g. S. pneumoniae. S_ pyogenes. S. aureus. E. faecalis. E. faecium. S. epidermidis and S. hemolyticus. and are particularly useful against strains of methicillin-resistant S. aureus.
  • wherin Ar is an aromatic group selected from optionally substituted phenyl, naphthyl or pyridyl.
  • Halogen includes chloro, bromo, fluoro and iodo, and is preferably chloro or bromo;
  • Trihalomethyl includes trichloromethyl, trifluoromethyl, tribromomethyl and triiodomethyl, but is preferably trifluoromethyl;
  • the aliphatic "alkyl”, “alkoxy” and “alkenyl” groups may be straight or branched chains having the specified number of carbon atoms. It is preferred that such groups have up to 6 carbon atoms and most preferably up to 4 carbon atoms;
  • "Heteroaryl” includes mono-, bi- and polycyclic aromatic heterocyclic groups containing 1-4 O, N or S atoms; preferred are 5- and 6-membered heterocyclic rings such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, etc.
  • the alkyl or cycloalkyl R 1 substituent is linked by a carbon atom to the quaternary nitrogen of the pyridine ring, e.g.
  • R 7 interrupted by — s — or — N — and /or optionally substituted by one or more of (C j -C ⁇ alkylthio, hydroxy, (C C 6 )alkylsulfinyl, ( -
  • C 6 alkylsulfonyl, carbamoyl, ureido, C 2 -C 6 alkenyl, halo, oxo, hydroxyimino, heteroaryl or phenyl in which the phenyl or heteroaryl group is optionally substituted by up to three hydroxy or ( -C alkoxy groups.
  • 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, trifluoroacetic, hydroiodic, hydrobromic, and the like.
  • acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like.
  • acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic,
  • 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)aminomethane), 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 8 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 compounds I 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, etc.
  • protecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl, p- methoxybenzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, acetonyl, o- nitrobenzyl, 4-pyridylrnethyl and (C,-C 6 )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,
  • a preferred embodiment of the present invention comprises compounds of formula I wherein R 1 is
  • R 4 , R 5 and R 6 are each independently hydrogen, halogen, (C j -C 6 )alkyl, trifluoromethyl, hydroxy, hydroxy(C 1 -C 6 )alkyl or amino.
  • R 1 is ( -C alkyl substituted by an oxo o c / group and a group selected from carboxy, S0 3 H and tetrazolyl.
  • R 1 groups include:
  • R 4 , R 5 and R 6 are each independently hydrogen, halogen, ( -C alkyl, trifluoromethyl, hydroxy, hydroxy(C,-C 6 )alkyl or amino.
  • the most preferred Ar substituents are
  • R 4 , R 5 and R 6 are each independently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy(C r C 6 )alkyl, (C r C 6 )alkyl, -(CH 2 ) n OR 7 or -(CH 2 ) n SR 7 ; n is an integer of from 1 to 6; R 7 is hydrogen or (C,-C 6 )alkyl; and R 8 is hydrogen or a protecting group; and pharmaceutically acceptable salts or prodrugs thereof.
  • the definitions and the preparative methods discussed herein for the formula I compounds also pertain to the formula IA compounds, as do the preferred Ar substituents.
  • the formula IA compounds are also potent gram- positive antibacterial agents especially useful for MRSA infections.
  • the compounds of the present invention can be made by conventional methods. Two suitable procedures are summarized in the following reaction scheme:
  • R ester protecting group such as diphenylmethyl (DP ) or para-methoxybenzyl (PMB) Method 1
  • thiol VII is converted into the arylthioacetic acid derivative VI by treatment with bromoacetic acid under basic conditions (e.g. aqueous sodium or potassium hydroxide).
  • the reaction temperature for this step is typically between 20 °C and 100 °C.
  • Starting thiol YJI is commercially available or can be prepared according to known literature procedures.
  • the product VI is typically isolated by crystallization or, if necessary, it can be purified by chromatography.
  • Arylthioacetic acid VI is then coupled with a suitable cephem intermediate having a 3-substituent leaving group.
  • the leaving group may be acetoxy or halo.
  • the cephem intermediate is the 3-chloro 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 VJ 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, 4-methoxybenzyl, diphenylmethyl, allyl, and the like. Other examples of suitable protecting groups are disclosed in Protective Groups in Organic Synthesis. Theodora W. Greene (John Wiley & Sons, 1981), Chapter 5.
  • intermediate V may be acylated with acid Yl 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 VJ 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.
  • cephem IV Conversion of cephem IV to the target quaternary cephems I is accomplished by two different methods.
  • One method for preparation of I entails displacement of an appropriate 3-substituent leaving group with 4- mercaptopyridine followed by quaternization of the pyridyl nitrogen, and then deprotection of the cephem carboxylate ester.
  • Reaction of thiopyridyl derivative H with a reactive alkylating agent provides the quaternary cephem intermediate T.
  • alkylating agents are ⁇ -halocarbonyl derivatives such as N- substituted haloacetamides.
  • the alkylation reaction is carried out in an inert solvent such as acetone, dimethylformamide, or tetrahydrofuran and is run at temperatures between -20 °C and 100 °C
  • Removal of the cephem carboxylate ester protecting group to give I is then accomplished under acidic conditions.
  • R is diphenylmethyl or 4-methoxybenzyl
  • I is obtained upon treatment of i_ 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.
  • cephem I is purified by column chromatography, for example on reversed- phase adsorbent.
  • intermediate IY is deprotected under acidic conditions, followed by reaction of the resulting intermediate IV with a thiopyridone derivative ffl.
  • a thiopyridone derivative ffl for example, when R is diphenylmethyl or 4-methoxybenzyl, cephem acid IV is obtained upon treatment of IY 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 III 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.
  • 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 fll 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.
  • 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.
  • 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.
  • 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 reverse phase column chromatography following removal of volatile solvents.
  • the thiopyridone derivatives of formula III are another aspect of the present invention.
  • the preferred R 1 , R 2 , R 3 , R 9 and R 10 substituents of derivatives III are as disclosed above in connection with the end-products of formula I.
  • reaction-sensitive functional groups such as carboxylate groups which might result in undesirable side-reactions
  • groups may be protected by conventional protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis. 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 HCl, HI or methanesulfonic acid to the
  • IA compounds wherein R ⁇ 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 waterbased paint and in the white water of paper
  • 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.
  • MIC Minimum Inhibitory Concentrations
  • hemolyticus A21638 0.015 - 8 5. hemolyticus A27235, methicillin resistant 0.25 - 32
  • Organisms 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
  • desired challenge amount of organisms given to mice
  • 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
  • Test duration A PD50 (the dose of drug given which protects 50% of mice from
  • mice are sacrificed at a PD50 value for each compound.
  • results The in vivo efficacy, expressed as the PD50 value, ranged from about 0.8
  • TMS tetramethylsilane
  • Hz Hertz
  • Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiple.; br, broad peak; dd, doublet of doublets; dt, doublet of triplets; and app d, apparent doublet, etc.
  • Infrared spectra were determined on a Perkin-Elmer 1800 FT-IR spectrometer from 4(
  • 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 (Ci ⁇ ), 40
  • Method a A solution of 2,5-dichlorophenylthioacetic acid (13.0 g, 54.9 mmol) in methylene chloride (55 mL) and thionyl chloride (10 mL, 137 mmol) was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The residue was evaporated two times from toluene to give 14 g of 2,5-dichlorophenylthioacetyl chloride (100% yield) as a

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Abstract

Dérivés cephem représentés par la formule générale: Ar-S-CH2-C-NH dans laquelle les substituants sont tels que définis ci-après. Ces composés sont des agents antibactériens gram-positifs utiles spécialement pour le traitement des maladies causées par le Staphylococcus aureus résistant à la méthicilline.
PCT/US1997/005271 1996-04-04 1997-03-27 Derives de cephalosporine WO1997037997A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24291/97A AU2429197A (en) 1996-04-04 1997-03-27 Cephalosporin derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1485196P 1996-04-04 1996-04-04
US60/014,851 1996-04-04
US2066096P 1996-06-27 1996-06-27
US60/020,660 1996-06-27

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WO1997037997A1 true WO1997037997A1 (fr) 1997-10-16

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6265394B1 (en) 1997-07-31 2001-07-24 Bristol-Myers Squibb Company Bis quaternary MRSA cephem derivatives
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5567698A (en) * 1995-02-15 1996-10-22 Bristol-Myers Squibb Company Pyridinium thiomethyl substituted chepholosporin derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5567698A (en) * 1995-02-15 1996-10-22 Bristol-Myers Squibb Company Pyridinium thiomethyl substituted chepholosporin derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6265394B1 (en) 1997-07-31 2001-07-24 Bristol-Myers Squibb Company Bis quaternary MRSA cephem derivatives
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds

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