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WO1999006048A1 - Derives de cepheme mrsa bisquaternaire - Google Patents

Derives de cepheme mrsa bisquaternaire Download PDF

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Publication number
WO1999006048A1
WO1999006048A1 PCT/US1998/014778 US9814778W WO9906048A1 WO 1999006048 A1 WO1999006048 A1 WO 1999006048A1 US 9814778 W US9814778 W US 9814778W WO 9906048 A1 WO9906048 A1 WO 9906048A1
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Prior art keywords
alkyl
compound
hydroxy
pharmaceutically acceptable
group
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PCT/US1998/014778
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English (en)
Inventor
Roman Z. Sterzycki
Oak K. Kim
Yasutsugu Ueda
Stanley V. D'andrea
Dane M. Springer
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Bristol-Myers Squibb Company
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Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU84088/98A priority Critical patent/AU8408898A/en
Publication of WO1999006048A1 publication Critical patent/WO1999006048A1/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
    • 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

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
  • L j and L 2 are (C 1 -C 6 )alkyl optionally substituted with hydroxy or keto and /or optionally interrupted with a vinyl group, S, O, aryl or heteroaryl, or a group of the formula
  • R 1 is hydrogen or (C 1 -C 6 )alkyl or can optionally contain A;
  • A is CO z H, P0 3 H, SO 3 H, tetrazole, squaric acid or a hydroxyl group;
  • R 2 , R 3 , R 9 and R 10 are hydrogen or optionally substituted (C C 6 )alkyl, or R 2 and R 9 or R 3 and R 10 can optionally be joined in a ring;
  • R 8 is hydrogen or a protecting group; and Q is a quatemized nitrogen group.
  • the derivatives IA, IB and IC 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.
  • Ar is an aryl group selected from
  • R 4 , R 5 and R 6 are each independently hydrogen, halogen, trihalomethyl, nitro, - 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 Q-Qalkyl; R 1 is -CR 8 R 9 R 10 , -(CH 2 ) n CONR 8 R 9 and -(CH 2 ) n COR 8 in which R 8 , R 9 and R 10 are each independently hydrogen, substituted or unsubstituted Q-Q 5 alkyl, C 2 -C 15 alkenyl or C 2 -C 15 alkynyl, substituted or unsubstituted phenyl, phenyl(Q-Q)alkyl, naphthyl or naphthyl(C 1 -C 6 )alkyl or a sugar moiety of the formula
  • n is as defined above;
  • R 2 and R 3 are each independently hydrogen, Q-Q alkyl, or amino (Q-Q)alkylcarbonyl-amino; and
  • R 11 is hydrogen, an anionic charge or a carboxyl-protecting group provided that when R 11 is hydrogen or a protecting group, there is also a counter ion; or a pharmaceutically acceptable
  • R 3 , R 4 and R 5 are each independently hydrogen, halogen, trihalomethyl, Q-Q alkyl, -(CH 2 ) n OR 6 or -(CH 2 ) n SR 6 , with the proviso that when Ar is a phenyl group, R 3 , R 4 and R 5 may not all be hydrogen; n is an integer of from 1 to 6; R 6 is hydrogen or Q-Q alkyl; R 1 and R 2 are each independently hydrogen, -(CH 2 ) m CONR 7 R 8 , -(CH 2 ) m COR 7 , -(CH 2 ) m C0 2 R 7 , -(CH 2 ) m CN, -(CH 2 ) m NR 7 R 8 , -(CH 2 ) m OR 7 , -(CH 2 ) m NHCONR 7 R 8 or -(CH 2 ) m NHCOR 7 in which m is 0 or an integer of from 1 to 6
  • R 1 and R 2 may not both be hydrogen; and R 9 is hydrogen, an anionic charge or a carboxyl-protecting group, provided that when R 9 is hydrogen or a protecting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.
  • 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 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; 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, (Q-Q 0 )alkyl or (Q-Q-)alkyl substituted by one or more, preferably one or two, substituents independently selected from CO-H, hydroxy and NR n R 12 in which R 11 and R 12 are each independently hydrogen or (Q-Q)alkyl, and R 2 and R 9 or R 3 and R 10 can optional
  • 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 1 -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 (d-Q . alkyl; L 1 and L 2 are each independently (C ⁇ -C 6 )alkyl optionally substituted with hydroxy or keto and /or optionally interrupted with a vinyl group, S, O, an aryl or heteroaryl residue, or
  • R 1 is H or Q-Q alkyl
  • A is CO 2 H, PO 3 H, SO 3 H, tetrazole, squaric acid, or a hydroxyl group
  • Q is selected from the group consisting of:
  • R 14 and R 15 are each independently (C ⁇ -C ⁇ o)alkyl optionally substituted with OH or C(0)NH 2 ;
  • X is CH 2 , O, S, N, SO or S0 ;
  • R 7 is H, (C r C 6 ) alkyl, (C 3 -C 6 )cycloalkyl, OH, CONH 2 , aryl or heteroaryl and can be located anywhere on the ring including X when X is CH 2 or N;
  • R 15 is (C ⁇ -C 6 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with OH or CONH 2 , or R 15 is aryl or heteroaryl;
  • a through F can be CH or N, and either 1 or 2 of the non- adjacent atoms being N with the remainder being CH, exactly one
  • N being quatemized by attachment to Li, L 2 , R 17 , or R 13 ;
  • R 13 is as
  • R 17 is as defined above for R 7 ;
  • G, H, I, and J are either CH or N, K is either CH2, NH, or S,
  • R 18 is as defined above for R 7 ;
  • R , R , R and R are each independently hydrogen, (C ⁇ -C ⁇ o)alkyl or (C C 10 )alkyl substituted by one or more substituents independently
  • 11 19 11 1 selected from hydroxy and NR R in which R and R are each
  • R 9 ⁇ 10 independently hydrogen or (C C 6 )alkyl, or R and R or R and R can optionally be joined in a ring; and R 8 is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug thereof.
  • 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 1 -C 6 )alkyl, (Q-C 6 )alkyl, -(CH 2 ) n OR or
  • n is an integer of from 1 to 6;
  • R 7 is hydrogen or (C 1 -C 6 )alkyl;
  • L 1 is (C ⁇ -Ce)alkyl optionally substituted with hydroxy or keto and /or optionally interrupted with a vinyl group, S, O, an aryl or heteroaryl residue or
  • R 1 is H or (Q-Q)alkyl
  • A is C0 2 H, PO 3 H, SO 3 H, tetrazole, squaric acid or a hydroxyl group
  • Q is selected from the group consisting of:
  • R 14 , R 15 and R 16 are each independently (Q-C ⁇ o)alkyl optionally substituted with OH or C(0)NH 2 ;
  • X is CH 2 , O, S, N, SO or SO 2 ;
  • R 7 is H, (C r C 6 ) alkyl, (C 3 -C 6 )cycloalkyl, OH, CONH 2 , aryl or heteroaryl and can be located anywhere on the ring including X when X is CH 2 or N; and R 14 is as defined above; (3)
  • R 15 is (C ⁇ -C 6 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with OH or CONH , or R 15 is aryl or heteroaryl; and R 14 is as defined above;
  • Y is CH or N and R 16 is as defined above for R 7 ;
  • a through F can be CH or N, either 1 or 2 of the non-
  • R 17 is as defined above for R 7 ;
  • G, H, I, and J are either CH or N
  • K is either CH 2 , NH, or S
  • R 18 is as defined above for R 7 ;
  • R , R , R and R are each independently hydrogen, (Q-C ⁇ o)alkyl or (Q-C ⁇ alkyl substituted by one or more substituents independently selected from hydroxy and NR R in which R and R are each independently hydrogen or (Q-C 6 )a_kyl, or R 2 and R 9 or R 3 and R 1 can
  • R 8 is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug thereof.
  • 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 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, -(CH2) n OR 7 or -(CH2) n SR 7 ; n is an integer of from 1 to 6; R 7 is hydrogen or (C 1 -C 6 )alkyl; L 1 is (C ⁇ -C 6 )alkyl optionally substituted with hydroxy or keto and /or optionally interrupted with a vinyl group, S, O, aryl or heteroaryl, or
  • R 1 is H or (Q-Q )alkyl
  • A is C0 2 H, PO 3 H, SO 3 H, tetrazole, squaric acid or a hydroxyl group
  • Q is selected from the group consisting of:
  • R 14 , R 15 and R 16 are each independently (C ⁇ -C ⁇ o)alkyl optionally substituted with OH or C(0)NH 2 ;
  • X is CH 2 , O, S, N, SO or S0 2 ;
  • R 7 is H, (C r C 6 alkyl), (C 3 -C 6 )cycloalkyl, OH, CONH 2 , aryl or heteroaryl and can be located anywhere on the ring including X when X is CH 2 or N; and R 14 is as defined above;
  • R 15 is (C ⁇ -C 6 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with OH or CONH 2 , or R 15 is aryl or heteroaryl; and R 14 is as defined above;
  • Y is CH or N and R 16 is as defined above for R 7 ;
  • a through F can be CH or N, and either 1 or 2 of the non- adjacent atoms being N with the remainder being CH, exactly one
  • N being quatemized by attachment to Li, I_2, R 17 , or R 13 ;
  • R 13 is as
  • R 17 is as defined above for R 7 ; and (6)
  • G, H, I, and J are either CH or N, K is either CH2, NH, or S,
  • R 18 is as defined above for R 7 ;
  • R , R and R are each independently hydrogen, (C 1 -C 10 )alkyl or (C ⁇ -C ⁇ o)alkyl substituted by one or more substituents independently selected from hydroxy and NR R in which R and R are each
  • R 9 Q independently hydrogen or (Q-Q ⁇ lkyl, or R and R can optionally be joined in a ring; and R 8 is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compounds of formulae IA, IB and IC 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 cephem derivatives of general formula IA, IB and IC 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, J epidermis and S. hemolyticus and are particularly useful against strains of methicillin-resistant S. aureus.
  • the compounds of the present invention are characterized by being a combination of a lipophilic 7-substitutent of the type
  • Ar is an aromatic group selected from optionally substituted phenyl, naphthyl or pyridyl and a 3-substituent of the type
  • Q contains two quaternary nitrogen atoms and an acidic functional group selected from C0 2 H, P0 3 H, S0 3 H, tetrazole, squaric acid or a hydroxyl group.
  • Halogen includes chloro, bromo, fluoro and iodo and is preferably chloro or bromo;
  • Trihalomethyl includes trichloromethyl, trifluoromethyl, tribromomethyl and triiodomethyl, but is preferably trifluoromethyl;
  • alkyl refers to a straight or branched chain monovalent alkane having the specified number of carbon atoms, e.g. in the case of (Q-Q)alkyl, the alkyl group may have from 1 to 6 carbon atoms.
  • aryl or "aryl residue” refers to aromatic carbocyclic containing from 6 to 22 atoms.
  • An aryl group can contain at least one ring having at least six carbons with up to five such rings being present containing up to 22 carbons.
  • Preferred aryl groups are phenyl, naphthyl and phenanthrenyl with phenyl and naphthyl being most preferred.
  • heteroaryl or “heteroaryl residue” refers to a monocyclic aromatic ring having 5 or 6 ring atoms, or a bicyclic aromatic ring having 8 to 10 ring atoms containing at least one heteroatom selected from O, S or N.
  • heteroaryl include thiazolyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
  • o (f ) "Keto" refers to - c —
  • salts as used herein is intended to include the nontoxic acid addition slats with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p- toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like.
  • acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p- toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like.
  • acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric
  • 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 carboxyl-protecting group R 8 is intended to include readily removable ester groups which have been 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-pyridylmethyl and (C ⁇ -C6)alkyl such as methyl, ethyl or t-butyl.
  • protecting groups include those which are hydrolyzed under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, and methoxymethyl.
  • Compounds of formula I with such physiologically hydrolyzable carboxyl protecting groups are also referred to herein and in the claims as "prodrugs".
  • Compounds of formula I where R° is a physiologically removable protecting group are useful directly as antibacterial agents.
  • Compounds where an R ⁇ protecting group is not physiologically removable are useful intermediates which can be easily converted to the active form by conventional deblocking procedures well- known to those skilled in the art.
  • R 4 , R 5 and R 6 are each independently hydrogen, halogen, (Q-Q)alkyl, trifluoromethyl, hydroxy, hydroxy(Q-Q)alkyl or amino
  • the compounds of the present invention can be made by conventional methods.
  • a suitable procedure is summarized by the following reaction scheme:
  • R ester protecting group such as diphenylmethyl (DPM) or para-methoxybenzyl (PMB)
  • 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.
  • the product VI is typically isolated by crystallization or, if necessary, it can be purified by chr omato gr aphy .
  • 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 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, 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 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 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.
  • intermediate IV is deprotected under acidic conditions, followed by reaction of the resulting intermediate IV with a thiopyridone derivative EL
  • a thiopyridone derivative EL 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.
  • 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.
  • 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.
  • 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.
  • MIC Minimum Inhibitory Concentrations
  • the MIC was defined as the lowest drug concentration that prevented visible growth. Microorganism MIC value in ug/ml
  • 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) 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 C ⁇ 2 inhalation.
  • results The in vivo efficacy, expressed as the PD50 value, ranged from about 0.8 to 16.5 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).
  • 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.
  • Infrared spectra were determined on a Per kin-Elmer 1800 FT-IR spectrometer from 4000 cm -1 to 400 cm -1 , calibrated to 1601 cm -1 absorption of a polystyrene film, and are reported in reciprocal centimeters (cm -1 ).
  • 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). Ultraviolet spectra were determined on a Hewlett Packard 8452 diode array spectrophotometer in the solvent indicated.
  • 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 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 ⁇ m.
  • 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 slightly colored product which was used in the next step without purification.

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Abstract

La présente invention concerne des dérivés de céphème, représentés par la formule générale: (IA) ou (IB) ou (IC), dans laquelle Ar désigne un groupe phényle, naphtyle, ou pyridyle lipophile éventuellement substitué; L1 et L2 désignent un (C1-C6)alkyle éventuellement substitué avec un hydroxy ou un radical céto, et/ou éventuellement interrompu par un groupe vinyle, S, O, un aryle, un hétéroaryle, (a) ou (b); ou R1 désignant H ou (C1-C6)alkyle; A désignant CO2H, PO3H, SO3H, le tétrazole, l'acide squarique ou un groupe hydroxyle; et Q représentant un groupe azote quaternisé. Ces dérivés constituent des agents bactéricides à gram positif particulièrement utiles au traitement de maladies causées par le Staphylococcus aureus résistant à la méthicilline.
PCT/US1998/014778 1997-07-31 1998-07-16 Derives de cepheme mrsa bisquaternaire WO1999006048A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109535174A (zh) * 2018-12-20 2019-03-29 桂林医学院 一种n-芳基二硫吡咯酮-吡喃酮杂合衍生物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5734047A (en) * 1995-12-20 1998-03-31 Bristol-Myers Squibb Company Cephalosporin derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5734047A (en) * 1995-12-20 1998-03-31 Bristol-Myers Squibb Company Cephalosporin derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109535174A (zh) * 2018-12-20 2019-03-29 桂林医学院 一种n-芳基二硫吡咯酮-吡喃酮杂合衍生物及其制备方法和应用

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ZA986613B (en) 1999-02-04
AU8408898A (en) 1999-02-22
AR015406A1 (es) 2001-05-02
CO4970698A1 (es) 2000-11-07

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