WO1997037997A1 - Cephalosporin derivatives - Google Patents
Cephalosporin derivatives Download PDFInfo
- 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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- WO
- WIPO (PCT)
- Prior art keywords
- carboxy
- oxo
- thia
- trans
- oct
- Prior art date
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- 229930186147 Cephalosporin Natural products 0.000 title description 6
- 229940124587 cephalosporin Drugs 0.000 title description 6
- 150000001780 cephalosporins Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 190
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 534
- -1 nitro, amino, hydroxy Chemical group 0.000 claims description 198
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 96
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 51
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- 229910006069 SO3H Inorganic materials 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 208000035143 Bacterial infection Diseases 0.000 claims 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VNXUJPCYZSNXDG-UHFFFAOYSA-N thiopyran-4-one Chemical compound O=C1C=CSC=C1 VNXUJPCYZSNXDG-UHFFFAOYSA-N 0.000 description 1
- 125000005413 thiopyridyl group Chemical group 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
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
Provided are cephem derivatives represented by the general formula: Ar-S-CH2-C-NH, wherein the substituents are herein defined. The compounds are gram-positive antibacterial agents, especially useful in the treatment of diseases caused by methicillin-resistant Staphylococcus aureus.
Description
CEPHALOSPORIN DERIVATIVES
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to new cephem derivatives represented by the general formula
in which the Acyl substituent is a group of the formula
o
II
Ar-S-CH2-C-
wherein Ar is an optionally substituted lipophilic phenyl, naphthyl or pyridyl group; R1 represents C C10 alkyl or C3-C6 cycloalkyl linked by a carbon atom to the quaternary nitrogen, said alkyl or cycloalkyl group having a carboxy, -S03H or tetrazolyl substituent and said alkyl group being optionally interrupted by -S- or
R7
I
N
and optionally substituted by one or more of ( -C alkylthio, hydroxy, (C C6)alkylsulfinyl, (Cj-C6)alkylsulfonyl, carbamoyl, ureido, C2-C6 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; R2, R3, R9 and R10 are each independently hydrogen, (C1-C10)alkyl or ( -C^alkyl substituted by one or more, preferably one or two, substituents independently selected from C02H, hydroxy and NRπR12 in which R11 and R12 are each independently hydrogen or (C1-C6)alkyl, and R2 and R9 or R3 and R10 can optionally be joined in a ring, preferably a 5-6 membered ring; and R7 is hydrogen or (C,-C6)alkyl. 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 MRS A 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. 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.
SUMMARY OF THE INVENTION
The present invention provides a novel series of cephem derivatives of the general formula
I wherein Ar is a group of the formula
in which R4, R5 and R6 are each independently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy (Cι-C6)alkyl, (Cι-C6)alkyl, - (CH2)n R7 or -(CH2)nSR7; n is an integer of from 1 to 6; R7 is hydrogen or(Cι- C6)alkyl; R1 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, -SO3H or tetrazolyl substituent, and said alkyl group being optionally interrupted by -S- or
R7 -N—
and optionally substituted by one or more of (Cι-C6)alkylthio, hydroxy, ( - C6)alkylsulfinyl, (Cι-C6)alkylsulfonyl, carbamoyl, ureido, C2-C6 alkenyl, halo, oxo, hydroxyimino, heteroaryl or phenyl in which the phenyl or heteroaryl group is optionally substituted by up to three hydroxy or (Cι-C6)alkoxy groups; R7 is as defined above; R2, R3, R9 and R10 are each independently hydrogen, (C C10)alkyl or (C C10)alkyl substituted by one or more, preferably one or two, substituents
independently selected from C02H, hydroxy and NRnR12 in which R11 and R12 are each independently hydrogen or (C C6)alkyl, and R2 and R9 or R3 and R10 can optionally be joined in a ring, preferably a 5-6 membered ring; and R8 is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug 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 diluents.
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 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.
The compounds of formula I are characterized by a substituted pyridiniumthiomethyl group of the type
at the 3-ρosition of the cephem ring and a lipophilic 7-substituent of the type
o II Ar - S - CH2 - C - NH -
wherin Ar is an aromatic group selected from optionally substituted phenyl, naphthyl or pyridyl.
To elaborate on the definitions for the substituents of the formula I compounds:
(a) "Halogen" includes chloro, bromo, fluoro and iodo, and is preferably chloro or bromo;
(b) "Trihalomethyl" includes trichloromethyl, trifluoromethyl, tribromomethyl and triiodomethyl, but is preferably trifluoromethyl;
(c) 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;
(d) "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.
(e) The alkyl or cycloalkyl R1 substituent is linked by a carbon atom to the quaternary nitrogen of the pyridine ring, e.g.
where C-Q represents the R1 substituent, and may be optionally
R7 interrupted by — s — or — N — and /or optionally substituted by one or more of (Cj-C^alkylthio, hydroxy, (C C6)alkylsulfinyl, ( -
C6)alkylsulfonyl, carbamoyl, ureido, C2-C6 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.
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, trifluoroacetic, 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)aminomethane), or with bases such as piperidine or morpholine, are also intended to be encompassed by the term "pharmaceutically acceptable salt".
Compounds of formula I in the form of acid addition salts may be written as
where X represents the acid anion and R8 is hydrogen or a carboxyl-protecting
Θ group. The counter anion X may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration.
The carboxyl-protecting group R8 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. 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-pyridylrnethyl and (C,-C6)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, α-pivaloyloxyethyl, and methoxy methyl. 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 R8 is a physiologically removable protecting group are useful directly as antibacterial agents. Compounds where an R8 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.
Compounds of formula I 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 and in the claims. Such hydroxyl protecting groups may be employed, for example, to increase the solubility of the formula I compound. Illustrative of suitable ester "prodrugs" of this type are
compounds of formula I wherein one or more hydroxy substituent groups are converted to sulfate (-OS03H) or phosphate (-OP03H2) groups.
A preferred embodiment of the present invention comprises compounds of formula I wherein R1 is
\ CO2H (D- ^, SO_NH2 <S)-CH2CH2CH2CH2CH(OH)CO-H , -CH2CH2CH2CH(0H)C02H
H H „
N N- N
-CH2CH2CH2S — r^ N .CH2C(0)NH— ^ ^N -CH2CH2C(0)NH— r^ ^ N
N- N , N" ' N- N' ,
H .
-CHjCH2CH2C(0)NH — ^ ,N -CH2CH2S03H f -(CH_)_C0NHCH_CH2S03H
N- N '
N-OH
\/ C02H or X/^ CO,H
The most preferred Ar substituents for the compounds of the present invention are
in which R4, R5 and R6 are each independently hydrogen, halogen, (Cj-C6)alkyl, trifluoromethyl, hydroxy, hydroxy(C1-C6)alkyl or amino.
Another preferred embodiment of the present invention comprises compounds of formula I in which R1 is ( -C alkyl substituted by an oxo o c / group and a group selected from carboxy, S03H and tetrazolyl. Examples of such R1 groups include:
-C
-C
Within this embodiment the preferred Ar substituents are
in which R4, R5 and R6 are each independently hydrogen, halogen, ( -C alkyl, trifluoromethyl, hydroxy, hydroxy(C,-C6)alkyl or amino. The most preferred Ar substituents are
In another aspect the present invention provides compounds of the formula
IA
wherein Ar is a group of the formula
in which R4, R5 and R6 are each independently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy(CrC6)alkyl, (CrC6)alkyl, -(CH2)nOR7 or -(CH2)nSR7;
n is an integer of from 1 to 6; R7 is hydrogen or (C,-C6)alkyl; and R8 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 preferred individual compounds of the present invention, all of
which have an MIC y_s a representative MRSA strain of < 8 μg/ml, are listed
below:
l-[2-carboxy-2-propen-l-yl]-4-[[(6R)-rrans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 1)
l-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 2)
l-(carboxymethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 3)
l-[(3-carboxy-l-propyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 4)
l-[(5-carboxy-l-pentyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-
dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 5)
l-[(R)-l-carboxy-l-ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 6)
l-[(l-carboxy-l-cyclopropyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 7)
l-[(S)-l-carboxy-2-hydroxy-l-ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 8)
1-[(1S, 2R, 3S, 4R)-l-carboxy-2,3,4,5-tetrahydroxy pent-l-yl]-4-[[(6R)-trans-2-carboxy-
8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 9)
l-[(S)-l-carboxy-3-(methylthio)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 10)
l-[(S)-l-carboxy-3-(methylsulfinyl)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 11)
l-[(S)-l-carboxy-3-(methylsulfonyl)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljxnethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 12)
l-[(S)-3-aminosulfonyl-l-carboxyprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 13)
l-[(S)-4-(aminocarbonyl)amino-l-carboxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 14)
l-[(S)-l-carboxy-(4-hydroxy phenyl)methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 15)
l-[(S)-l-carboxy-2-(2-thienyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 16)
l-[3-carboxy-2-hydroxy-l-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 17)
l-[(S)-5-carboxy-5-hydroxypent-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 18)
l-[(S)-5-carboxy-5-hydroxypent-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 19)
l-[(S)-4-carboxy-4-hydroxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 20)
l-[(S)-4-carboxy-4-hydroxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 21)
l-[(R)-4-carboxy-4-hydroxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 22)
l-[(R)-4-carboxy-4-hydroxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 23)
l-[(S)-3-carboxy-3-hydroxyprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 24)
l-[(S)-3-carboxy-3-hydroxyprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 25)
l-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 26)
l-[(S)-3-carboxy-3-hydroxy-2,2-dimethylprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 27)
l-[(2R,3R)-3-carboxy-2,3-dihydroxyprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 28)
l-[(2,2-dimethyl-4-carboxydioxolan-5-yl)methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 29)
l-[2-carboxy-2-oxoeth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 30)
l-[2-carboxy-2-oxoeth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4- yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium
inner salt or a pharmaceutically acceptable salt thereof (compound of Example 31)
l-[3-carbomethoxy-2-oxoprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-
dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 32)
l-[4-carboxy-2-oxoprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 33)
l-[2,2-dimethyl-3-carboxy-3-oxoprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 34)
l-[2-carboxy-2-fluoroeth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 35)
l-[3-carboxy-3-fluoroprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 36)
l-[3-carboxy-3,3-difluoroprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 37)
l-[2-(carboxymethylthio)eth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 38)
l-[3-(2-carboxyethylthio)-l-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 39)
l-[N-(carboxymethyl)-aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-l ,abicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 40)
l-[N-(carboxymethyl)-aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-
[(2,4,5-trichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 41)
l-[N-(carboxymethyl)-aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 42)
1 - [N-(2-carboxyethy l)-aminocarbonylmethy l]-4- [ [ (6R)-trans-2-carboxy-8-oxo-7- [ (2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 43)
l-[N-(2-carboxyethyl)-aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 44)
l-[N-(2-carboxyethyl-2-hydroxy)aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 45)
l-[N-(l-carboxy-2-hydroxyeth-l-yl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy- 8-oxo-7-[(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 46)
l-[N-(l-carboxy-2-hydroxyeth-l-yl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy- 8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2- en-3-yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 47)
l-[N-(l-carboxy-3-thiomethylprop-l-yl)aminocarbonylmethylj-4-[[(6R)-trans-2- carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0j-oct- 2-en-3-yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 48)
l-[2-((S)-N-prolyl)-2-oxoeth-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 49)
l-[N-(l-carboxy-2-phenylethyl)aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof
(compound of Example 50)
l-[N-(l-carboxy-2-(4-hydroxyphenyl)ethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-
carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct- 2-en-3-yl]methylthiojρyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 51)
l-[N-(l-carboxy-2-histidylethyl)aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 52)
l-[N-(carboxymethyl)-l-aminocarbonyleth-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 53)
l-[N-methyl-N-(carboxymethyl)aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 54)
l-(sulfomethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 55)
l-(2-sulfoeth-l-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 56)
2,6-dimethyl-l-(2-sulfoeth-l-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 57)
2-ethyl-l-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 58)
2,3-dimethyl-l-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 59)
l-[N-(2-sulfoethyl)aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof
(compound of Example 60)
l-[N-(2-sulfoethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 61)
l-[N-(2-sulfoethyl)-2-aminocarbonylethylJ-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 62)
l-[N-(2-sulfoethyl)-2-aminocarbonylethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 63)
1 -[3-(5-tetrazolylthio)prop-l -yl]-4-[ [ (6R)-trans-2-carboxy-8-oxo-7- [(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 64)
l-[N-(5-tetrazolyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 65)
l-[N-(5-tetrazolyl)-2-aminocarbonyleth-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 66)
l-[N-(5-tetrazolyl)-3-aminocarbonylprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 67)
l-[2-carboxy-2-(hydroxyimino)eth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 68)
l-[N-methyl-N-(3-carboxy-l-oxoprop-l-yl)-2-aminoeth-l-yl]-4-[[(6R)-trans-2- carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct- 2-en-3-yl]methylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 69)
l-[l-carboxy-2-hydroxy-2-(2-thienyl)eth-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 70)
l-[N-(2-carboxy-l-oxoeth-l-yl)-2-aminoeth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 71); and
l-[2-(2-sulfoethylthio)eth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 72).
The more preferred individual compounds of the present invention, all of
which have a MIC < 8 μg/mL are listed below:
l-[2-carboxy-2-propen-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 1)
l-[2-carboxy-2-hydroxy ethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 2)
l-[(R)-l-carboxy-l-ethylJ-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 6)
l-[(S)-l-carboxy-3-(methylsulfinyl)prop-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 11)
l-[(S)-l-carboxy-3-(methylsulfonyl)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof
(compound of Example 12)
l-[(S)-3-aminosulfonyl-l-carboxyprop-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 13)
l-[(S)-5-carboxy-5-hydroxypent-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 18)
l-[(S)-4-carboxy-4-hydroxybut-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 20)
l-[(R)-4-carboxy-4-hydroxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 22)
l-[(S)-3-carboxy-3-hydroxyprop-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamidoJ-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 25)
l-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 26)
l-[2-carboxy-2-oxoeth-l-ylJ-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 30)
1 - [2-carboxy-2-oxoeth- 1 -y 1J-4- [ [ (6R)-trans-2-carboxy-8-oxo-7- [ (2,6-dichloropy ridin-4- yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-yljmethylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 31)
l-[3-carbomethoxy-2-oxoprop-l-ylJ-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 32)
l-[2-(carboxymethylthio)eth-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 38)
l-[3-(2-carboxyethylthio)-l-propylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 39)
l-[N-(carboxymethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 40)
l-[N-(carboxymethyl)-aminocarbonylmethylJ-4-[[(6R)-trans-2-carboxy-8-oxo-7- [ (2,6-dichloropy ridin-4-y 1) thioacetamido] -5-thia- 1 -azabicyclo [4.2.0] -oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 42)
l-[N-(2-carboxyethyl)-aminocarbonylmethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 44)
l-[N-(l-carboxy-2-phenylethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 50)
1 -(sulf omethy l)-4- [ [ (6R)-trans-2-carboxy-8-oxo-7-[ (2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 55)
l-(2-sulfoeth-l-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 56)
2,6-dimethyl-l-(2-sulfoeth-l-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 57)
2-ethyl-l-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 58)
2,3-dimethyl-l-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 59)
l-[N-(2-sulfoethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 60)
l-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 62)
l-[N-(2-sulfoethyl)-2-aminocarbonylethylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 63)
l-[3-(5-tetrazolylthio)prop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 64)
l-[N-(5-tetrazolyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 65)
l-[N-(5-tetrazolyl)-2-aminocarbonyleth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 66)
l-[N-(5-tetrazolyl)-3-aminocarbonylprop-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 67)
l-[2-carboxy-2-(hydroxyimino)eth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof
(compound of Example 68)
l-[l-carboxy-2-hydroxy-2-(2-thienyl)eth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 70); and
l-[2-(2-sulfoethylthio)eth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 72).
The most preferred individual compounds of the present invention are listed below:
l-[2-carboxy-2-propen-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 1)
l-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 2)
l-[(S)-3-aminosulfonyl-l-carboxyprop-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 13)
l-[(S)-5-carboxy-5-hydroxypent-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 18)
l-[(S)-4-carboxy-4-hydroxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 20)
l-[(R)-4-carboxy-4-hydroxybut-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 22)
l-[(S)-3-carboxy-3-hydroxyprop-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 25)
l-[2-carboxy-2-oxoeth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-
dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 30)
l-[2-carboxy-2-oxoeth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4- yl)thioacetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3-yl]methylthioJpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 31)
l-[2-(carboxymethylthio)eth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 38)
l-[3-(2-carboxyethylthio)-l-propylJ-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 39)
l-[N-(2-carboxyethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 44)
l-(2-sulfoeth-l-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0j-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 56)
2,6-dimethyl-l-(2-sulfoeth-l-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 57)
2,3-dimethyl-l-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 59)
l-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3-
yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 62)
l-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamidoj-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 63)
l-[3-(5-tetrazolylthio)prop-l-yIJ-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 64)
l-[N-(5-tetrazolyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 65)
l-[N-(5-tetrazolyl)-2-aminocarbonyleth-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 66)
l-[N-(5-tetrazolyl)-3-aminocarbonylprop-l-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 67); and
l-[2-carboxy-2-(hydroxyimino)eth-l-ylj-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium inner salt or a pharmaceutically acceptable salt thereof (compound of Example 68).
The compounds of the present invention can be made by conventional methods. Two suitable procedures are summarized in the following reaction scheme:
Ar . OH
ArSH
Y
R = ester protecting group such as diphenylmethyl (DP ) or para-methoxybenzyl (PMB)
Method 1
Method 2
UI
To elaborate on the above process, 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. Following acidification of the reaction mixture, 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. For example, the leaving group may be acetoxy or halo. In the preferred embodiment illustrated by the reaction scheme, 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. 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, 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. In one embodiment, 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. 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 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. 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.
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. For example, cephem IY (X = Cl) is treated with optionally substituted 4-mercaptopyridine and sodium iodide in a one-pot reaction to give intermediate fl. Reaction of thiopyridyl derivative H with a reactive alkylating agent provides the quaternary cephem intermediate T. Examples of alkylating agents are α-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. For example, when 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. In some cases, cephem I is purified by column chromatography, for example on reversed- phase adsorbent.
In a second method of preparing quaternary cephems I, intermediate IY is deprotected under acidic conditions, followed by reaction of the resulting intermediate IV with 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. 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. 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 reverse phase column chromatography following removal of volatile solvents.
The thiopyridone derivatives of formula III are another aspect of the present invention. The preferred R1, R2, R3, R9 and R10 substituents of
derivatives III are as disclosed above in connection with the end-products of formula I.
It will be understood that where the substituent groups used in the above
reactions contain certain reaction-sensitive functional groups such as 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. 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
zwitterion. Compounds of formula I where Rβ is hydrogen, 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 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
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 - 72 after solution in water and dilution with Nutrient Broth were found to exhibit the following ranges of Minimum Inhibitory Concentrations (MIC) 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% CO2). The MIC was defined as the lowest drug
concentration that prevented visible growth.
Microorganism MIC range in ug/ml
S. aureus methicillin resistant A27223 1 - 8
S. pneumoniae A9585 0.0005 - 2
S. pyogenes A9604 0.0005 - 2
E. faecalis A20688 0.25 - 8
E. faecium A24885 0.5 - 16 5. aureus A9537, penicillinase negative 0.0005 - 0.125
S. aureus A15090, penicillinase positive 0.03 - 1
S. epidermidis A24548 0.001 - 1
S. epidermidis A25783, methicillin resistant 0.015 - 2
S. hemolyticus A21638 0.015 - 8 5. hemolyticus A27235, methicillin resistant 0.25 - 32
IN VIVO ACTIVITY
The in vivo therapeutic efficacy of the compounds prepared in Examples 1 - 72 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) 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 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:
In the following examples, all temperatures are given in degrees
Centigrade. Melting points were determined on an electrothermal apparatus and
are not corrected. Proton and carbon-13 nuclear magnetic resonance (*H and 13C 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, 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(
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 (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 (Ciβ), 40
μm.
Example 1
l-f2-carboxy-2-propen-l-ylj-4-fr(6R -trans-2-carboxy-8-oxo-7-r(2.5- dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.01-oct-2-en-3- yljmethylthiojpyridinium bromide
A. 2.5-Dichlorophenylthioacetic acid
A mixture of 2,5-dichlorothiophenol (10.3 g, 57.5 mmol) and bromoacetic acid (8.03 g, 57.8 mmol) in water (225 mL) was treated with 10 N NaOH (13 mL, 130 mmol) and the mixture was heated at 100 °C for 1 h. The reaction mixture was then cooled to 0 °C and acidified to pH 1 with 6N HCl. The product precipitated and was collected by filtration to give 13.0 g (95% yield) of 2,5-
dichlorophenylthioacetic acid as white crystals, m.p. 118 °C. H NMR (300 MHz, CDC13) δ 3.74 (s, 2 H), 7.15 (dd, J=2, 9 Hz, 1 H), 7.32 (d, J=9 Hz, 1 H), 7.36 (d, J=2 Hz, 1
H). Anal. Calcd. for C8H602SCl2: C, 40.53; H, 2.55. Found: C, 40.46; H, 2.64.
B. (6R)-trans-3-ChIoromethyl-7-f(2,5-dichlorophenyl)thioacet-amidol-8-oxo-g- thia-l-azabicyclol4.2.01oct-2-ene-2-carboxylate. diphenylmethyl ester
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. *H NMR (300 MHz, CDCI3) δ 4.13 (s, 2 H), 7.22 (dd, J=2, 9 Hz, 1 H), 7.35 (d, J=9 Hz, 1 H),
7.39 (d, J=2 Hz, 1 H).
(6R)-trans-3-Chloromethyl-7-amino-8-oxo-5-thia-l-azabicyclo-[4.2.0Joct-2-
ene-2-carboxylate, diphenylmethyl ester, HCl salt was stirred in a biphasic mixture of EtOAc and saturated NaHCθ3 for 0.5 h. The layers were separated,
and the organic solution was dried over anhydrous MgSO_ι, filtered, and
concentrated to dryness. The free base (9.15 g, 22.0 mmol) was dissolved in THF (200 mL), cooled to 0 °C, and treated with N-methylmorpholine (3.34 g, 33.0 mmol) and 2,5-dichlorophenylthioacetyl chloride (6.75 g, 26.4 mmol). The reaction mixture was stirred for 1 h at 0 °C, diluted with EtOAc (1000 mL) and washed with water (1000 mL) and brine (100 mL). The organic solution was then dried (MgSO-i) and the solvents were evaporated in vacuo. The residue was
stirred with ether (100 mL). The product solidified and was collected by filtration to give 12.0 g (86% yield) of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)- thioacetamidoj-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,
diphenylmethyl ester, m.p. 120 °C. H NMR (300 MHz, CDC13) δ 3.43 (d, J=18 Hz,
1 H), 3.59 (d, J=18 Hz, 1 H), 3.69 (d, J=17 Hz, 1 H), 3.79 (d, J=17 Hz, 1 H), 4.36 (d, J=12 Hz, 1 H), 4.41 (d, J=12 Hz, 1 H), 4.98 (d, J=5 Hz, 1 H), 5.81 (dd, J=5, 9 Hz, 1 H), 6.98 (s, 1 H), 7.14-7.44 (m, 14 H). Anal. Calcd for C29H23N2O4S2CI3: C, 54.94; H, 3.66; N, 4.42. Found: C, 55.18; H, 3.84; N, 4.62.
Method b: (6R)-trans-3-Chloromethyl-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0joct- 2-ene-2-carboxylate, diphenylmethyl ester, HCl salt (Otsuka, 248 g, 0.55 mol) was treated with NaHCθ3 (56 g, 0.66 mol) in water (1.6 L) at 0 °C The mixture was
stirred at 0 °C for 0.5 h and then CH2CI2 (1.5 L) was added. The biphasic mixture
was filtered through Celite and the Celite pad was washed with CH2CI2 (2 L total).
The layers were separated and the organic solution was dried over anhydrous MgSθ4, filtered, and concentrated to a volume of ca. 2 L. The free amine solution
was then added to a mixture of 2,5-dichlorothio-phenylacetic acid (130 g, 0.55
mol) and dicyclohexylcarbodiimide (144 g, 0.70 mol) in THF (1 L) at room temperature. The reaction mixture was stirred for 2.5 h and then was filtered through Celite, washing the Celite pad with several portions of acetone. The filtrate was concentrated in vacuo to give a solid mass. The solid was slurried in Et2θ and then collected by filtration, washing the solid with several portions of
Et2θ. The solid was dried under high vacuum over P2O5 to give 268 g (77% yield)
of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia- l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (see above for analytical data).
C (6R)-tτans-3-(4-Pyridylthiomethyl)-7-K2,5-dichlorophenvl)-thioacetamidol- 8-oxo-5-thia-l-azabicyclo[4.2.01oct-2-ene-2-carboxylate, diphenylmethyl ester
A solution of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)- thioacetamidoj-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (6.00 g, 9.46 mmol) in acetone (100 mL) was treated with sodium iodide (4.26 g, 28.4 mmol). The mixture was stirred at 20 °C for 3 h and then condensed under reduced pressure to a volume of 50 mL. The concentrated solution was diluted with EtOAc (200 mL) and washed with ice water (100 mL). The organic solution was washed with saturated NaHSθ4 (20 mL), dried
(MgSθ4), and evaporated under reduced pressure. The residue was stirred with
ether (30 mL). The product solidified and was collected by filtration to give 6.40 g of (6R)-trans-3-iodomethyl-7-[(2,5-dichlorophenyl)thio-acetamido]-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (93% yield) as a tan
solid, m.p. 124 °C. Η NMR (300 MHz, CDCI3) δ 3.43 (d, J=18 Hz, 1 H), 3.69 (d, J=17
Hz, 1 H), 3.70 (d, J=18 Hz, 1 H), 3.78 (d, J=17 Hz, 1 H), 4.27 (d, J=9 Hz, 1 H), 4.33 (d, J=9 Hz, 1 H), 4.96 (d, J=5 Hz, 1 H), 5.75 (dd, J=5, 9 Hz, 1 H), 7.00 (s, 1 H), 7.20-7.46 (m, 14 H). Anal. Calcd. for C29H23N2O4S2CI2I: C, 48.01; H, 3.20; N, 3.86. Found: C,
48.00; H, 3.14; N, 3.76.
(6R)-trans-3-Iodomethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (3.00 g, 4.14 mmol) was dissolved in THF (50 L) at 0 °C and treated with 4-mercaptopyridine (0.504 g, 4.54 mmol). A solution of 2,6-lutidine (0.576 g, 5.38 mmol) in THF (1 mL) was added next, and the reaction mixture was stirred at 0 °C for 0.5 h and then at 20 °C for 1 h. The mixture was diluted with ethyl acetate (500 mL) and the organic solution was washed with water (2 x 500 mL) and brine (100 mL). The solution was then dried (MgSθ4) and evaporated under reduced pressure to give an oil which was treated with E.2O (50 mL) to give a solid. The solid was
collected by filtration and purified by column chromatography on silica gel (CH2CI2 to 30% EtOAc/CH2Cl2) to give 1.50 g of (6R)-trans-3-[(4-
pyridylthiomethyl]-7-[(2,5-dichlorophenyl)-thioacetamidoJ-8-oxo-5-thia-l- azabicyclo[4.2.0Joct-2-ene-2-carboxylate, diphenylmethyl ester as a tan solid (49%
yield), m.p. 122 °C *H NMR (300 MHz, CDCI3) δ 3.37 (d, J=18 Hz, 1 H), 3.52 (d, J=18
Hz, 1 H), 3.68 (d, J=17 Hz, 1 H), 3.76 (d, J=17 Hz, 1 H), 3.96 (d, J=13 Hz, 1 H), 4.16 (d, J=13 Hz, 1 H), 4.93 (d, J=5 Hz, 1 H), 5.76 (dd, J=5, 9 Hz, 1 H), 6.95-7.42 (m, 16 H), 7.49 (d, J=9 Hz, 1 H), 8.29 (d, J=6 Hz, 2 H). Anal. Calcd. for C34H27N3O4S3CI2: C, 57.62; H, 3.84; N, 5.93. Found: C, 57.27; H, 3.68; N, 5.79.
D. l-f2-Carboxy-2-propen-l-yll-4-ff(6R)-trans-2-(diphenylmethyl-carboxy)-8- oxo-7-f(2.5-dichlorophenylthio)acetamidol-5-thia-l-azabicyclof4.2.01-oct-2-en-3- yllmethylthiolpyridinium bromide
A solution of (6R)-trans-3-(4-pyridylthiomethyl)-7-[(2,5-dichlorophenyl)- thioacetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0joct-2-ene-2-carboxylate, diphenylmethyl ester (600 mg, 0.845 mmol) in 5 mL of DMF was treated with 2-
(bromomethyl) acrylic acid (Aldrich) (279 mg, 1.69 mmol). This mixture was stirred at rt for 4 h, and then 50 mL of ether was added, resulting in the precipitation of the desired product. The solid was collected by filtration washing with ether to give 667 mg (85%) of l-[2-carboxy-2-propen-l-yl]-4-[[(6R)-trans-2- (diphenylmethyl carboxy )-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-l-
azabicyclo[4.2.0]-oct-2-en-3-yljmethylthio]pyridinium bromide, as a tan solid. 1H
NMR (DMSO-d6) δ 9.35 (d, J=8 Hz, IH), 8.73 (d, J=7 Hz, 2H), 7.88 (d, J=7 Hz, 2H),
7.18-7.49 (m, 13 H), 6.97 (s, IH), 6.48 (s, IH), 6.18 (s, IH), 5.81 (dd, J=5,8 Hz, IH), 5.35 (s, 2H), 5.23 (d, J=5 Hz, IH), 4.31 (d, J=12 Hz, IH), 7.23 (d, J=12 Hz, IH), 3.95 (s, 2H),
3.83 (d, J=18 Hz, IH), 3.59 (d, J=18 Hz, IH). IR (KBr) 1780, 1714, 1626, 1450, 1106 cnr
!; MS (ESI) 792 (MH)+; Anal, calcd. for C38H31N3O6S3 2 • HBr • 0.35 HC(O)
N(CH3)2 • 1.5 H20: C, 50.64; H, 4.08; N, 5.07. Found: C, 50.68, H, 3.93; N, 5.05.
E. l-r2-Carboxy-2-propen-l-yll-4-rr(6R)-trans-2-carboxy-8-oxo-7-r(2.5- dichlorophenyIthio)acetamidol-5-thia-l-azabicyclof4.2.01-oct-2-en-3- yllmethylthiolpyridinium bromide
A slurry of l-[2-carboxy-2-propen-l-yl]-4-[[(6R)-trans-2-(diphenylmethyl carboxy)-8-oxo-7-[(2,5-dichlorophenylthio)acetamidoj-5-thia-l-azabicyclo[4.2.0J-oct-
2-en-3-yl]methylthio]pyridinium bromide (580 mg, 0.665 mmol) in 22 mL of
CH2CI2 was cooled to 0°C (ice bath) under an atomosphere of N2. Anisole (2.8
mL) was added followed by trifluoroacetic acid (8 mL). The cooling bath was removed, and the reaction was allowed to stir at rt for 1 h. The solution was concentrated in vacuo to remove the CH2CI2 and most of the trifluoroacetic acid.
The residue was treated with ether to precipitate a yellow solid. This solid was collected by filtration washing with ether. The solid was stirred with ethyl acetate for 30 min. stirred with acetone for 30 min., collected by filtration, and dried in vacuo to give 322 mg (66%) of l-[2-carboxy-2-propen-l-yl]-4-[[(6R)-trans-2-carboxy- 8-oxo- 7-[(2,5-dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3-
yljmethylthiojpyridinium bromide as a tan solid. IH NMR (DMSO-d6) δ 9.27 (d,
J=8 Hz, IH), 8.73 (d, J=6 Hz, 2H), 8.06 (d, J=6 Hz, 2H), 7.45-8.48 (m, 2H), 7.24 (dd, J=2,9 Hz, 2 H), 6.41 (s, IH), 6.08 (s, IH), 5.63 (dd, J=5,8 Hz, IH), 5.19 (s, 2H), 5.09 (d, J=5 Hz, IH), 4.43 (s, 2H), 3.92 (s, 2H), 3.70 (d, J=18 Hz, IH), 3.48 (d, J=18 Hz, IH). IR (KBr) 1774, 1702, 1680, 1628, 1106 cm-1; MS (ESI) 626 (MH)+, Anal: Calcd for
C25H2iN3θ6S3Cl2xHBr x0.5Me CO; C, 42.44; H, 3.13; N, 5.94. Found: C, 43.25; H,
3.42, N, 5.71.
Example 2
l-r2-Carboxy-2-hydroxyethyll-4-r[(6Rl-trans-2-carboxy-8-oxo-7-[(2.5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclof4.2.0j-oct-2-en-3- yljmethylthiojpyridinium chloride
A. (6R)-trans-3-Chloromethyl-7-[(2.5-dichlorophenyl)-thioacetamidol-8-oxo-5- thia-l-azabicycIo[4.2.01oct-2-ene-2-carboxylic acid
A slurry of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)- thioacetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0joct-2-ene-2-carboxylate, diphenylmethyl ester (10.0 g, 15.8 mmol) in CH2CI2 (200 mL) at 0 °C was treated
with anisole (24 mL) and then trifluoroacetic acid (80 mL). The solution was stirred for 1 h at 0 °C and then concentrated under reduced pressure. The residue was stirred with Et2θ, and the resulting solid was collected by filtration to give
5.20 g of (6R)-trans-3-chloro-methyl-7-[(2,5-dichlorophenyl)-thioacetamidoj-8-oxo- 5-thia-l-azabicyclo[4.2.0joct-2-ene-2-carboxylic acid as a white solid (70% yield),
m.p. 125 °C. *H NMR (300 MHz, DMSO-d6) δ9.28 (d, J=8 Hz, 1 H), 7.47 (dd, J=2, 8
Hz, 2 H), 7.24 (dd, J=2, 8 Hz, 1 H), 5.70 (dd, J=5, 8 Hz, 1 H), 5.13 (d, J=5 Hz, 1 H), 4.58 (d, J=ll Hz, 1 H), 4.52 (d, J=ll Hz, 1 H), 3.91 (s, 2 H), 3.70 (d, J=18 Hz, 1 H) 3.51 (d, J=18 Hz, 1 H).
B. l-f2-carboxy-2-hydroxyethy11-4-rr(6R)-trans-2-carboxv-8-oxo-7-r(2.5- dichlorophenylthio)acetamidol-5-thia-l-azabicycIof4.2.01-oct-2-en-3- yllmethylthiolpyridinium chloride
1. Preparation of l-[N-(2-carboxy-2-hydroxyethyl)-4-thiopyridone sodium salt
A solution of D,L-isoserine (1.00 g, 9.52 mmol) in a mixture of water (10 mL) and ethanol (10 mL) was treated with 9.52 mL of IN NaHCθ3 followed by
thiopyrone (1.07 g, 9.52 mmol). The mixture was stirred at reflux for 2 h, and concentrated in vacuo. The residue was triturated with ether to give 1.78 g (85%) of l-[N-(2-carboxy-2-hydroxyethyl)-4-thiopyridone sodium salt as a brown solid.
H NMR (DMSO-d6) δ 7.50 (d, J=7 Hz, 2H), 7.08 (d, J=7 Hz, 2H), 4.17 (dd, J=3,4 Hz,
IH), 4.03 (dd, J=6,14 Hz, IH), 3.83 (dd, J=3,6 Hz, IH). ^C (75 MHz) δ 188.62, 172.79,
137.09, 129.44, 70.78, 60.40; IR (KBr) 3384 (br), 1622, 1114 cur1; MS (ESI) 198 (M)\
2. l-[2-Carboxy-2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0]-oct-2-en-3- yljmethylthiojpyridinium chloride
A solution of cephem 6(R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)- thioacetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (60 Omg, 1.28 mmol) in 5 mL of DMF was treated with thiopyridone l-[N-(2-carboxy-2- hydroxyethyl)-4-thiopyridone Na salt(255 mg, 1.28 mmol). After stirring the mixture for 3h at rt under a nitrogen atmosphere, it was concentrated in vacuo. The residue was stirred with ether until a solid formed. This solid was collected by filtration and washed with ethyl acetate followed by acetone to give 564 mg (63%) of l-[2-carboxy-2-hydroxyethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamidoJ-5-thia-l-azabicyclo[4.2.0J-oct-2-en-3-
yljmethylthiojpyridinium chloride as a tan solid. H NMR (DMSO-d6) δ 9.36 (d,
J=6 Hz, IH), 8.67 (d, J=6 Hz, 2H), 8.07 (d, J=6 Hz, 2H), 7.42-7.48 (m, 2H), 7.21 (dd,
J=2,9 Hz IH), 5.57 (dd, J=5,8 Hz, IH), 5.05 (d, J=5 Hz, IH), 4.80 (d, J=ll Hz, IH), 4.39- 4.60 (m, 4H), 3.93 (s, 2H), 3.64 (d, J=18 Hz, IH), 3.45 (d, J=18 Hz, IH). IR (KBr) 3422
(br), 1774 , 1703, 1675, 1628, 1450, 1108 cm"1. MS (ESI) 630 (MH)+; Anal. Calcd. for C24H21O7N3S3CI2 • HCl • 2.0 H20: C, 40.97; H, 3.69; N, 5.97. Found: C, 40.95; H,
3.43; N, 5.83
The following additional compounds were prepared according to the general procedures of Examples 1 and 2 by varying the thiol starting material and the pyridine or thiopyridone derivative:
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Claims
1. A compound of the formula
Ar-S-CH2-C "-HNL . S. π K<r' ^ /R2
oXΪvfj- C' H2-S— y N-R1
CCX)R8 Rj0' N R3
wherein Ar is a group of the formula 
R4
R5- 
R6 ' <' ^=s >- R / ' -vv^ 'I ^vS"— or R ry^
R6 in which R4, R5 and R6 are each independently hydrogen, halo
trihalomethyl, nitro, amino, hydroxy, hydroxy(C,-C6)alkyl, (C1- 
C6) alkyl, - (CH2)nOR7 or -(CH2)nSR7; n is an integer of from 1 to 6; R7 is hydrogen or (Q- C6)alkyl; R1 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, -SO3H or tetrazolyl substituent,
group is optionally substituted by up to three hydroxy or (C1-C6)alkoxy groups; R7 is as defined above; R2, R3, R9 and R10 are each independently hydrogen, (C1- C10)alkyl or (C1-C10)alkyl substituted by one or more substituents independently selected from CO2H, hydroxy and NR11R12 in which R11 and R12 are each independently hydrogen or (C1-C6)alkyl, and R2 and R9 or R3 and R10 can optionally be joined in a ring; and R8 is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug thereof.
2. A compound of Claim 1 wherein R1 is
3. A compound of Claim 1 or Claim 2 wherein Ar is
4. A compound of the formula
trihalomethyl, nitro, amino, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6)alkyl, - (CH2)nOR7 or -(CH2)nSR7; n is an integer of from 1 to 6; R7 is hydrogen or(C1- C6)alkyl; and R8 is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug thereof.
5. A compound of Claim 4 wherein Ar is 
in which R4, R5 and R6 are each independently hydrogen, halogen, (C1-C6)alkyl, trifluoromethyl, hydroxy, hydroxy(C1-C6) alkyl or amino.
6. A compound of the formula
wherein Ar is a group of the formula 
in which R4, R5 and R6 are each independently hydrogen, halogen,
trihalomethyl, nitro, amino, hydroxy, hydroxy(-CJalkyl, (C1-C6)alkyl, -
(CH2)nOR7 or -(CH2)nSR7; n is an integer of from 1 to 6; R7 is hydrogen or (C1- C6)alkyl; R1 is (C1-C6)alkyl substituted by an oxo group and a group selected from carboxy, -SO3H and tetrazolyl; R2 and R3 are each independently hydrogen or (C1- C6)alkyl; and R8 is hydrogen or a protecting group; or a pharmaceutically acceptable salt or prodrug thereof.
7. A compound of Claim 6 wherein R1 is
\
<v
8. A compound of Claim 6 or Claim 7 wherein Ar is
in which R4, R5 and R6 are each independently hydrogen, halogen, (C1-C6) alkyl, trifluoromethyl, hydroxy, hydroxy(C1-C6)alkyl or amino.
9. A compound of Claim 6 or Claim 7 wherein Ar is
10. A compound selected from the group consisting of:
1-[2-carboxy-2-propen-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-hy droxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-(carboxymethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(3-carboxy-1-propyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[(5-carboxy-1-pentyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(R)-1-carboxy-1-ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(1-carboxy-1-cyclopropyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-1-carboxy-2-hydroxy-1-ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(1S, 2R, 3S, 4R)-1-carboxy-2,3,4,5-tetrahydroxy pent-1-yl]-4-[[(6R)-trans-2-carboxy- 8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-1-carboxy-3-(methylthio)ρrop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[(S)-1-carboxy-3-(methylsulfinyl)proρ-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-1-carboxy-3-(methylsulfonyl)prop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-aminosulfonyl-1-carboxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-4-(aminocarbonyl)amino-1-carboxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [ (2,5-dichloropheny lthio)acetamido]-5-thia-1-azabicyclo [4.2.0 ] -oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-1-carboxy-(4-hydroxy phenyl)methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-1-carboxy-2-(2-thienyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[3-carboxy-2-hydroxy-1-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-5-carboxy-5-hydroxypent-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-5-carboxy-5-hydroxypent-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(R)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[(R)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-carboxy-3-hydroxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-carboxy-3-hydroxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-carboxy-3-hydroxy-2,2-dimethylprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido3-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(2R,3R)-3-carboxy-2,3-dihydroxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[(2,2-dimethyl-4-carboxydioxolan-5-yl)methyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-oxoeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1 - [2-carboxy-2-oxoeth-1-yl]-4-[ [ (6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropy ridin-4- yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthioJpyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-carbomethoxy-2-oxoprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[4-carboxy-2-oxoprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2,2-dimethyl-3-carboxy-3-oxoprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[2-carboxy-2-fluoroeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-carboxy-3-fluoroprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-carboxy-3,3-difluoroprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-(carboxymethylthio)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-(2-carboxyethylthio)-1-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(carboxymethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(carboxymethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(carboxymethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(2-carboxyethyl)-aminocarbonyImethy1]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[ (2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-carboxyethyl)-aminocarbonyImethy1]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[ (2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-carboxyethyl-2-hydroxy)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(1-carboxy-2-hydroxyeth-1-yl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy- 8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(1-carboxy-2-hydroxyeth-1-yl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy- 8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2- en-3-yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(1-carboxy-3-thiomethylprop-1-yl)aminocarbonylmethyl]-4-[[(6R)-trans-2- carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct- 2-en-3-yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-((S)-N-prolyl)-2-oxoeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(1-carboxy-2-phenylethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(1-carboxy-2-(4-hydroxyphenyl)ethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2- carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct- 2-en-3-yl]methylthioJpyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(1-carboxy-2-histidylethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(carboxymethyl)-1-aminocarbonyleth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-methyl-N-(carboxymethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-(sulfomethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-(2-sulfoeth-1-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
2,6-dimethy 1-1 -(2-sulf oeth-1 -yl)-4-[ [(6R)-trans-2-carboxy-8-oxo-7-[ (2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 2-ethyl-1-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
2,3-dimethyl-1-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[3-(5-tetrazolylthio)prop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(5-tetrazolyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(5-tetrazolyl)-2-aminocarbonyleth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(5-tetrazolyl)-3-aminocarbonylprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-(hydroxyimino)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-methyl-N-(3-carboxy-1-oxoprop-1-yl)-2-aminoeth-1-yl]-4-[[(6R)-trans-2- carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct- 2-en-3-yl]methylthioJpyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[1-carboxy-2-hydroxy-2-(2-thienyl)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-carboxy-1-oxoeth-1-yl)-2-aminoeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof ; and
1-[2-(2-sulfoethylthio)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof.
11. A compound selected from the group composed of
1-[2-carboxy-2-propen-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(R)-1-carboxy-1-ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-1-carboxy-3-(methylsulfinyl)prop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-1-carboxy-3-(methylsulfonyl)prop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-aminosulfonyl-1-carboxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-5-carboxy-5-hydroxypent-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[(S)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(R)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-carboxy-3-hydroxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-oxoeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyc.o[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-oxoeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4- yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthioJpyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[3-carbomethoxy-2-oxoprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-(carboxymethylthio)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-(2-carboxyethylthio)-1-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(carboxymethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(carboxymethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-carboxyethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(1-carboxy-2-phenylethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8- oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-(sulfomethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-(2-sulfoeth-1-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
2,6-dimethyl-1-(2-sulfoeth-1-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
2-ethyl-1-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
2,3-dimethyl-1-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(2-sulfoethyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-(5-tetrazolylthio)prop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(5-tetrazolyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(5-tetrazolyl)-2-aminocarbonyleth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(5-tetrazolyl)-3-aminocarbonylprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-(hydroxyimino)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[1-carboxy-2-hydroxy-2-(2-thienyl)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof; and
1-[2-(2-sulfoethylthio)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof.
12. A compound selected from the group consisting of
1-[2-carboxy-2-propen-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[2-carboxy-2-hydroxy ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-aminosulfonyl-1-carboxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-5-carboxy-5-hydroxypent-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(R)-4-carboxy-4-hydroxybut-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[(S)-3-carboxy-3-hydroxyprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[2-carboxy-2-oxoeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-carboxy-2-oxoeth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4- yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[2-(carboxymethylthio)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-(2-carboxyethylthio)-1-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-carboxyethyl)-aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-(2-sulfoeth-1-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 2,6-dimethyl-1-(2-sulfoeth-1-yl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
2,3-dimethyl-1-(2-sulfoethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(2-sulfoethyl)-2-aminocarbonylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6- dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[3-(5-tetrazolylthio)prop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(5-tetrazolyl)aminocarbonylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof 1-[N-(5-tetrazolyl)-2-aminocarbonyleth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof
1-[N-(5-tetrazolyl)-3-aminocarbonylprop-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7- [(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt thereof; and
1-[2-carboxy-2-(hydroxyimino)eth-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3- yl]methylthio]pyridinium inner salt or a pharmaceutically acceptable salt 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 pharmaceutical composition comprising an effective antibacterial amount of a compound of Claim 4 and a pharmaceutically acceptable carrier or excipient.
15. A method of treating a bacterial infection which comprises acministering to a host afflicted with such infection an effective antibacterial amount of a compuund of Claim 1.
16. 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 4.
17. 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.
18. 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 4.
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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997037997A1 true WO1997037997A1 (en) | 1997-10-16 |
Family
ID=26686610
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/005271 WO1997037997A1 (en) | 1996-04-04 | 1997-03-27 | Cephalosporin derivatives |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2429197A (en) |
| WO (1) | WO1997037997A1 (en) |
Cited By (2)
| 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)
| 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 |
-
1997
- 1997-03-27 WO PCT/US1997/005271 patent/WO1997037997A1/en active Application Filing
- 1997-03-27 AU AU24291/97A patent/AU2429197A/en not_active Abandoned
Patent Citations (1)
| 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)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2429197A (en) | 1997-10-29 |
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