7-N-HETEROCYCLYL CEPHALOSPORINS, A PROCESS FOR PREPARING AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Abstract: Disclosed are antibiotic cephalosporins (I) of the formula: Wherein the stylized radical attached to the 7-amino nitrogen of the cephalosporin moiety represents a nitrogen-containing heterocyclic group (mono- or polycyclic); R is, inter alia, hydrogen, alkyl, heterocyclylalkyl, aryl, alkenyl, aralkyl, -NR₂, -OR, COOR, CONR₂ or CN; A is conventionally known in the cephalosporin art; and R² is H, or loweralkoxyl; X is S, O, CH₂, or NR⁷ (R⁷ is, inter alia, hydrogen, alkyl or aralkyl. Also disclosed are the pharmaceutically acceptable salt and ester derivatives of I; processes for the preparation of such compounds; and pharmaceutical compositions comprising such compounds.

Description: 7-N-HETEROCYCLYL CEPHALOSPORINS, A PROCESS FOR PREPARING AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME BACKGROUND OF THE INVENTION This invention relates to a new class of cephalosporins (I) and their pharmaceutically acceptable salts and esters which are useful as antibiotics: EMI1.1 wherein the stylized radical (hereafter referred to as R'): EMI1.2 attached to the 7-amino nitrogen moiety of- the cephalosporin nucleus represents a mono- or polycyclic N-containing heterocyclic group; X is S, O, CH2 or NR7 (R7 is hydrogen; alkyl having 1-6 carbon atoms such as methyl, ethyl, i-propyl, n-butyl, n-pentyl, n-hexyl and the like; formyl; or benzyl); R is, inter alia, hydrogen, substituted and unsubstituted: alkyl, aryl, alkenyl, heterocyclylalkyl, aralkyl, -NR2, COOR, CONR2,. -OR, or CN; R2 is H, or lower alkoxyl. The heterocyclic radical R', is further defined below; also defined below is the radical "A" of structure I. However, for purposes of definition, it suffices to notice that group "A" of structure I is conventionally known in the cephalosporin antibiotic art and in the oxa-, aza- and carbadethiacephalosporin antibiotic art. Such l-oxa-, 1-aza-, and l-carbadethiacephalosporins are known; see for example: U.S. Patent 4,138,486 (6 February 1979) and British Patent 1455016 (10 November 1976); to the extent that these patents conveniently define such cephalosporin nuclear analogues; and to the extent that they define (at least in part) side chain "A" of structure I, above, herein by reference. The compounds of the present invention are most conveniently isolated as the zwitterionic species demonstrated by structure I. This structure is the principal one and is utilized in the claims; however, one should be aware of other salt forms which are imposed by distinct, less preferred isolation procedures. Isolation from acidic solution provides salts which may be represented by the following EMI2.1 wherein Y is a pharmaceutically acceptable anion such as chloride, sulphate, acetate, propionate, citrate, tartrate or the like. Isolation from basic, solution (aqueous, for example) yields salts which may be represented by the following structures; wherein equilibrium with the imino form is indicated: EMI3.1 wherein M is an alkali or alkaline earth metal cation, for example, sodium, or potassium. Isolation from basic,non-aqueous solution such as dimethylformamide (DMF) in the presence of an amine NR03 (R is,for example, loweralkyl) yields salts which may be represented by the following structure: EMI3.2 The above structure assumes that NR3 is a stronger base than the iminoheterocyclyl moiety, EMI3.3 This invention also relates to processes for the preparation of such compounds (I);. pharmaceutical compositions comprising such compounds; and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated. There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues. Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and D. subti2is, and gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Xlebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts and esters; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are prepared by reacting an appropriately substituted 7-arnino- cephalosporin(-)l with a chosen electrophilic N-heterocyclic reagent(2 or 3) calculated to provide the species of the present invention I. The following reaction diagram conveniently.summarizes this process and introduces the precise identity of such electrophilic reagents and the nature of the products of this reaction (I, above). EMI5.1 wherein: B is, inter alia, the residue of a 5-, or a 6-membered aromatic heterocycle; or a 5,5-, 6,5-; or 6,6 bicyclic aromatic heterocycle; wherein the additional ring atoms are chosen either entirely as carbon, or include one or more atoms selected from S, N and 0. The carbon and nitrogen atoms of any such ring may carry substituents such as substituted and unsubstituted: alkyl and alkenyl having 1-6 carbon atoms, phenyl, phenylalkyl having 1-6 carbon atoms in the alkyl moiety, 5- or 6-membered heterocyclyl wherein the hetero atom or atoms are selected from O, N or S, -OR2, -NR2, -COOR, -CONR2, -CN, halo, -NHCONH,, 53 R, -S02NR2 (R is defined immediately below), -(OR0)2 (RO is hydrogen or alkyl having 1-6 carbon atoms); wherein the substituent or substi tuents are selected from halogen such as chlorine or fluorine, hydroxyl, phenyl, alkyl, alkoxyl, carboxyl and phenylalkyl (each alkyl having 1-6 carbon atoms); R is selected from H; substituted and unsubstituted: alkyl, having 1-10 carbon atoms, alkenyl havinq 2-10 carbon atoms, phenyl, phenylalkyl, phenylalkenyl having 7-12 carbon atoms, 5- or 6-membered heterocyclylalkyl wherein the hetero atom or atoms are selected from 0, N or S and the alkyl has 1-6 carbon atoms, NR2, OR, COOR, CN, and CONR2 (R is defined here); wherein the substituent or substituents on R are selected from halogen such as chloro and fluoro, hydroxyl, OR, NR2, COOR, CONR2, CN, EMI6.1 (R is hydrogen or alkyl having 1-6 carbon atoms), and alkyl having 1-6 carbon atoms; R and B together may be joined to yield 6,5- and 6,6 bicyclic heterocycles in which the N is at a bridgehead; X is a leaving group cuch as halogen, preferably fluorine; other leaving groups include: OCH3, SCH; OSO2OCH3 OSO2OCF3 EMI7.1 tR is hydrogen or C16 alkyl) Y is a non-critical counter anion and retresentativelv is: Cl#, Br#, I#, EMI7.2 #OSO2OR , BF4', ClO4# and the like; wherein R is H, loweralkyl or phenyl; A is conventionally known in the antibiotic cephalosporin art; is H, or an alkali or alkaline earth metal cation such as Na or K , a tertiary amine salt, or the like; R2 is hydrogen or lower alkoxyl such as methoxy; X is as defined above: SiO, CH2 or NH7. In general words relative to the above reaction diagram, an appropriately substituted 7-amino cephalosporin or nuclear analogue, thereof, (1) or a salt tnereof in a solvent such as water at pH 7 to 8, tetrahydrofuran (THF), dimethylformamide (DMF) or the like or aqueous mixtures thereof (ideally such nonaqueous systems contain a base such as triethylamine, methyldiisopropylamine, or the like, to neutralize the acid HX produced by the addition/elimination reaction) is treated with a stoichiometric to four-fold excess of the illustrated electrophilic reagent (2 or 3) calculated to provide the desired product. Typically, the reaction is conducted at a temperature of from 0 to 400C and is accomplished within 1 to 5 hours. As demonstrated by the follwoing examples, there are no undue criticalities in the parameters of reaction. More specifically, relative to the above reaction scheme, a set of representative conditions may be recited to illustrate a convenient preparation of the compounds of the present invention (I); such recitation, however1 is solely for purposes of demonstration and is not to be construed as introducing any undue criticalities of reaction. Standard Reaction Conditions: Using a pH meter coupled to an automatic burette containing 1.0 to 2.5N aqueous sodium hydroxide, a magnetically stirred suspension of the appropriate 7-aminoceph-3-em-4-carboxylic acid in water is solubilized at pH 7 to pH 7.5 at 200C. The heterocyclic reagent (stoichiometric to two-fold excess) is dissolved in water at 200C and added to the above solution. Alkali is automatically added to maintain the selected pH in the range 7 to 7.5, the rate of addition being a measure of the extent of reaction. The reaction may also be monitored by removing aliquots at timed intervals for analysis. A particularly suitable analytical scheme is liquid chromatography, for example, hig pressure liquid chromatography(HPLC) over a reverse phase co of octadecylsilane (ODS) bonded to silica, using a U.V. detector and aqueous ThF (tetrahydrofuran) solution (1 to 30%) as the mobile phase. The reaction typically takes from 15 minutes to 5 hours at 200C. The resulting reaction solution at pH 7 is worked up by partition chromatography over a column of Amberlite XAD-2 resin, eluting with aqueous THF solutions (up to 20%) and monitoring the fractions by HPLC as above. However, with the increasing availability of large scale ODS silica columns, the preferred method of product isolation is by preparative reverse phase HPLC directly on the reaction solution at pH 7. The appropriate fractions are combined, evaporated to small volume and lyophilized to yield the product, which is conveniently characterized by IR., U.V., NMR., and analytical HPLC. In certain cases, the products are sufficiently insoluble in water to separate from the reaction solution at pH 7, and may be isolated simply by filtration. Again, in reference to the above reaction diagram, the reaction when R2 is alkoxyl, such as methoxyl, is sluggish. Thus a preferred preparation for species wherein R2 is not hydrogen involves operating upon the product I (R2 r H) in the following manner to provide desired species I wherein R2 is, for example, -OCH3: EMI9.1 EMI9.2 An analogous reaction is known for conventional cephalosporins and penicillins; see G.A. Koppel and R.E. Koehier, J.A.C.S. 2403, 95, 1973 and J.E. Baldwin, F.J. Urban, R.D.G. Cooper and F.L. Jose, J.A.C.S, 95, 2401, 1973. According to this scheme, the starting material, in a solvent such as methanol, is treated with lithium methoxide at a temperature of -68 to OC; followed by addition of. the t-butylhypochlorite. The instant scheme differs from the reported procedures in that there is no need to protect the carboxyl group. It should be noted that the 3-substituent "A" may be established subsequent to the above addition/elimination reaction: EMI10.1 wherein R', R2 are as defined; and Ac is EMI10.2 This basic scheme, Ia Ib, for the establishment of any desired 3-substituent A is, of course, well known in the related cephalosporin art. Representative examples are included below. Finally, a special circumstance should be mentioned. In the basic reaction, first described, the condensation of the cephem starting material and the reagent of choice does not occur readily when the group, R, attached directly to the ring nitrogen of the reagent is hydrogen In such circumstance, it is-preferred to employ a quaternized ring nitrogen prior to reaction. The quaternizing group may be removed after the amino heterocycle bond has been formed to yield species of the present invention, I, wherein R is hydrogen: EMI10.3 wherein R is -CH2OCH3, -CH2OCOCH3 or the like. According to the above scheme, Ic#Id, the group R is conveniently removed by treating Ic in anhydrous sulpholane at 20 C with a 3- to 4-fold molar ration of I Si(CH3)3, followed by hydrolysis to yield Id. A representative example is included below. The reaction may schematically be shown as follows: EMI11.1 EMI11.2 The product Id is then isolated directly from the reaction solution at pH 7 by preparative reverse phase HPLC as already described. IDENTIFICATION OF REAGENTS The necessary electrophilic, N-heterocyclic reagents 2 and are known and commercially available or may be prepared according to known procedures; see, for example: Advances in Heterocyclic Chemistry, pp. 1-56, Vol. 3 (1964) and pp. 71-121, Vol. 22 (1978); Academic Press. The following list representatively illustrates such reagents. EMI12.1 EMI13.1 EMI14.1 wherein all symbols have previously been defined; the dotted line indicates both saturated and unsaturated rings. Relative to the above-listed reagents, the preferred values for the radical R which is directly attached to the ring nitrogen atom are: hydrogen; loweralkyl having from 1-10 carbon atoms; substituted alkyl wherein the substituent is chloro, fluoro, hydroxyl, carboxyl, amino, sulfo and monoand dialkylamino wherein each alkylbas 1-6 carbon atoms; phenylalkyl (alkyl moiety having 1-6 carbon atoms) and substituted phenylalkyl wherein the substituents are selected from chloro, fluoro. carboxyl, amino. hvdrxv1. lower alkoxyl having from 1-6 carbon atoms, sulfo, EMI15.1 and EMI15.2 (Re is hydrogen or alkyl having 1-6 carbon atoms). The quinolizinium and indolizinium examples are a special category of preferred values of R, in that R is there an integral part of a bicyclic system (R', defined above). The preferred values for the other, non-positionspecific ring substituent R are: chloro, fluoro, carboxyl and loweralkyl having from 1-6 carbon atoms; substituted lower alkyl wherein the substituent is carboxyl, cyano, alkoxyl having 1-6 carbon atoms, phenyl, and phenyloxy; the preferred value for n is O or 1. The preferred leaving group X is chloro or fluoro. The preferred species of the present invention (structure I, above) are those wherein X is sulfur or oxygen, with sulfur being most preferred. EMI15.3 Identification of A EMI16.1 As previously mentioned, the group A in structure I embraces all known 3-substituents in the cephalosporin art. The following references are incorporated herein by reference to the extent that they recite preferred values of A in structure I: U.S. Patent 4,138,486 (6 Feb.l' and British patent 1455016 (10 Nov. 1976). Especially preferred values for A include: EMI16.2 EMI17.1 -CH2#O#CO#NH2 -CH2#O#CO#CH3 -CH3 -H, -Cl, -OCH3, -CH=CH-COO#M# -CH2OH, -CH2Br, EMI17.2 (Y is as previously defined and may be, inter alia, acetate; and M# is a pharmaceutically acceptable cation, such as Na+, K+ or the like. The compounds of the present invention (I) are valuable antibiotics active against various gram-positive and gram-negative bacteria and accordingly find utility in human and veterinary medicine. Representative pathogens which are sensitive to antibiotics I include: Staphyloccus aureus, Escherichia coli, Xlebsiella penumoniae, Bacillus subtilis, Salmonella typhosa, Pseudomonas and Bacterium proteus. The antibacteials of the invention are not limited to utility as medicaments; they may be used in all manner of industry, for example: additives to animal feed, preservation of food, disinfectants, and in other industrial systems where control of bacterial growth is desired. For example, they may be employed in aqueous compositions in concentrations ranging from 0.1 to 100 parts of antibiotic per million parts of solution in order to destroy and inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example in waterbased paints and in the white water of paper mills to inhibit the growth of harmful bacteria. The products of this invention may be used in any of a variety of pharmaceutical preparations. They may be employed in capsule, powder form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal-interest include: orally, topically or parenterally by injection (intravenously or intramuscularly). Such tablets and capsules, designed for oral administration, may be in unit dosage form, and may contain conventional excipients, such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, sugar, cornstarch, calcium phosphate, sorbitol, or glycine; lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica; disintegrants, for example, potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of aqueous or oily suspensions, or solutions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, or carboxymethyl cellulose. Suppositories will contain conventional suppository bases, such as cocoa butter or other glycerides. Compositions for injection, the preferred route of delivery, may be prepared in unit dosage form in ampules, cr in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water. The compositions may also be prepared in suitable forms for absorption through the mucous membranes of the nose and throat or bronchial tissues and may conveniently take the form of liquid sprays or inhalants, lozenges, or throat paints. For medication of the eyes or ears, the preparation may be presented in liquid or semi-solid form. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders. The dosage to be administered depends to a large extent upon the condition and size of the subject being treated as well as the route and frequency of administration -- the parenteral route by injection being preferred for generalized infections. Such matters, however are left to the routine discretion of the therapist according to principles of treatment well known in the antibiotic art. In general, a daily dosage consists of from about 5 to about 600 mg of active ingredient per kg. of body weight of the subject in one or more treatments per day. A preferred daily dosage for adult humans lies in the range of from about 10 to 240 mg. of active ingredient per'kg. of body weight. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the chosen species of this invention (I). The compositions for human delivery per unit dosage, whether liquid or solid, may contain from 0.18 to 99% of active material, the preferred range being from about 10-60%. The composition will generally contain from about 15 mg. to about 1500 mg. of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage is usually the pure zwitterionic compound in sterile water solution or in the form of a soluble powder intended for solution. The pH of such solutions typically will correspond to the zwitterionic' point; however, consideration of individual properties of solubility and stability may require such aqueous solutions to have a pH other than that of the zwitterionic point, for example in the range of 5.5 to 8.2 The following examples, illustrate but do not limit the product, process, compositional or method of treatment aspects of the present invention. All reaction temperatures are in OC. EXAMPLE 1 EMI22.1 With an end-point set at pH = 7.5, aqueous 1.0 N-NaOH is added from an automatic burette to a vigorously magnetically stirred suspension of 1 (7-ACA; 200 mg, 0.73 mmole), in distilled, deionized water (3.0 ml) at 200C (initial' pH # 4.1). The solid slowly dissolves giving a clear yellow solution at pH = 7.5. The reagent 2, 4-f luoro-l-methylpyridinium iodide is added (261 mg, 1.10 mmole) in one portion to the above stirred solution; it dissolves instantly, causing a rather slow response from the automatic burette to maintain pH 7.5 The addition of base from the automatic burette practially ceasedafter 2.0 hours, thus signaling completion of the reaction 1 + 2 # 3. The resulting reaction solution is put on a 3.6 x 46cm column of Amberlite XAD-2 resin prepared in distilled, deionized water; eluting with the same solvent, water.. With the flow rate set at 1 drop/sec., individual fractions comprising 200 drops each are collected. Absorbance at 254 nm is observed. Unreacted starting materials 1 and 2 come off first, their departure being signaled by a long minimum in absorbance at 254 nm. At fraction No. 77, the eluting solvent is changed to aqueous 5% tetrahydrofuran (THF). Fractions No.'s 117-124 are pooled and lyophylized to yield pure product 3 as an off-white, fluffy powder (242 mg; 90% yield). The pooled fractions are known to contain pure 3 on assay by HPLC, using a C18 reverse phase column and aqueous 10% THF as the mobile phase. IR: strong -lactam at 1775cm 1 and EMI23.1 at 1727 cm NMR: (T-60) : D20; 2.07 (s, 3H; CH3#CO#O), + 3.53 (ABq, 2H, J=18Hz; S-CH2), 3.98 3H; N -CH3), 4.83 (ABq, 2H, J-12.SHz; CH2-OAc), 5.31 (d, lH, J=5Hz; H6), 5.70 (d, 1H, J=SHz; H7), 7.06 (d, 2H, J=7Hz; pyridinium H3+H5), 8.16 (d, 2H, J=7Hz; pyridinium H2+H6) 2'MR - 300 MHz; shows pyridinium H2+ H6 as a broad sinqlet UV: "t (H 0) 196; 214; and 279 nm (# 15,650; 14,210; and 27,710, respectively). EXAMPLE 2 EMI24.1 EMI24.2 The product of Example 1 (1, above), N-(l'-methyl-4'pyridinium)-7ACA (200 mg 1.0 mol) is dissolved in anhydrous methanol (1.0 ml) at r.t. (20 C) and the pale yellow solution is cooled to -680C under an atmosphere of dry N2, in an acetone/solid CO2 bath. The solution becomes turbid at -680C. A solution of lithium methoxide in methanol (1.83 ml, 5.0 mol., of 1.5N-LiOMe/MeOH) is added by syringe through a rubber septum to the magnetically stirred solution which at once becomes clear and orange colored. After 2 minutes t-butylhypochlorite ("t-BuOCl, 79W1, density = 0.91, 1.2 mol.) is added by syringe as above; the solution rapidly becomes a very pale yellow. Stirring is continued for 5 minutes at -68 C; whereupon the reaction is quenched by adding acetic acid (315 jil 10.0 mol). The solution is evaporated at 25'C under reduced pressure to yield a yellow gum (557 mg) which is redissolved in water (20 ml) and lyophilized to give a pale brown foam (-405 mg). The resulting product is chromatographed in pure distilled water over a 3.1 x 43cm. column of Amberlite XAD-2 resin. Initial elution was by water at a flow rate of 2 drops/sec.; individual fractions comprising 400 drops each (N 26 ml) are collected. Absorbance at 254 nm is observed. At fraction No. 24, the solvent is changed to aqueous 5% THF. On the shoulder of increasing absorbance, the fraction volume from No. 38 on is cut to 100 drops (-6 ml). Fractions No.'s 56-67 are pooled and lyophylized to yield 136 mg of an off-white fluffy powder judged to be 818 product 2 and 19% starting material. A 30 mg fraction is purified by preparative reverse phase liquid chromatography to yield the desired product 2 as a colorless foam (18 mg, 98% pure). IR: 5-lactam at 1774 cm NMR - 300 MHZ: (D2O) : 2.09 (s,3H,OAc); 3.30 (d, 1H, J=18Hz S-CH&beta;); 3.67 (d, 1H, J=18Hz, S-CH a) 3.55 3.55 (s,3H, 7&alpha;-OCH3); 4.06 (s,3H, +N-CH3); 4.72 (d, 1H, J=13Hz, 3-CHA-OAc); 4.87 (d, 1H, J=13Hz, 3-CHA, -OAc), 5.39 (s, 1H, H6) 7.31 (d, 2H, J=8Hz, Py H3+H5); 8.27 (d, 2H, J=8Hz, Py H2+H6). UV: #max (H20) 195; 212 and 277 nm ( 16,450; 16,090; and 28,840) EXAMPLE 3 EMI26.1 With the end-point set at 7.5 pH, aqueous 1.0N NaOH is added roman automatic burette to a vigorously magnetically stirred suspension of 7-amino-3-(1'-methyltetrazol-5'- ylthiomethyl)ceph-3-em-4-oic acid (li 200 mg; 0.6mmole) in distilled water (2.5 ml) (initial pH = 4.0; 200C). The solid readily dissolves giving a clear brown solution at pH = 7.5. A quantity (175 mg; 0.73mmole) of 4-fluoro-l-methylpyridinium iodide (% is dissolved in distilled water (0.5 ml), added in one portion at 200C to the above stirred solution. The automatic burette responds at once to maintain pH - 7.5. After 1.0 hour, more pyridinium reagent 2 (43 mg; 0.18 mmole; i.e., 0.91 mmole total) is added directly to the reaction solution; and after 1 hour additional reaction, the entire solution at pH - 7.5 is put directly on to a 3.1 x 45 cm. Amberlite XAD-2 resin column prepared in distilled water. Initially, distilled water is used as the eluting solvent. The flow rate is adjusted to 4 drops/sec., and individual fractions comprising 400 drops each ( 26 ml) are collected. Absorbance at 254 nm is observed. At fraction No. 45, the solvent is changed to aqueous 5% THF. At fraction No. 60, the fraction volume is reduced to 100 drops; fractions Nos. 79-120 are combined and lyophylized to yield a pale yellow powder (122 mg). This product is shown by analytical liquid chromatography (C18 reverse phase column using aqueous 10% ThF as the mobile phase) to be a two component mixture. Separation is achieved by preparative reverse phase liquid chromatography, yielding a faster moving component [X] as a colorless fluffy powder (43 mg), which by IR, W and NMR is shown to be the desired product, above. The slower moving component [Y] is similarly obtained as a colorless fluffy powder (33 mg) which is shown by IR, W, and NMR to be the 7-epimer of !X). Characterization (NMR; IR; W) of the desired product 3 (isomer "X") and is 7-epimer "Y" is given below. [X) (43 m) NMR: (300 MHz)(D20) 3.51 (d, 1H, J=18Hz, ring S-CH3); 3.84 (d, 1H, J=18, ring S-CHa); 4.01 (s, 3H, N-CH3); 4.05 (d, lH, J=14Hz, position 3-CHA): 4.07 (s, 3H, tetrazole N-CH3); 4.35 (d, 1H, J=l4Hz, position 3-CHA, 5.30 (d, 1H, J=5Hz, H6); 5.67 (d, 1H, J=5Hz, H7) 7.06 (d, 2H, J=6Hz, pyridinium H3+H5); 8.16 (broad s, 2H, pyridinium H2+H6). IR: ss-lactam at 1776 cm-1 W: #max (H2O) 197; 211; 279.5 nm (# 20,770; 19,790; and 36,170) [Y] (33 mg) NMR: 300 MHz (D2O) 3.52 (d, 1H, J=18Hz, ring 3.84 (d, 1H, J=18Hz, ring S-CH2); 4.00 (s, 3H, N-CH3); 4.03 (d, 1H, Js14Hz, position 3-CHA); 4.07 (s, 3H, tetrazole N-CH3); 4.28 (d, 1H, J=14Hz, position 3-CHA,); 4.93 (d, 1H, J=1Hz, H7); 5,20 ( d, 1H, J=lHz, H6); 7.02(d, 2H, J=6Hz, pyridine H3+H5); 8.14 (broad s, 2H, pyridine H2+H6) IR: ss-lactam at 1767 cm 1. W:. i max (H2O) 196; 213; 283.5 nm ( 19,960; 18,380; and 34,410) EXAMPLE 4 EMI29.1 EMI29.2 With the end point set at pH = 7.5, aqueous NaOH (2.5 N) is added from an automatic burette to a magnetically stirred suspension of 7-ACA (1; 0.500g; 1.836 mmole) to form a clear brown solution. The reagent 2, 4-chloro-1-methylquinolinium iodide (0.673g; 2.203 mmole), is added in one portion to the above solution producing a rather slow response from the automatic burette to maintain pH - 7.5. Progress of the reaction is monitored by analytical liquid chromatography, using a C18 reverse phase column, aq. 10% ThF as the mobile phase, and a W detector. At 1 1/2 hours the reaction is not complete. More 4-chloro-1-methylquinolinium iodide (168 mg,0.55mmole)is added to the now almost black reaction solution and stirring at 200C/pH 7.5 continued, for a total of 3 hours. Thereafter, the solution is diluted. to 40 ml with distilled water and worked up directly by preparative reverse phase liquid chromatography using a 5 x 30 cm C18 column, aq. 2.5%/THF as the mobile phase and a variable wave length W detector. The first 6.2 litres of eluate is discarded and the product is collected in the next 3.5 litres. This solution is evaporated at 350C/ 0.1 mm to 100 ml then lyophylized yielding as a pale brown fluffy powder (402 mg. 53%) characterized by IR, UV and NMR. IR: -lactam strong at 1774 cm 1. UV: # max (H2O) 216; 233; 334; 345 ( 22,195; 26,965; 18,750; 17,325) NMR 300MHz(D20) 2.12 (s, 3H, OAc); 3.42 (d, 1H, J=18Hz, S-CHss); 3.85 (d, 1H, J= 18Hz, S-CHa); 4.24 (s, 3H, N-CH3); 4.75 (d, 1H, J=13Hz, CHA-OAc); 4.91 (d, 1H, J=13Hz, CHA-OAc); 5.46 (d, lH,J=SHz H6); 5.89 (d, 1H, J=5Hz, H7); 6.98 (d, 1H, J=7Hz, H3') 7.84 (m, lH, For H7); 8.09 (m, 2H, aromatic ); 8.39 (d, 1H, J=9Hz, aromatic); 8.56 (d, 1H, J=7Hz, H2'). EXAMPLE 5 EMI31.1 With the end-point set at pH 7.5, aqueous NaOH (1.ON) is added from an automatic burette to a magnetically stirred suspension of 7ss-amino-3-(1'-methyltetrazol-5'- ylthiomethyl)ceph-3-em-4-oic acid (1, 200 mg; 0.609 mmole) in distilled deionized water (2.5 ml) at 200C. The initial pH is 3.3; the solid readily dissolves to give a clear brown solution at pH 7.5 after the addition of 0.552 ml 1.0 NNaOH. The reagent 2, 4-fluoro-l-ethylpyridinium tetrafluoroborate (378 mg, 70% purity,l.22mmole) is dissolved in distilled deionized water (0.5 ml) and added in one portion to the above solution at 200C producing a rapid response from the auto burette to maintain pH 7.5. After 1 hour, the reaction solution is extracted with CH2C12 (2 x 20 ml) and ether (20 ml) to remove some dark colored contaminants. The polar, zwitterionic product is then isolated from the pH 7.5 aqueous phase by reverse phase liquid chromatography yielding a pale yellow fluffy powder 3 (188 mg, 71%). NMR - 300 MHz(D20)1.48 (3H, t, J=7.2 Hz, CH3 of ethyl); 3.49 (1H, d, J=18Hz, ring S-CHss); 3.82 (1H, d, J=18Hz, ring S-CHa); 4.04 (1H, d, J=14Hz, hetero S-CHA) 4.06 (s, 3H, tetrazole N-CH3); 4.26 (2H, q, J=7.2Hz #N-CH2); 4.32 (2H, d, J=14Hz, hetero S-CHA,); 5.28 (1H, d, J=4.5Hz, H6); 5.65 (1H, d, J=4.5Hz, H7) 7.06 (2H, d, J=7Hz, H3, +H5) 8.22 (2H, broad s, H2+H6) IR: strong ss-lactam at 1777 cm-1. UV#max 198; 213; 280 (# 18,440; 18,220; and 34,300) EXAMPLE 6 EMI33.1 With the end-point set at pH 7.0 aqueous NaOH (2.5N) is added from an automatic burette to a magnetically stirred suspension of 75-amino-3-(1'-methyltetrazol-5'-ylthiomethyl)- ceph-3-em-4-oic acid (1; 1.0 g) indistilled deionized water (8.0 ml) at 200C. At pH 7.0 almost all the solid dissolves in 10 minutes, giving a brown opaque solution. The reagent 2, 4-fluoro-1-(2'-methylphenyl)pyridinium p-toluenesulphonate (1.095g) is dissolved in distilled, deionized water (2.0 ml) giving a clear pale pink solution which is added rapidly ( 1/2 min) to the above sodium cephalosporate solution with magnetic stirring at 200C. Instantaneous reaction ensues as evidenced by a marked fall in pH, formation of a clear brown solution and a rapid response from the burette to restore pH = 7.0. In 20 minutes crystals begin to separate from sloution. In 2 hours the mixture is filtered with some difficulty because of the extremely gelatinous nature of the solid. This material is dried at 25-C/ 0.1 min. to yield a pale brown powder (842 mg) shown by NMR to be the desired product contaminated with 22% of sodium p-toluene sulphonate and a trace of l-(o-tolyl)-4-pyridone. Purification is accomplished by preparative reverse phase L.C. using a 2.0 x 61 cm. Bondapak C18 (37-75 ) column, a U.V. detector and aq. 5% THF as the mobile phase at a flow rate of 19.8 ml/minute. The maxiumumloading of the column under the above conditions is 120 mg. The combined eluates from repetitive injections were evaporated to 150 ml and lyophilized to yield 3 as a yellow fluffy solid (357 mg) Work up of the filtrate from the initial crystallization using the same conditions yields additional desired product 3 t372 mg) Total yield 48%. NMR 300 MHz: (D-DMSO) 2.L8 (s, 3H, tolyl-CH3): 3.55 (d, 1H, J=l8Hz, ring S-CHss); 3.87 (d, J=18Hz, lH, ring S-CHHa); 4.06 (d, J=l4Hz, 1H, position.3-CHA); 4.08 (s, 3N, tetrazole-Ch3); 4.36 8d, J=14Hz, 1H, piosition 3-CHA,) 5.76(d, J=4Hz, 1H, H6) 5.36(d, J=4Hz, 1H, 7.24 (d, J=6Hz, 2H, H3, + H5' py.) 7.44 - 7.62 (m, tolyl aromatic) 8.26 & 8.34 (broad, H2 + H6 - py.) U.V: #max (H2O) 222; 288 nm (# 29,780; and 39,970) IR: strong ss-lactam at 1775 cm 1. EXAMPLE 7 EMI35.1 To a solution of 4-chloropyridine (5.90 g, 1.0 mmole; 1) in nitromethane (10 ml) cooled to 0 C in an ice bath, is added rapidly (over 3 minutes) a solution of triethyloxonium tetrafluoroborate (2; 9.87g) in nitromethane (20 ml) forming an intensely orange solution. After 10 minutes at room temperature, 20 C, the solution is evaporated at 600C/ 1.0 mm leaving a partially crystalline orange gum. Acetonitrile (10 ml) is added and the solution heated to 600C. The solution becomes pale yellow and shows some very finely divided material in suspension. This mixture is left at 200C overnight with no change in appearance. It is then filtered, the solid washed with CH3CN, and discarded. Evaporation of the filtrate leaves a viscous oil which slowly crystallized at ¯ 600/0.5 mm. Acetonitrile (10 ml) is added and the solution -heated at 60 C for 5 minutes, cooled to 200C, some insolubles filtered off and the solution evaporated at 60 /0.5 mm, leaving an offwhite slightly oily solid (10.16 g 64%), m.p. wide range 70-980, shown by NMR to be the correct product: 4-chloro1-ethylpyridinium tetrafluoroborate (3) NMR - T60 (D2O) 1.63 (t, J=7.5Hz, 3H, -CH3); 4.63 (q, J=5.5Hz, 2H, N-CH2-); 8.14 (d, J=7Hz, 2H, H3+H5); 8.83 (d, J=7Hz, 2H, H2+H6). A portion, (l0.Og, 1.0 mol) of 3, 4-chloro-l-ethylpyridinium tetrafluoroborate, is dissolved in sieve-dried DMF (30 ml) and commercial anhydrous KF (8.86 g 3.5 mol.) added, producing a yellow brown mixture. The solution/suspension is stirred at 200C under N2 over the weekend, remaining a suspension and becoming dark brown. Ether is added (100 ml) to the above mixture, precipitating a dark brown oily solid which is separated by decanting the clear orange supernatant layer. The insoluble product is washed with more ether (2 x 25 ml) and is then extracted with nitromethane (3 x 20 ml) with filtration to remove the inorganic salts. The combined CH3N02 filtrates are combined and evaporated at 500C/lmm. leaving a dark brown viscous oil (6.062 g) shown by NMR to be a mixture of the desired 1-ethyl-4-fluoropyridinium tetrafluoroborate 4 (70%) NMR [A) and l-ethyl-4-pyridcne. NMR [B] N. T60 (D2O) NMR [A] NCH2 4.68 (q.); H3+H5 7.94 (m); H2+H6 8.96 (m) NMR[B] N-OH2 4.22 (q); H3+H5 6.-86 (d); H2+H6 8.10 (d) J=7Hz). EXAMPLE 8 EMI37.1 l-(o-tolyl)-4-pyridone (1; 1.0g) is dissolved on heating in toluene (10 ml) and the solution is dried by boiling out the azeotrope. To the solution at gentle reflux is added recrystallized p-toluenesulphonyl chloride (2; 1.03g) in one portion. The solid dissolves immediately, forming an opaque white suspension, which in a few more seconds changes to a pale brown oil precipitated from a clear solution. After a total of 5 minutes at reflux, the mixture is cooled to 200C; the supernatant toluene decanted, the oil washed with more toluene (5 ml) with decantation, then heated at 50 C/ 0.1 mm to remove the last traces of toluene, becoming a glass on cooling (,v3; 2.054a) NMR: (T-60, D-DMSO): 2.18 (s, 3H, tolyl-CH3); 2.31 (s, 3H, tosyl-CH3); 7-7.7 (aromatic) 8.58 (d, 2H, J=7.0Hz, H3+H5 py.); 9.30 (d; 2H, J=7+0Hz, H2+H6 PY.) Commercial anhydrous KF (1.255g, 4.0 mol) is added to the above product 3 (2.054 g, 1.0 mol) followed by sieve-dried dimethylformamide (DMF) (5.0 ml.). The mixture is magnetically stirred at room temperature 20oC under N2 becoming a pale pink suspension of KF in the DMF as the chloropyridinium tosylate.slowly dissolves. After 45 minutes, the mixture, unchanged in appearance is filtered; solids are washed with dry DMF (2 x 0.5 ml) and the combined pinkish brown filtrate is evaporated at 5.0 C/0.1 mm. leaving a pale brown gum, which is extracted with hot ( 70 ) toluene (3 x 10 ml; previously azeotroped dry) with decantation. Some flocculent white solid (probably KF) is decanted off with the toluene and is filtered off. The combined toluene extracts are evaporated at 500C/0.lmm leaving a colorless crystalline solid (141 mg) which is shown by NMR (T60; D-DMSO)to be starting material 1, l-(o-tolyl)-4-pyridone. Material insoluble in the hot toluene is a pale brown syrup which gradually solidifies at 50 C/0.1 mm to a pale pink mass, which is broken up and left at 20 C/0.1 mm overnight to remove all traces of solvents. The resulting product 4 is finally obtained as a pale pink powder (1.596 g). NMR-T60 (D-DMSO) 8.39 (dd, 2H, J(3,5)(2.6) = 7.0Hz, J(3,5)F)=7.0Hz) 9.41 (dd, 2H, J(3,5) 5)(2,6)=7*0HZ J(2,6)F=5.0Hz NMR-T60; (D20) 8.04 (dd, H3H5); 9.02 (dd, H2H6). EXAMPLE 9 EMI39.1 Sieve-dried triethylamine is added to a suspension of 7p-amino-3-(1'-methyltetrazol-5-ylthiomethy;)ceph-3-em-4-oic acid (1; 25 mg) in D-DMSO (0.5 ml) at 200C forming a clear, light brown solution. The reagent 2, 4-fluoro-l-methylpyridinium iodide (22 mg).is added in one portion reacting instantly; NMR (T60) shows complete conversion to the desired product 3. The solution is then shaken with excess of ether (3 x 2 ml) with decantation. The precipitated product is dried in vacuo to yield the desired product 3. EXAMPLE 9a EMI40.1 The 3-acetoxymethyl pyridinium cephem (1) (1.0 mmole) is dissolved in water (5 - 50 ml) at pH 7 containing the alkali metal salt of the heterocyclic thiol 2 (1.0 mmole) . This solution is maintained at 250C for 2 hours, following the progress of the exchange by analytical L.C. of aliquots over a 0.4 x 30 cm WC18 reverse phase column, using a U.V. (254 nm) detector and aqueous ThF (5 - 30%) as mobile phase. The product 3 is isolated by partition chromatography over Amberlite XAD-2 resin with aqueous ThF (0-1o%) as mobile phase, monitoring the eluate by analytical L.C. as above. The appropriate fractions are combined, evaporated at 300/lmm to small volume (50-100mlr and lyophilized. Following the procedure exactly as described, except that the final isolation is accomplished by preparative reverse phase L.C. using C18 columns up to 5x30 ct, the appropriate fractions are again combined, evaporated to small volume and lyophilized to provide 3. EXAMPLE 10 Preparation of EMI41.1 One gram of 7-aminocephalosporanic acid is suspended in 10 ml. water and dissolved by addition of 1N NaOH from an automatic burette set at a pH of 7. l-benzyl-4-fluoro-pyridinium bromide, 1.46 grams in 5 ml. of water is added. The pH is maintained at 7. After 2.5 hours the reaction is filtered. The filtrate is washed with EtOAc and cooled to OOC. overnight. After thawing 0.46 grams of precipitate is collected by filtration. This precipitate is dissolved in methanol, filtered to remove insolubles and concentrated under reduced pressure to a solid. After trituration with dimethylformamide and then ether, a portion of the precipitate is chromatographed in 5% tetrahydrofuran/water on 30-70p Bondapak reverse phase column. The eluent is concentrated to a small volume and lyophilized yielding 0.151 grams product. NMR 300MHz (D20) 2.10 (s, 3H, OCOCH3); 3.41 (d, 1H, J=18-Hz, ring S-CH ) 3.68 (d, 1H, J=18 Hz, ring S-CH ); 4.74 (d, 1H, J=13 Hz, position 3-CHA); 4.90 (d, 1H, J=13Hz, position 3-CHA,): 5.32 (d, -lH, J=5 Hz, H6); 5.43 (s, 2H, benzylic CH2); 5.70 (d, 1H, J-5 Hz, H7); 7.08 (d, 2H, Js8 Hz; H3, + H5, pyridinium); 7.42 - 7.54 (m, aromatics); 8.27 (broad S, 2' + H6, pyridinium). EXAMPLE 11 Preparation of: EMI42.1 One gram of 7ss amino-3-(1-methyl-1H-tetrazol-5-yl)thio) methyl)-3-cephem-4-carboxylate is suspended in water (10 ml) and dissolved by the addition of 1N NaOH from an automatic burette set at a pH of 7.5. The mixture is filtered and the filtrate is added to 2.9 mmoles ofl-(4'-bromobenzyl)-4-fluoro- pyridinium bromide. The pH is maintained at 7. 5 with 1N NaOH. After about half the theoretical amount of base is added a dark sticky.precipitate begins to form. Based on the con sumption of alkali the reaction is complete in about one hour. The precipitate is isolated by filtration and dried. This solid is extensively washed with 100 ml. d methanol to extract the desired product. This methanol solution is concentrated under reduced pressure to a solid which is-tríturated with water and then acetone. The remaining solid is dissolved with difficulty in 30% tetrahydrofuran and water, and chromatographed on pC8 Chromegaprep reverse phase column in 30% THF/Water. The eluted fractions are concentrated under reduced pressure and lyophilizedto yield the desired product. EXAMPLE 12 EMI43.1 One gram of 7ss amino-3-(((l methyl-lH-tetrazol-5 yl)thio)methyl)-3 cephem-4-carboxylate is suspended in 6 ml. water and dissolved by the addition of 1N NaOH from an automatic burette set at a pH of 7.5. 2-Fluoro-lmethyl-pyridinium iodide, 1.30 grams in 2 ml. of water is added. The pH is maintained at 7.5 with 1N NaOH. After five hours the reaction is diluted with water and washed with five equal portions of ethylacetate. The aqueous phase is filtered and concentrated under reduced pressure to remove remaining EtOAc. This dark brown solution is chromatographed on a Waters Prep 500 reverse phase column eluting with 1.25t tetrahydrofuran water and monitoring fractions with a variable wavelength U.V. detector. The main fraction of 3.5 1. is concentrated and lyophylized yielding 0.70 grams of the desired product. NMR 300 MHz(D20) 3.51(d, 1H,J=17Hz, ring s-CH); 3.83(d, in, J=17Hz, ring s-CHa); 3.96(s, 3H, N-CH3); 4.03(d, 1H, J=13Hz, position 3-CHA); 4.04 (s, 3H, N-CH3); 4.31 (d, lH, J-13 Hz, position 3-CHA,); 5.31 (d, 1H, J=4 Hz, H6); 5.70 (d, 1H, J=4 Hz, H7); 7.17 (dd, 1H, J5,4=7Hz, J5,6=7 Hz, H5,); 7.29 (d, 1H, J3,4=8 Hz, H3,); 8.13 (m, 2H, H4,+H6,). EXAMPLE 13 Preparation of EMI44.1 One gram of 7ss-amino-3-(((1 methyl-lH-tetrazol-5yl)thio)methyl)-3-cephem-4-carbocxylate is suspended in H20 (10 ml) and dissolved by the addition of IN NaOH from an automatic burette set at a pH of 7.5. Solid 1-benzyl-4-fluoropyridinium bromide, 1.2 grams-, is added. The pH is maintained at 7.5 with 1N NaOH. After two hours the thick precipitate which had formed is collected by filtration, washed with water and dried under reduced pressure. The solid (1.0 g) is twice crystallized from hot water. The resulting crystals are washed consecutively with small volumes of H2O, acetone and ether yielding 0.2 grams product. NMR 300MHz (D2O) 3.49 (d, 1H, J=17 Hz, ring S-CHss); 3.82 (d, 1H, J=17 Hz' ring SCHa); 4.04 (d, 1H, J=14 Hz, position 3-CHA); 4.05- (s, 3H, N-CH3); 4.32 (d, 1H, J=14 Hz, position 3-CHA'); 5.28 (d, 1H, J=5 Hz H6); 5.42 (s, 2H, benzylic CH2); 5.64 (d, 1H, J-5 Hz, H7); 7.06 (d, 2H, J=7 Hz, H3, + H5, pyridinium); 7.40 - 7.50 (m. aromatics); 8.26 (broad s, 2H, H2, + H6, pyridinium). EXAMPLE 14 Preparation of EMI45.1 4-Chloro-1,3-dimethyl-pyridinium Iodide A solution of 7.2 g. (56.6 mmoles; 6.25 ml.) of 4-chloro-3-methyl pyridine in 39.4 g. (283 mmoles; 17.3 ml.) of cold methyl iodide is kept at 50 for 20 hours. The mixture is diluted with 30 ml. of ether and filtered. The solid is washed with ether and dried yielding 11.2 g. of 4-cAloro-1,3-dimethyl- pyridinium iodide, NMR (60 MHz-DMSO.-d6) 2.5 (s, 3H), 4.3 (s, 3H), 8.3 (d, 1H), 8.9 (dd, 1H), 9.1 (d, 1H). EMI45.2 4-Fluoro-1,3-dimethyl-pyridinium Iodide A solution of 5.4 g. (20 mmoles) of 4-chloro-1,3dimethyl-pyridinium iodide in 30 ml. of dimethylformamide is treated with 4.1 g. (70 mmoles) of anhydrous KI and stirred at 550 for 24 hours. Stirring is continued at 250 for 48 hours. The mixture is filtered and the filtrate is diluted with an equal volume of ether. The solid which separates is filtered, washed with ether and dried to yield 3.57 g. of 4-fluoro-1,3-dimethyl pyridinium iodide. NMR (60 MH DMSO-d6) 2.2 (s, 3H), 4.3 (s, 3H), 8.1 (t, 1H), 9.1 (m, 2H). EXAMPLE 15 EMI46.1 4-((2-Carboxy-3-([(1-methyl-1H-tetrazol-5-yl)thio] methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7ss-yl) amino)-1,3-dimethylpyridinium Hydroxide Inner Salt A mixture of 1 g. (3 mmoles) of 2-carboxy-3-([(1- methyl-lH-tetrazol-5-yl)tnio]methyl)-7 > -amino-8-oXo-5- thia-l-azabicyclo[4.3.0loct-2-ene in 10 ml. of H20 is neutralized to pH 7.4 with 1N NaOH in a pH-Stat. Complete solution is obtained in 30 minutes and 1.14g (4.5 mmoles) of 4-fluoro-1,3-dimethyl-pyridinium iodide is then added. Reaction requires a total of 6 hours, and a total of 2.44 ml. of 1N NaOH is required to obtain a final pH of 7.0. The reaction solution is diluted to 100 ml. with water and freeze-dried yielding 2.2 g. of crude product. The crude is purified by high performance liquid chromatography and the. fraction containing the product (identified by a U.V. maximum at 282 nm) is concentrated. The concentrate (250 ml.) is freeze-dried to give 460 mg. of the subject compound. NMR 300 MHz - (D20) 2.25 (5, 3H), 3.7 (q, 2H), 4.0 (s, 3H), 4.05 (s, 3H), 4.2 (q, 2H), 5.34 (d, 1H), 5.7 (d, 1H), 7.05 (d, 1H), 8.1 (s, lH), 8.17 (d, 1H). EXAMPLE 16 EMI47.1 1-Carboethoxymethyl-4-chloropyridinium bromide A solution of 1.1 g. (10 mmoles; 0.95 ml.) of 4-chloropyridine in 10 g. (60 mmoles) of ethyl bromoacetate is kept at 50 for 48 hours. The mixture is diluted with 15 ml. of ether, filtered and the solid is washed well with ether. After drying 2.29 g. of 4-chloro-1-carboethoxymethyl pyridinium bromide is obtained. NMR (60 MHz - DMSO - d6) 1.3 (t, 3H), 4.3 ( q, 2H) , 5.9 (s , 2H) , 8.6 (d, 2H) 9.3 (d, 2H), EXAMPLE 17 EMI48.1 4- ( (2-Carboxy-3-( [(l-methyl-lH-tetrazol-5-yl)thio] methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-7- yl)amino)-l-carboethoxymethyl)pyridinium Hydroxide Inner Salt A mixture of 1 g. (3 mmoles) of 2-carboxy--3 ([(l-methyl-lH-tetrazol-5-yl)thio]methyl)-7ss-amino- 8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene in 10 ml. of H2O is stirred and neutralized to pH 7.4 with 1N NaOH in a pH-stat. Complete solution requires 60 minutes and 2.96 ml. of NaOH is used. A 840 mg. (3 mmoles) sample of 4-chloro-l-carboethoxymethylpyridinium bromide is added and titration continued with 1N NaOH to pH 7.0. The reaction takes 4 hours and uses 2.96 ml. of NaOH. The reaction solution is washed with three 10-ml. portions of ethyl acetate, diluted to 50 ml. with water and freeze-dried to yield 1.9 g. of crude product. A 500-mg. portion of the crude product is partially dissolved in 10 ml. of water. After centrifugation, the supernatant is purified by high performance liquid chromatography. Fractions containing product are concentrated and freeze-dried to yield 19 mg. of the subject compound. NMR (300 MHz - D20) 1.3 (t, 3H), 3.7 (S, 2H), 4.1 (s, 3H), 4.2 (qt 2H), 4.32 (q, 2H), 5.18 (s, 2H), 5.3 (d, 1H), 5.72 (d, 1H), 7.15 (d, 2H), 8.2 (d, 2H). EXAMPLE 18 EMI49.1 A solution of 25 mg. (0.05 mmoles) of 4-((2 carboxy-3-([(1-methyl-lH-tetrazol-5-yl)thio]methyl)-8- oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-7ss-yl)amino)-1carboethoxymethyl)pyridinium hydroxide inner salt in 2 ml. of H20 is titrated in a pH-stat with 0.05N NaOH to pH 9. Over a period of 45 minutes, 1.02 ml. of NaOH is consumed. The pH of the reaction solution is adjusted to 7 and freeze-dried to yield 18.9 mg. of 4-((2-carboxy-3-([1-methyl-1H-tetrazol-5-yl]-thio] methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7ssyl)amino)-l-(carboxymethyl)pyridinium hydroxide inner salt, sodium salt. NMR (60 MHZ - D20) 3.8 (q, 2H), 4.2 (s, 3H), 4.3 (q, 2H), 4.95 (s, 2H), 5.4 (d, 1H), 5.8 (d, 1H), 7.2 (d, 2H), 8.2 (d, 2H). EXAMPLE 19 EMI50.1 A cold solution of 200 mmoles of 4-methoxybenzyl bromide in 100 ml. of benzene is treated with 5 g. (50 mmoles; 4.6 ml.) of 4-chloropyridine and kept at 50 for 48 hours. The precipitate is filtered, washed well with ether and dried to give 7.2 g. of 1-(4methoxybenzyl)-4-chloropyridinium chloride. NMR (60 MHz - DMSO-d6) 3.7 (s, 3H) , 5.8 ( S 2H), 6.9 (d, 2H) , 7.5 (d, 2H) 8.3 (d, 2H), 9.2 (d, 2H). EMI50.2 A mixture of 1.25 g. (4 mmoles) of 1-(4-methoxybenzyl)-4-chloropyridinium bromide and 0.93 g. (15 mmoles) of anhydrous KF in 10 ml. of dry dimethylformamide was stirred at 25 under N,2. After 2.5 hours the mixture was filtered and the filtrate was concentrated to a residual 2.2 g. of oily 1-(4-methoxybenzyl)-4-fluoro- pyridinium bromide. NMR (60 MHz - D2O) 3.9 (s, , 3H), 5.9 (5, 2H), 7.15 (d, 2H), 7.7 (d, 2H), 8.1 (t, 2H), 9.1 , 2H). EXAMPLE 20 EMI51.1 A suspension of 1.35 g. (4 mmoles) of 2-carboxy-3 ([(l-methyl-lH-tetrazol-5-yl)thio]methyl)-7ss-amino-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene in 8 ml. of H2 0 is stirred and titrated with 2.5N NaOH in a pH-stat to pH 7.5. After the addition of 1.7 ml. of 2.5N NaOH complete solution is obtained. A solution of 4 mmoles of l-(4-methoxybenzyl)-4-fluoropyridinium bromide in 5 ml. of water is added and titration at pH 7 is continued. After the addition of 1.5 ml. of 2.SN NaOH the reaction is complete and the precipitated product is filtered and washed with water and dried to yield 1.87 g. of 4-((2-carboxy-3-([(1-methyl-lH-tetrazol-5-yl)thio] methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7ssyl)amino)-l-(4-methoxybenzyl)pyridinium hydroxide inner salt. NMR (300 MHz - DMSO-d6) 3.5 (q, 2H), 3.75 (s, 3H), 3.9 (s, 3H), 4.32 (q, 2H), 5.13 (d, lH), 5.38 (s, 2H), 5.65 (m, 1H), 7.0 (d, 2H), 7.2 (m, 2H), 7.42 (d, 2H), 8.43 (d, 1H), 8.63 (d, 1H), 9.5 (d, 1H). EXAMPLE 21 EMI52.1 A solution of 5 g. (40 mmoles; 3.35 ml.) of bromomethyl methyl ether in 20 ml. of ether is cooled to -10 and treated dropwise over 20 minutes while being stirred with a solution of 2 g. (20 mmoles; 1.9 ml.) of 4-chloropyridine in 8 ml. of ether. An immediate precipitation of a white solid occurs. Stirring is continued an additional 20 minutes and the solid is filtered and washed with ether and dried to yield 3.8 g. of l-methoxymethyl-4-chloropyridine. NMR (60 MHz - D20) 2.5 (s, 3H), 4.85 (s, 2H), 7.3 (d, 2H), 8.0 (d, 2H). EXAMPLE 22 EMI52.2 4-((2-Carboxy-3-([(1-methyl-lH-tetrazol-5-yl)thio]- methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7ss-yl)- aminoEl-methoxymethylpyridinium Hydroxide Inner Salt A suspension of 340 mg. (1 mmole) of 2-carboxy-3 ([(1-methyl-1H-tetrazol-5-yl)thio]methyl)-7ss-amino-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene in 5 ml. of water is neutralized to pH 7.0 with 1N NaOH in a pHstat. Complete solution is obtained in 5 minutes after the addition of 1 ml. of 1N NaOH. The solution is treated with 250 mg. (1 mmole) of 1-methoxymethyl-4chloropyridinium bromide and titration with 1N NaOH is -' continued. After an uptake of 1 ml. of alkali, the reaction is complete and is diluted to 25 ml. with water and freeze-dried to give 556 mg. of crude product. A solution of the crude product in 25 ml. of water is purified by HPLC on 2.0 x 61 cm. Bondapak column in the system 2.596 tetrahydrofuran in water. The combined product fractions are concentrated and the concentrate is freeze-dried to give 71 mg. of 4-((2-carboxy-3-([(1methyl-1H-tetrazol-5yl)thio]methyl)-8-oxo-5-thia-1 azabicyclo[4.2.030ct-2-en-7ss-yl)amino)-l-methOxymethyl- pyridinium hydroxide inner salt. NMR (300 MHz - D20) d 3.2 (S, 3H), 3.65 (q, 2H), 4.05 (s, 3H), 4.18 (q, 2H), 5.3 (d, 1H), 5.5 (s, 2H), 5.7 (d, 1H), 7.15 (d, 2H), 8.35 (d, 2H). EXAMPLE 23 EMI53.1 l-Furfuryl-4-chloropyridinium Bromide A solution of 4 g. (40 mmoles; 3.5 ml.) of furfuryl alcohol in 40 ml. of ether is cooled to 5 , stirred and treated dropwise with a solution of 4 g. (14.8 mmoles; 1,4 ml.) of PBr3 in 6 ml. of ether over a period of 30 minutes. After an additional 15 minutes the ether solution is decanted from a dark insoluble oil and stirred for 15 minutes at 50 with one gram of K2CO3 (anhydrous). The mixture is filtered and the filtrate is treated with 2 g. (20 mmoles; 1.9 ml.) of 4-chloropyridine. The precipitate which forms immediately is filtered and the filtrate is treated with an additional 2 g. (20 mmoles; 1.9 ml.) of 4-chloropyridine and is kept at 250 for 5 days. The solid which separates is filtered and washed well with ether and dried to give 1.7 g. of l-furfuryl-4- chloropyridinium bromide. NMR (60 NHz - D20) 5.9 (s, 2H), 6.6 (q, 1H), 6.95 (d, 1H), 7.7 (d, 1H), 8.25 (d, 2H), 8.95 (d, 2H). EXAMPLE 24 EMI54.1 4-((2-Carboxy-3([(1-methyl-lH-tetrazol-5-yl)thio]methyl) 8-oXo-5-thia-1-azobicyclol4.2.01oct-2-en-7ss-yl)amino)-1- furfuryl pyridinium Hydroxide Inner Salt A suspension of 670 mg. (2 mmoles) of 2-carboxy-3 ([(l-methyl-lH-tetrazol-5-yl)thiolmethyl)-7ss-amino-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene in 5 ml. of water is neutralized to pH 7.0 with 1N NaOH in a pH-stat. After 1.5 hours, 550 mg. (2 mmoles) of l-furfuryl-4- chloropyridinium chloride is added and titration is continued with 1N NaOH. After an uptake of 1.2 ml. of alkali, the reaction solution is diluted to 50 ml. with water and freeze-dried to give 1.19g of crude product. The crude product is dissolved in 20 ml of water and purified by HPLC on a 2.0 x 61 cm Bondapak C18 reverse phase column in the system 3.75% tetrahydrofuran in water, using a U.V. detector. The fractions containing product are combined and concentrated and the concentrate is freeze-dried yielding 123 mg. of 4-(2-carboxy-3-([(1 methyl-lH-tetrazol-5-yl)thio]methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-en-7ss-yl)amino)-1-furfurylpyridi nium hydroxide inner salt. 'NMR (300 MHz - D20) 3.7 (q, 2H), 4.05 6, 3H), 4.2 (q, 2H), 5.3 (d, 1H), 5.45 (5, 2H), 5.65 (d, 1H), 6.55 k I 1H), 6.7 (d, 1H), 7.05 (d, 2H), 7.6 (d, 1H), 8.15 (d, 2H). EXAMPLE 25 EMI56.1 EMI56.2 Iodotrimethylsi.lane(3.Ommoles) is added by syringe through a rubber septum to a solution of 4-[2 carboxy-3-[(1-methyl-lH-teerazol-5-yl)thiolmethyl- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7ss-yl]amino 1-methoxmethylpyridinium hydroxide inner salt (1) (1.0 mmole) in dry tetramethyienesulphone (5 ml) at 200C in an atmosphere of dry nitrogen. The mixture is magnetically stirred at 200C for 24 hours and is then diluted with an equal volume of water. The product is isolated directly from this solution by preparative high performance liquid chromatography over a 5 x 30 cm C18 Bondapak reverse phase column with aqueous 2% tetrahydrofuran as the mobile phase and monitoring the eluate with a variable wavelength U.V. detector. The appropriate eluate fraction is evaporated at 25 /lmm to approximately 100 ml. then lyophylized to yield 4-t2-carboxy-3-[1-methyl-lH-tetrazol-5-yl)thio3methyl-8- oxo-5-thia-azabicyclo[4.2.0]oct-2-en-7ss-yl]aminopyridinium hydroxide inner salt (2), characterized by U.V. IR., and NMR, the latter in particular missing the two S sharp singlets at J 3.2 and 5.5 for the N-methoxymethyiene group of the starting material. EXAMPLE 26 EMI57.1 EMI57.2 The product of Example 25 (2 mmole) is dissolved in water (20 ml) and the pH of the solution adjusted to 9 by adding aq. 2.5N NaOH from an automatic burette controlled by'a pH stat. The solution is cooled to 20 in an ice bath and hydroxylamine O-sulphonic acid (4 mmole) added with magnetic stirring. The mixture is stirred at 200/pH = 9 for 10 hours. The -pH is then adjusted to 7 by adding aq. 2.5N-HC1 and the product is isolated directly from this solution by preparative reverse phase HPLC over a 5 x 30 cm C18 Bondapak column with aq. 2% tetrahydrofuran as the mobile phase and monitoring the eluate with a variable wavelength detector. The appropriate eluate fraction is evaporated at 25 /lmm to approximately 100 ml then lyophylized to yield the desired product characterized by U.V., IR, and NMR. EXAMPLE 26a Following the procedure of Examples 1, 2, 3, 4, 5, 6, 9, 9a, 10, 11, 12, 13, 15, 17, 18, 20, 22, 24, 25 and 26 the following compounds of the present invention are obtained, respectively, when the indicated cephalosporin starting material is replaced by an equivalent amount of its l-oxadethia analogue: EMI58.1 EMI59.1 EMI60.1 EMI61.1 EXAMPLE 27 Following the procedure described in the foregoing text and Examples, the following compounds listed in Table I are detailed. In Table I, appropriate remarks are entered to signal any departure from established procedure. Alos listed under "Remarks" in Table I are the necessary reagents. TABLE I EMI62.1 EMI63.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remnarks <tb> <SEP> 1 <SEP> H <SEP> # <SEP> #- <SEP> CH2-S-N- <SEP> # <SEP> #-F <tb> <SEP> CH3 <SEP> N <SEP> CH3 <SEP> I# <tb> <SEP> # <SEP> # <tb> <SEP> N <SEP> N <tb> <SEP> CH3 <tb> <SEP> 2 <SEP> H <SEP> # <SEP> #- <SEP> " <SEP> # <SEP> #-F <tb> <SEP> CH3CH2 <SEP> CH3CH2 <SEP> BF4# <tb> <SEP> 3 <SEP> H <SEP> # <SEP> #- <SEP> " <SEP> # <SEP> #-F <tb> <SEP> (CH3)2CH <SEP> (CH3)2CH <tb> <SEP> # <SEP> O#SO2-#-CH3 <tb> EMI64.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 4 <SEP> H <SEP> ## <SEP> CH2-S# <SEP> ##F <tb> <SEP> CH2=CH#CH2 <SEP> CH3 <SEP> CH2=CHCH2# <tb> <SEP> O#SO2#CH3 <tb> <SEP> 5 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3CH3 <SEP> CH3CH3BF4# <tb> <SEP> 6 <SEP> H <SEP> CH3# <SEP> " <SEP> CH3 <SEP> F <tb> <SEP> ## <tb> <SEP> CH3CH3#PF6 <tb> EMI65.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 7 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> ##F <tb> <SEP> CH3#O#CH2 <SEP> CH3OCH2 <SEP> Br# <tb> <SEP> 8 <SEP> H <SEP> ## <SEP> " <SEP> From <SEP> Compound <SEP> 7 <SEP> by <SEP> reaction <tb> <SEP> with <SEP> (a) <SEP> ISi(CH3)3 <SEP> then <tb> <SEP> (b) <SEP> H2O. <tb> <SEP> 9 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> COOCH3 <SEP> CH3 <SEP> COOCH3 <SEP> I# <tb> EMI66.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 10 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> from <SEP> compound <SEP> 9 <SEP> by <tb> <SEP> CH3 <SEP> COO#M# <SEP> hydrolysis <SEP> at <SEP> pH <SEP> = <SEP> 9 <tb> <SEP> then <SEP> titration <SEP> to <SEP> pH <SEP> = <SEP> 7 <tb> <SEP> 11 <SEP> H <SEP> ## <SEP> " <SEP> ##Cl <tb> <SEP> CH3 <SEP> COOCH3 <SEP> CH3 <SEP> BF4#COOCH3 <tb> <SEP> 12 <SEP> H <SEP> ## <SEP> " <SEP> from <SEP> compound <SEP> 11 <SEP> by <tb> <SEP> CH3 <SEP> COO#M# <SEP> hydrolysis <SEP> at <SEP> pH <SEP> = <SEP> ) <tb> <SEP> then <SEP> titration <SEP> to <SEP> pH <SEP> = <SEP> 7 <tb> EMI67.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 13 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> ##Cl <tb> <SEP> CH3OOC#CH2 <SEP> CH3 <SEP> CH3OOC#CH2 <SEP> Br# <tb> <SEP> 14 <SEP> H <SEP> ## <SEP> " <SEP> from <SEP> compound <SEP> 13 <SEP> by <tb> <SEP> M##OOCCH2 <SEP> hydrolysis <SEP> at <SEP> pH <SEP> = <SEP> 9 <tb> <SEP> then <SEP> titration <SEP> at <SEP> pH <SEP> = <SEP> 7 <tb> <SEP> 15 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> Cl <SEP> CH3 <SEP> Cl <tb> <SEP> BF4# <tb> EMI68.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 16 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> ##F <tb> <SEP> CH3 <SEP> OCH3 <SEP> CH3 <SEP> CH3 <SEP> OCH3 <tb> <SEP> BF4# <tb> <SEP> 17 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> # <SEP> # <SEP> #OSO2#-CH3 <tb> <SEP> 18 <SEP> H <SEP> ### <SEP> " <SEP> ###F <tb> <SEP> Br# <tb> EMI69.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 19 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> ##F <tb> <SEP> HO <SEP> CH3 <SEP> #O <tb> <SEP> 20 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3O <SEP> CH3O <SEP> BF4# <tb> <SEP> 21 <SEP> H <SEP> ## <SEP> " <SEP> from <SEP> compound <SEP> 8. <SEP> by <tb> <SEP> NH2 <SEP> reaction <SEP> with <SEP> H2N.O.SO3H <tb> EMI70.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 22 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> ##F <tb> <SEP> CH3 <SEP> SO3#M# <SEP> CH3 <SEP> CH3 <SEP> SO3CH3 <tb> <SEP> #BF4# <tb> <SEP> and <SEP> subsequent <SEP> hydrolysis <tb> <SEP> at <SEP> pH <SEP> = <SEP> 9 <SEP> and <SEP> titration <SEP> to <tb> <SEP> pH <SEP> = <SEP> 7 <tb> <SEP> 23 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> NH2 <SEP> CH3 <SEP> NH#CO#OBut <tb> <SEP> BF4# <tb> <SEP> and <SEP> subsequent <SEP> cleavage <tb> <SEP> by <SEP> CF3COOH <tb> <SEP> 24 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> CH3 <tb> <SEP> NH2 <SEP> NH#CO#OBut <tb> <SEP> BF4# <tb> <SEP> andsubsequent <SEP> cleavage <tb> <SEP> by <SEP> CF3COOH <tb> EMI71.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 25 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> ##F <tb> <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> OCH3 <tb> <SEP> #PF6 <tb> <SEP> 26 <SEP> H <SEP> ## <SEP> " <SEP> from <SEP> compound <SEP> 25 <SEP> by <SEP> reaction <tb> <SEP> CH3 <SEP> OH <SEP> with <SEP> (a) <SEP> ISi(CH3)3 <SEP> then <tb> <SEP> (b)H2O <tb> <SEP> 27 <SEP> H <SEP> # <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> CH3 <SEP> #PF6 <tb> <SEP> OCH3 <SEP> OCH3 <tb> EMI72.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 28 <SEP> H <SEP> # <SEP> CH2-S-# <SEP> from <SEP> compound <SEP> 27 <SEP> by <SEP> reaction <tb> <SEP> CH3 <SEP> CH3 <SEP> with <SEP> (a) <SEP> ISi(CH3)3; <SEP> (b) <SEP> H2O; <tb> <SEP> then <SEP> M#OH# <SEP> to <SEP> pH7 <SEP> isolating <tb> <SEP> the <SEP> product <SEP> as <SEP> the <SEP> cephem <tb> <SEP> -COO#M# <tb> <SEP> 29 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> CH2OCH3 <SEP> CH3 <SEP> CH2OCH3 <tb> <SEP> I# <tb> <SEP> 30 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> CO#NH2 <SEP> CH3 <SEP> CO#NH2 <tb> <SEP> BF4# <tb> EMI73.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 31 <SEP> H <SEP> ## <SEP> CH2-S-# <SEP> ##F <tb> <SEP> CH3 <SEP> CO#NH2 <SEP> CH3 <SEP> CH3 <SEP> CO#NH2 <tb> <SEP> BF4# <tb> <SEP> 32 <SEP> H <SEP> ## <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> NHCONH2 <SEP> CH3 <SEP> NH#CO#NH2 <tb> <SEP> BF4# <tb> <SEP> 33 <SEP> H <SEP> O## <SEP> " <SEP> O##Cl <tb> <SEP> CH3 <SEP> CH3 <tb> <SEP> Br# <tb> EMI74.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 34 <SEP> H <SEP> O## <SEP> CH2-S-# <SEP> O##Cl <tb> <SEP> # <SEP> CH3 <SEP> # <SEP> Br# <tb> <SEP> 35 <SEP> H <SEP> ## <SEP> " <SEP> ###Cl <tb> <SEP> Br# <tb> <SEP> 36 <SEP> H <SEP> ### <SEP> " <SEP> ###Cl <tb> <SEP> # <SEP> # <SEP> Br# <tb> <SEP> COOCH3 <SEP> COOCH3 <tb> EMI75.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> 37 <SEP> H <SEP> ### <SEP> CH2-S# <SEP> from <SEP> compound <SEP> 36 <SEP> by <tb> <SEP> # <SEP> CH3 <SEP> hydrolysis <SEP> at <SEP> pH <SEP> 9. <tb> <SEP> COO#M# <SEP> then <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> <SEP> 38 <SEP> H <SEP> M#OOC### <SEP> " <SEP> CH3OOC###F <tb> <SEP> Br# <tb> <SEP> and <SEP> subsequent <SEP> hydrolysis <tb> <SEP> at <SEP> pH <SEP> = <SEP> 9 <SEP> titration <SEP> to <tb> <SEP> pH <SEP> = <SEP> 7 <tb> <SEP> 39 <SEP> H <SEP> ### <SEP> CH2-S-# <SEP> ###F <tb> <SEP> CH2COO#M# <SEP> # <tb> <SEP> Br# <tb> EMI76.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 40 <SEP> H <SEP> ### <SEP> CH2-S <SEP> N <SEP> ###F <tb> <SEP> # <SEP> # <SEP> #N <tb> <SEP> N-N <tb> <SEP> # <tb> <SEP> CH2CH2SO3#M# <tb> <SEP> Br# <tb> 41 <SEP> H <SEP> ##N# <SEP> CH2-S <SEP> N# <SEP> ###Cl <tb> <SEP> O <SEP> N <SEP> O <tb> <SEP> # <SEP> # <SEP> N <tb> <SEP> N-N <tb> <SEP> # <tb> <SEP> CH2CH2N(CH3)2 <tb> <SEP> Br# <tb> 42 <SEP> OCH3 <SEP> ### <SEP> CH2-S <SEP> N# <tb> <SEP> # <SEP> N <SEP> from <SEP> compound <SEP> 35 <SEP> by <SEP> reaction <tb> <SEP> N-N <SEP> with <SEP> (a)Li0CH3 <SEP> then <SEP> (b)Cl0But <tb> <SEP> # <tb> <SEP> CH3 <tb> EMI77.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 43 <SEP> OCH3 <SEP> ### <SEP> CH2-S <SEP> N <tb> <SEP> # <SEP> N <SEP> from <SEP> compound <SEP> 39 <SEP> by <SEP> reaction <tb> <SEP> # <SEP> # <SEP> with <SEP> LiOCH3 <SEP> then <SEP> (b) <SEP> ClOBut <tb> <SEP> N-N <tb> <SEP> # <tb> <SEP> CH2COO#M# <tb> 44 <SEP> H <SEP> HO### <SEP> -CH3 <SEP> from <SEP> CH3CO.O###F <tb> <SEP> Br# <tb> <SEP> and <SEP> subsequent <SEP> hydrolysis <SEP> at <tb> <SEP> pH <SEP> 9 <SEP> and <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> 45 <SEP> H <SEP> " <SEP> CH2-S <SEP> N# <tb> <SEP> # <SEP> N <tb> <SEP> # <SEP> # <tb> <SEP> S## <tb> <SEP> CH3 <tb> EMI78.1 Compund <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 46 <SEP> H <SEP> CH3O <SEP> ### <SEP> CH2-S <SEP> N# <SEP> CH3O###F <tb> <SEP> CH3O <SEP> # <SEP> N <SEP> CH3O <tb> <SEP> N-N <SEP> Br# <tb> <SEP> # <tb> <SEP> CH3 <tb> 47 <SEP> H <SEP> ### <SEP> " <SEP> ### <SEP> F <tb> <SEP> COOH3 <SEP> Br# <SEP> COOCH3 <tb> 48 <SEP> H <SEP> ### <SEP> " <SEP> from <SEP> compound <SEP> 47 <SEP> by <tb> <SEP> COO#M# <SEP> hydrolysis <SEP> at <SEP> pH <SEP> 9 <SEP> then <tb> <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> EMI79.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 49 <SEP> H <SEP> ### <SEP> CH2-S <SEP> N <SEP> ### <SEP> F <tb> <SEP> N <SEP> Br# <tb> <SEP> N <tb> <SEP> CH3 <SEP> CH2OH <tb> 50 <SEP> H <SEP> ### <SEP> CH2.O.COOH3 <SEP> " <tb> 51 <SEP> H <SEP> CH3SO <SEP> ### <SEP> CH2O.COCH3 <SEP> CH3SO <SEP> ### <SEP> F <tb> <SEP> N <tb> <SEP> Br# <tb> EMI80.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 52 <SEP> H <SEP> CH3 <SEP> CH2-SNN# <SEP> I <SEP> CH3 <tb> <SEP> N <SEP> CH3NN <SEP> N <SEP> #F <tb> <SEP> # <tb> 53 <SEP> H <SEP> CH3 <SEP> " <SEP> I <SEP> CH3 <tb> <SEP> N <SEP> #N <SEP> F <tb> <SEP> # <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> by <SEP> reaction <SEP> in <SEP> anhydrous <SEP> DMF <tb> <SEP> with <SEP> Et2NPi <SEP> as <SEP> base. <tb> 54 <SEP> H <SEP> CH3 <SEP> " <SEP> BF4 <SEP> CH3 <tb> <SEP> CH3OOC <SEP> N <SEP> CH3OOC <SEP> N <SEP> F <tb> <SEP> # <SEP> # <tb> EMI81.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 55 <SEP> H <SEP> M <SEP> OOC <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> from <SEP> compound <SEP> 54 <SEP> by <SEP> hydro <SEP> N <SEP> #N <SEP> lysis <SEP> at <SEP> pH <SEP> 9 <SEP> then <SEP> titration <tb> <SEP> # <SEP> CH3N <SEP> N <SEP> to <SEP> pH <SEP> 7 <tb> 56 <SEP> H <SEP> CH3 <SEP> " <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> CH3OOC <tb> <SEP> CH3OOC <tb> 57 <SEP> H <SEP> CH3 <SEP> " <SEP> from <SEP> compound <SEP> 56 <SEP> by <SEP> hydrolysis <tb> <SEP> N <SEP> at <SEP> pH <SEP> 9 <SEP> then <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> <SEP> # <tb> <SEP> M <SEP> OOC <tb> EMI82.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 58 <SEP> H <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> N <SEP> N <SEP> # <tb> <SEP> H2NOC <SEP> CH3 <SEP> H2NOC <tb> 59 <SEP> H <SEP> CH3 <SEP> " <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> # <tb> <SEP> Cl <SEP> Cl <tb> 60 <SEP> H <SEP> CH3 <SEP> " <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> # <tb> <SEP> Cl <SEP> Cl <tb> EMI83.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 61 <SEP> H <SEP> CH3 <SEP> CH2-S <SEP> A <SEP> BF4 <SEP> CH3 <tb> <SEP> CH3 <SEP> N <SEP> # <SEP> N <SEP> CH3 <SEP> N <SEP> F <tb> <SEP> # <SEP> CH3 <SEP> N <SEP> N <SEP> # <tb> 62 <SEP> H <SEP> CH3#O#CH2 <SEP> " <SEP> CH3.O.CH2 <tb> <SEP> N <SEP> Br <SEP> N <SEP> F <tb> <SEP> # <SEP> # <tb> 63 <SEP> H <SEP> H <SEP> " <SEP> from <SEP> compound <SEP> 62 <SEP> by <SEP> reaction <tb> <SEP> N <SEP> with <SEP> (a) <SEP> ISi(CH3)3 <SEP> then <tb> <SEP> # <SEP> (b) <SEP> H2O <tb> EMI84.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 64 <SEP> H <SEP> HO <SEP> CH2-S <SEP> N <SEP> O <tb> <SEP> N <SEP> # <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> CH3 <SEP> N <SEP> N <SEP> # <tb> 65 <SEP> H <SEP> CH3O <SEP> " <SEP> BF4 <SEP> CH3O <tb> <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> # <tb> 66 <SEP> H <SEP> NH2 <SEP> " <SEP> from <SEP> compound <SEP> 63 <SEP> by <SEP> reaction <tb> <SEP> N <SEP> with <SEP> H2NO#SO3H <tb> <SEP> # <tb> EMI85.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 67 <SEP> H <SEP> CHOOC#CH2 <SEP> CH2-S <SEP> N <SEP> CH3OOC#CH3 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> CH3 <SEP> N <SEP> N <SEP> Br <SEP> # <tb> 68 <SEP> H <SEP> M <SEP> OOC#CH2 <SEP> " <SEP> from <SEP> compound <SEP> 67 <SEP> by <tb> <SEP> N <SEP> hydrolysis <SEP> at <SEP> pH <SEP> 9 <tb> <SEP> # <SEP> then <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> 69 <SEP> H <SEP> CH3 <SEP> " <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> N <SEP> #F <tb> <SEP> # <SEP> ButO#CONH <tb> <SEP> H2N <SEP> ams <SEP> subsequent <SEP> cleavage <SEP> by <tb> <SEP> CF3#COOH <tb> EMI86.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 70 <SEP> H <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <SEP> Cl <tb> <SEP> # <SEP> CH3 <SEP> N <SEP> N <SEP> # <tb> <SEP> M <SEP> O3S <SEP> O <tb> <SEP> CH3 <SEP> O <SEP> S <tb> <SEP> O <tb> <SEP> and <SEP> subsequent <tb> <SEP> hydrolisis <SEP> at <SEP> pH <SEP> 9 <tb> <SEP> and <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> 71 <SEP> H <SEP> # <SEP> CH2 <SEP> " <SEP> # <SEP> CH2 <tb> <SEP> N <SEP> Br <SEP> N <SEP> F <tb> <SEP> # <SEP> # <tb> 72 <SEP> H <SEP> HO <SEP> # <SEP> " <SEP> From <SEP> CH3COO# <tb> <SEP> CH2 <SEP> Br <SEP> CH2 <tb> <SEP> N <SEP> N <tb> <SEP> # <SEP> #F <tb> <SEP> and <SEP> subsequent <SEP> hydrolysis <SEP> at <tb> <SEP> pH <SEP> 9 <SEP> and <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> EMI87.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 73 <SEP> H <SEP> CH3OOC <SEP> CH2-S <SEP> N <SEP> CH3OOC <tb> <SEP> # <SEP> CH2 <SEP> # <SEP> N <SEP> # <tb> <SEP> N <SEP> CH3 <SEP> N <SEP> N <SEP> CH3 <tb> <SEP> # <SEP> Br <SEP> N <tb> <SEP> # <SEP> F <tb> 74 <SEP> H <SEP> M <SEP> OOC# <SEP> " <SEP> from <SEP> compound <SEP> 73 <SEP> by <SEP> hydro <SEP> CH2 <SEP> lysis <SEP> at <SEP> pH <SEP> 9 <SEP> then <SEP> titration <tb> <SEP> N <SEP> to <SEP> pH <SEP> 7 <tb> <SEP> # <tb> 75 <SEP> H <SEP> #O#-CH2 <SEP> " <SEP> #O#-CH2 <tb> <SEP> N <SEP> N <tb> <SEP> # <SEP> Br <SEP> # <tb> EMI88.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 76 <SEP> H <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> I <SEP> CH3 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> N <SEP> N <SEP> # <tb> <SEP> CH2#COOM <tb> 77 <SEP> OCH3 <SEP> CH3 <SEP> " <SEP> from <SEP> compound <SEP> 76 <SEP> by <SEP> reaction <tb> <SEP> N <SEP> with <SEP> (a) <SEP> LiOCH3 <SEP> then <SEP> (b) <SEP> ClOBut <tb> <SEP> # <tb> 78 <SEP> H <SEP> # <SEP> " <SEP> # <tb> <SEP> CH2 <SEP> CH2 <tb> <SEP> N <SEP> N <tb> <SEP> # <SEP> Br <SEP> # <SEP> F <tb> EMI89.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 79 <SEP> H <SEP> #O#-CH2 <SEP> CH2-S <SEP> N <SEP> #O#-CH2 <tb> <SEP> N <SEP> # <SEP> N <SEP> Br <SEP> N <SEP> F <tb> <SEP> # <SEP> N <SEP> N <SEP> # <tb> <SEP> CH2COOM <tb> 80 <SEP> OCH3 <SEP> #O#-CH2 <SEP> " <SEP> from <SEP> compound <SEP> 79 <SEP> by <tb> <SEP> N <SEP> reaction <SEP> with <SEP> (a) <SEP> LiOCH3 <tb> <SEP> # <SEP> then <SEP> (b) <SEP> ClOBut <tb> 81 <SEP> H <SEP> Cl <SEP> Ch2-S <SEP> N <SEP> Cl <tb> <SEP> # <SEP> # <SEP> N <SEP> # <tb> <SEP> Cl <SEP> CH2 <SEP> N <SEP> N <SEP> Cl <SEP> CH2 <tb> <SEP> N <SEP> CH2CH2SO3M <SEP> Br <SEP> N <tb> <SEP> # <SEP> # <SEP> F <tb> EMI90.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 82 <SEP> H <SEP> HO <SEP> CH2-S <SEP> N <SEP> CH3COO <tb> <SEP> # <SEP> # <SEP> N <SEP> # <tb> <SEP> CH2 <SEP> N <SEP> CH2OH <SEP> Br <SEP> N <tb> <SEP> N <SEP> CH3 <SEP> # <SEP> F <tb> <SEP> # <SEP> and <SEP> subsequent <SEP> hydrolysis <tb> <SEP> at <SEP> pH <SEP> 9 <SEP> and <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> 83 <SEP> H <SEP> # <SEP> CH2O#CO#NH2 <SEP> # <tb> <SEP> N <SEP> N <tb> <SEP> # <SEP> # <SEP> F <tb> <SEP> OSO2-#-CH3 <tb> 84 <SEP> H <SEP> CH3OOC <SEP> CH2#S <SEP> N <SEP> CH3OOC <tb> <SEP> # <SEP> # <SEP> N <SEP> # <tb> <SEP> N <SEP> N <SEP> N <SEP> N <tb> <SEP> # <SEP> CH3 <SEP> # <SEP> F <tb> <SEP> OSO2-#-CH3 <tb> EMI91.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 85 <SEP> H <SEP> M <SEP> OOC <SEP> CH2-S <SEP> N <SEP> from <SEP> compound <SEP> 84 <SEP> by <SEP> hydro <SEP> # <SEP> N <SEP> lysis <SEP> at <SEP> pH <SEP> 9 <SEP> then <SEP> titration <tb> <SEP> N <SEP> N <SEP> N <SEP> to <SEP> pH <SEP> 7 <tb> <SEP> # <SEP> CH3 <tb> 86 <SEP> H <SEP> CH3OOC <SEP> " <SEP> CH3OOC <tb> <SEP> # <SEP> # <tb> <SEP> N <SEP> CH3 <SEP> N <SEP> CH3 <tb> <SEP> # <SEP> # <tb> <SEP> OSO2-#-CH3 <tb> 87 <SEP> H <SEP> M <SEP> OOC <SEP> " <SEP> from <SEP> compound <SEP> 86 <SEP> by <SEP> hydrolysis <tb> <SEP> # <SEP> at <SEP> pH <SEP> 9 <SEP> then <SEP> titration <SEP> to <SEP> pH <SEP> 7 <tb> <SEP> N <SEP> CH3 <tb> <SEP> # <tb> EMI92.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 88 <SEP> H <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> N <SEP> N <tb> <SEP> #N <SEP> N <SEP> N <SEP> # <SEP> F <tb> <SEP> CH3 <SEP> N <tb> 89 <SEP> OCH3 <SEP> CH3 <SEP> " <SEP> from <SEP> compound <SEP> 88 <SEP> by <SEP> reaction <tb> <SEP> N <SEP> with <SEP> (a) <SEP> LiOCH3 <SEP> then <SEP> (b) <tb> <SEP> #N <SEP> ClOBut <tb> 90 <SEP> H <SEP> CH2#CH3 <SEP> " <SEP> BF4 <SEP> CH2#CH3 <tb> <SEP> N <SEP> N <tb> <SEP> #N <SEP> # <SEP> F <tb> <SEP> N <tb> EMI93.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 91 <SEP> H <SEP> N <SEP> CH2-S <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> # <SEP> N <SEP> # <tb> <SEP> CH3 <SEP> N <SEP> N <SEP> N <SEP> CH3 <SEP> N <tb> <SEP> CH3 <SEP> OSO2#CH3 <tb> 92 <SEP> H <SEP> # <SEP> N <SEP> " <SEP> # <SEP> N <SEP> F <tb> <SEP> N <SEP> # <SEP> N <SEP> # <tb> <SEP> OSO2#CH3 <tb> 93 <SEP> H <SEP> # <SEP> CH2 <SEP> CH2-S <SEP> N <SEP> # <tb> <SEP> N <SEP> # <SEP> N <SEP> CH2 <tb> <SEP> #N <SEP> N <SEP> N <SEP> N <SEP> F <tb> <SEP> CH2#COOM <SEP> # <tb> <SEP> OSO2#CH3 <tb> EMI94.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 94 <SEP> H <SEP> # <SEP> CH2-S <SEP> N <SEP> # <tb> <SEP> CH3 <SEP> # <SEP> N <SEP> CH3 <tb> <SEP> N <SEP> N <SEP> N <SEP> N <tb> <SEP> #N <SEP> CH2#CH2#SO3M <SEP> # <tb> <SEP> F <tb> <SEP> N <tb> <SEP> OSO2#CH3 <tb> 95 <SEP> OCH3 <SEP> # <SEP> N <SEP> CH2-S <SEP> N <SEP> from <SEP> compound <SEP> 92 <SEP> by <SEP> reaction <tb> <SEP> N <SEP> # <SEP> # <SEP> N <SEP> with <SEP> (a) <SEP> LiOCH3 <SEP> then <SEP> (b) <SEP> ClOBut <tb> <SEP> N <SEP> N <tb> <SEP> CH3 <tb> 96 <SEP> H <SEP> CH3 <SEP> " <SEP> BF4 <SEP> CH3 <tb> <SEP> N <SEP> N <tb> <SEP> # <SEP> # <SEP> F <tb> <SEP> S <SEP> S <tb> EMI95.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 97 <SEP> H <SEP> # <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> # <SEP> CH3 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <tb> <SEP> # <SEP> N <SEP> N <SEP> # <SEP> F <tb> <SEP> S <SEP> CH2#COOM <SEP> S <tb> <SEP> BF4 <tb> 98 <SEP> H <SEP> CH2CH3 <SEP> CH2-S <SEP> N <SEP> CH2CH3 <tb> <SEP> CH3 <SEP> N <SEP> # <SEP> N <SEP> CH3 <SEP> N <tb> <SEP> # <SEP> S <SEP> SCH2COOM <SEP> # <SEP> F <tb> <SEP> S <SEP> S <tb> <SEP> BF4 <tb> 99 <SEP> OCH3 <SEP> CH2CH3 <SEP> " <SEP> from <SEP> compound <SEP> 98 <SEP> by <SEP> reaction <tb> <SEP> CH3 <SEP> N <SEP> with <SEP> (a) <SEP> LiOCH3 <SEP> then <SEP> (b) <tb> <SEP> # <SEP> ClOBut <tb> <SEP> S <tb> EMI96.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 100 <SEP> H <SEP> CH2CH3 <SEP> CH2-S <SEP> N <SEP> BF4 <SEP> CH2CH3 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <tb> <SEP> O <SEP> # <SEP> S <SEP> SCH2COOM <SEP> O <SEP> # <SEP> F <tb> <SEP> # <SEP> # <tb> 101 <SEP> H <SEP> CH2CH3 <SEP> CH2-S <SEP> N <SEP> BF4 <SEP> CH2CH3 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <tb> <SEP> O <SEP> # <SEP> N <SEP> N <SEP> O <SEP> # <SEP> F <tb> <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> 102 <SEP> H <SEP> CH2#CH3 <SEP> " <SEP> BF4 <SEP> CH2CH3 <tb> <SEP> N <SEP> N <tb> <SEP> S <SEP> # <SEP> S <SEP> # <SEP> F <tb> EMI97.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 103 <SEP> H <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> CH3 <SEP> BF4 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <tb> <SEP> ## <SEP> N <SEP> N <SEP> ##F <tb> <SEP> N <SEP> CH3 <SEP> N <tb> <SEP> CH3 <SEP> CH3 <tb> 104 <SEP> H <SEP> CH3OOC <SEP> CH3 <SEP> " <SEP> CH3OOC <SEP> CH3 <SEP> BF4 <tb> <SEP> N <SEP> N <tb> <SEP> ## <SEP> ##F <tb> <SEP> N <SEP> N <tb> <SEP> CH3 <SEP> CH3 <tb> 105 <SEP> H <SEP> M <SEP> OOC <SEP> CH3 <SEP> " <SEP> from <SEP> compound <SEP> 104 <SEP> by <SEP> hydro <SEP> N <SEP> lysis <SEP> at <SEP> pH <SEP> 9 <SEP> then <SEP> titration <tb> <SEP> ## <SEP> to <SEP> pH <SEP> 7 <tb> <SEP> N <tb> <SEP> CH3 <tb> EMI98.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 106 <SEP> H <SEP> CH3O <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> CH3 <SEP> BF4 <tb> <SEP> N <SEP> # <SEP> N <SEP> CH3 <SEP> N <tb> <SEP> ## <SEP> N <SEP> N <SEP> ##F <tb> <SEP> N <SEP> CH2#COOM <SEP> N <tb> <SEP> CH3 <SEP> CH3 <tb> 107 <SEP> OCH3 <SEP> CH3O <SEP> CH3 <SEP> " <SEP> from <SEP> compound <SEP> 106 <SEP> by <SEP> reaction <tb> <SEP> N <SEP> with <SEP> (a) <SEP> LiOCH3 <SEP> then <SEP> (b) <SEP> ClOBut <tb> <SEP> ## <tb> <SEP> N <tb> <SEP> CH3 <tb> 108 <SEP> H <SEP> CH2CH3 <SEP> CH2-S <SEP> N <SEP> CH2CH3 <SEP> BF4 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <tb> <SEP> ## <SEP> N <SEP> N <SEP> ##F <tb> <SEP> O <SEP> CH3 <SEP> O <tb> EMI99.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 109 <SEP> H <SEP> CH3 <SEP> CH2-S <SEP> N <SEP> CH3 <SEP> BF4 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <tb> <SEP> ## <SEP> N <SEP> N <SEP> ##F <tb> <SEP> O <SEP> CH3 <SEP> O <tb> 110 <SEP> H <SEP> CH3 <SEP> " <SEP> CH3 <SEP> BF4 <tb> <SEP> N <SEP> N <tb> <SEP> ## <SEP> ##F <tb> <SEP> S <SEP> S <tb> 111 <SEP> H <SEP> N# <SEP> " <SEP> F <tb> <SEP> NC <SEP> # <tb> <SEP> NC <SEP> N <tb> <SEP> OSO2#CH3 <tb> 112 <SEP> H <SEP> CH <SEP> " <SEP> CN <tb> <SEP> N <SEP> N <SEP> F <tb> <SEP> # <SEP> # <tb> <SEP> OSO2#CH3 <tb> EMI100.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 113 <SEP> H <SEP> #N# <SEP> CH2-S <SEP> N <SEP> ##F <tb> <SEP> # <SEP> N <SEP> N <SEP> Br <tb> <SEP> N <SEP> N <tb> <SEP> CH3 <tb> 114 <SEP> H <SEP> #N# <SEP> " <SEP> ##F <tb> <SEP> CH3 <SEP> N <tb> <SEP> CH3 <SEP> Br <tb> 115 <SEP> H <SEP> #N# <SEP> " <SEP> F <tb> <SEP> #N# <tb> <SEP> Cl4 <tb> EMI101.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 116 <SEP> H <SEP> #N# <SEP> CH2-S <SEP> N <SEP> #N#F <tb> <SEP> # <SEP> N <SEP> OSO2#CH3 <tb> <SEP> CH3 <tb> 117 <SEP> H <SEP> #N# <SEP> " <SEP> F <tb> <SEP> #N# <tb> <SEP> OSO2#CH3 <tb> 118 <SEP> H <SEP> #N# <SEP> CH2-S <SEP> N <SEP> #N#F <tb> <SEP> # <SEP> N <SEP> Br <tb> <SEP> N <SEP> N <tb> <SEP> CH2COOM <tb> EMI102.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 119 <SEP> OCH3 <SEP> #N# <SEP> CH2-S <SEP> N <SEP> from <SEP> compound <SEP> 118 <SEP> by <tb> <SEP> # <SEP> N <SEP> reaction <SEP> with <SEP> (a) <SEP> LiOCH3 <tb> <SEP> N <SEP> N <SEP> then <SEP> (b) <SEP> ClOBut <tb> <SEP> CH2COOM <tb> 120 <SEP> H <SEP> #N# <SEP> CH2#O#CO#CH3 <SEP> #NF <tb> <SEP> Br <tb> 121 <SEP> H <SEP> #N# <SEP> CH2-N-# <SEP> from <SEP> compound <SEP> 120, <SEP> by <SEP> reaction <tb> <SEP> O#CO#CH3 <SEP> with <SEP> N# <SEP> in <SEP> aqueous <tb> <SEP> solution <tb> EMI103.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 122 <SEP> H <SEP> #N# <SEP> CH2-N#-CONH2 <SEP> from <SEP> compound <SEP> 120 <SEP> by <tb> <SEP> O#CO#CH3 <SEP> reaction <SEP> with <tb> <SEP> N#-CO#NH2 <tb> <SEP> in <SEP> aqueous <SEP> solution <tb> 123 <SEP> OCH3 <SEP> #N# <SEP> CH2#O#CO#CH3 <SEP> from <SEP> compound <SEP> 120 <SEP> by <SEP> reaction <tb> <SEP> with <SEP> (a) <SEP> LiOCH3 <SEP> then <SEP> (b) <SEP> ClOBut <tb> 124 <SEP> OCH3 <SEP> " <SEP> CH2#N#-CO#NH2 <SEP> from <SEP> compound <SEP> 123 <SEP> by <SEP> reaction <tb> <SEP> O#CO#CH3 <SEP> with <SEP> N#CO#NH2 <SEP> in <SEP> aq. <tb> <SEP> solution <tb> EMI104.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 125 <SEP> H <SEP> CH3OCH2 <SEP> CH2-S <SEP> N <SEP> CH3OCH2 <tb> <SEP> N <SEP> # <SEP> N <SEP> N <tb> <SEP> #F <SEP> N <SEP> N <SEP> #F <tb> <SEP> N <SEP> CH3 <SEP> N <SEP> Br <tb> 126 <SEP> H <SEP> H <SEP> " <SEP> prepared <SEP> from <SEP> compound <SEP> 125 <tb> <SEP> N <SEP> by <SEP> reaction <SEP> with <SEP> (a) <SEP> ISi(CH3)3 <tb> <SEP> #F <SEP> then <SEP> (b) <SEP> H2O <tb> <SEP> N <SEP> " <SEP> NC#N#F <tb> 127 <SEP> H <SEP> NC#N# <SEP> Br <tb> EMI105.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> 128 <SEP> H <SEP> (CH3)2N <SEP> CH2-S <SEP> N <SEP> (CH3)2N <tb> <SEP> #N# <SEP> # <SEP> N <SEP> #N#F <tb> <SEP> N <SEP> N <SEP> Br <tb> <SEP> CH3 <tb> 129 <SEP> H <SEP> # <SEP> " <SEP> F <tb> <SEP> N <SEP> # <tb> <SEP> # <SEP> N <tb> <SEP> OTs <tb> <SEP> F <tb> 130 <SEP> H <SEP> ClC#CH2#O#CH2-N# <SEP> " <SEP> Cl3C#CH2#OCH2-N# <tb> <SEP> Br <tb> EMI106.1 Compound <SEP> Rê <SEP> R' <SEP> A <SEP> Remarks <tb> <SEP> F <tb> 131 <SEP> H <SEP> Cl3C.Ch2.OCH2-N# <SEP> N <SEP> N <SEP> Cl3C.CH2.OCH2-N# <tb> <SEP> -CH2S <SEP> N <SEP> Br <tb> <SEP> N <tb> <SEP> (CH2)2N(CH3)2 <tb> <SEP> N <SEP> N <tb> 132 <SEP> H <SEP> " <SEP> -CH2-S <SEP> S.CH2.COONa <SEP> " <tb> <SEP> S <tb> EXAMPLE 28 EMI107.1 Preparation of Pharmaceutical Compositions One such unit dosage form comprises a blend of 120 mg of 4-[(3-[(1-[{(1-methylmetrazol-5-yl)thio} methyl] 2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.03oct-2-en-72- yl 3 amino] -l-benzylpyridinium hydroxide inner salt with. 20 mg of lactose and 5 mg of magnesium stearate which is placed in a No. 3 gelatin capsule. Similarly, by employing more of the active ingredient and less lactose, other dosage forms can be prepared; should it be necessary to mix more than 145 mg. of ingredients together, larger capsules may be employed. Equivalently, compressed tablets and pills can be prepared. The following examples are further illustrative of the preparation of phtrmaceutical formulations: TABLET PER TABLET 4-1( 3- 1 (l-methyltetrazol-5-yl) - thio methyl]-2-carboxy-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-en-7ss ylfamino]-l-benzylpyridinium hydroxide inner salt 125 mg. Dicalcium Phosphate 200 mg Cornstarch, U.S.?. 6 mg. Lactose, U.S.P 200 mg. Magnesium Stearate 270 mg. The above ingredients are combined and the mixture is compressed into tablets, approximately 0.5 inch in diameter each weighing 800 mg. EXAMPLE 28a EMI108.1 Preparation of Pharmaceutical Compositions One such unit dosage form comprises a blend of 120 mg of 4-[#[{(1-methylmetrazol-5-yl)thio} methyl]2-carboxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-en-7ssyl ' amino]-l-benzylpyridinium hydroxide inner salt with 20 mg of lactose and 5 mg of magnesium stearate which is placed in a No. 3 gelatin capsule. Similarly, by employing more of the active ingredient and less lactose, other dosage forms can be prepared; should it be necessary to mix more than 145 mg. of ingredients together, larger capsules may be employed. Equivalently, compressed tablets and pills can be prepared. The following examples are further illustrative of the preparation of pharmaceutical fòrmulations: TABLET PER TABLET 4-[I3-11( l-methyltetrazol-5-y1) - thio methyl]-2-carboxy-8-oxo-5oxa-1-azabicyclo[4.2.0]oct-2-en-7ss ylamino] -l-benzylpyridinium hydroxide inner salt 125 mg. Dicalcium Phosphate 200 mg Cornstarch, U.S.P. 6 mg. Lactose, U.S.P 200 mg. Magnesium Stearate The above ingredients are combined and the mixture is compressed into tablets, approximately 0.5 inch in diameter each weighing 800 mg.

Claims: WHAT IS CLAIMED IS 1. A compound having the structural formula: EMI109.1 and the pharmaceutically acceptable salts and esters thereof wherein: B is S, O, CH2 or NR7; R2 is hydrogen or methoxyl; R' is selected from the group consisting of: EMI109.2 EMI110.1 EMI111.1 wherein the dotted line indicates both saturated and unsaturated rings and wherein: A is conventionally known in the cephalosporin art; and R is hydrogen, alkyl having from 1-6 carbon atoms, substituted alkyl having from 1-6 carbon atoms wherein the substituent is chloro, fluoro, hydroxyl, alkoxyl (C1-6) r carboxyl, amino, sulfo and mono- and dialkylamino wherein each alkyl has 1-6 carbon atoms substituted and unsubstituted: phenylalkyl and phenylalkenyl having 7-12 carbon atoms wherein the substituent is selected from chloro, fluoro, carboxyl, amino, cyano, hydroxyl and sulfo; R is chloro, fluoro, hydroxyl, carboxyl, sulfo, cyano, amino, mono- and dialkylamino, alkoxyl, alkyl having from 1-6 carbon atoms, substituted alkyl having 1-6 carbon atoms wherein the substituent is carboxyl, cyano, alkoxyl having 1-6 carbon atoms, phenyl and phenyloxy; - rr is an integer selected from 0 to 3; and R7 is hydrogen, alkyl having 1-6 carbon atoms, phenylalkyl having 7 to 10 carbon atoms, or formyl. 2. A compound according to Claim 1 wherein B is oxygen or sulfur. 3. A compound according to Claim 2 wherein A is selected from: EMI113.1 EMI114.1 -CH2#O#CO-NH2 -CH2#O#CO#CH3 -CH3 -H, -C1, -OCH3, -CH=CH-COO-M+ -CH2OH , -CH2Br EMI114.2 wherein Y is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation. 4. A compound according to Claim 3 wherein n is O or 1; and R is hydrogen or substituted or unsubstituted alkyl or phenylalkyl. 5 A compound according to Claim 4 wherein A is selected from the group consisting of: EMI115.1 EMI115.2 -CH2OCONH21 EMI115.3 -CH3, -C1; and R' is selected from: EMI116.1 6. A process for preparing a compound according to Claim 1 comprising reacting: EMI117.1 with an N-heterocyclic reagent selected from: EMI117.2 EMI118.1 EMI119.1 wherein the dotted line indicates both saturated and unsaturated rings; Y is a counter anion; and wherein X is a leaving group. An An antibiotic pharmaceutical composition comprising a therapeutically.effective amount of a compound according to Claim 1 and a pharmaceutical carrier therefor. Claims for Austria 1. A process for preparing a compound having the structural formula: EMI121.1 and the pharmaceutically acceptable salts and esters thereof wherein: B is S, O, CH2 or NR7 R2 is hydrogen or methoxyl; R' is selected from the group consisting of: EMI121.2 EMI122.1 EMI123.1 wherein the dotted line indicates both saturated and unsaturated rings; and wherein: A is conventionally known in the cephalosporin art; and R is hydrogen, alkyl having from 1-6 carbon atoms, substituted alkyl having from 1-6 carbon atoms wherein' the substituent is chloro, fluoro, hydroxyl, alkoxyl (C1¯6), carboxyl, amino, sulfo and mono- and dialkylamino wherein each alkyl has 1-6 carbon atoms substituted and Unsubstituted: phenylalkyl and phenylalkenyl having 7-12 carbon atoms wherein the substituent is selected from chloro, fluoro, carboxyl, amino, cyano, hydroxyl and sulfo; R3 is chloro, fluoro, hydroxyl, carboxyl, sulfo, cyano, amino, mono- and dialkylamino, alkoxyl, alkyl having from 1-6 carbon atoms, substituted alkyl having 1-6 carbon atoms wherein the substituent is carboxyl, cyano, alkoxyl having 1-6 carbonbatoms, phenyl and phenyloxy; n is an integer selected from 0 to 3; and R7 is hydrogen, alkyl having 1-6 carbon atoms, phenylalkyl having 7 to 10 carbon atoms, or formyl comprising reacting: EMI124.1 with an N-heterocyclic reagent R'X Y- wherein X is a leaving group and Y- is a counter anion. 2. A Process according to Claim 1 wherein B is oxygen or sulfur. 3. A Process according to Claim 2 wherein A is selected from: EMI125.1 EMI126.1 -CH2#O#CO#NH2 -CH2#O#CO#CH3 -CH3 -H, -Cl, -OCH3, -CH=CH-COO-M+ -CH2OH , -CH2Br EMI126.2 wherein Y is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation. 4. A Process according to Claim 3 wherein n is O or 1; and R is hydrogen or substituted or unsubstituted alkyl or phenylalkyl. for A Process according to Claim 4 wherein A is selected from the group consisting of: EMI127.1 EMI127.2 -CH2OCONH2, EMI127.3 -CH3, -Cl; and R'X Y- is selected from: EMI128.1

Inventors: HANNAH, JOHN
Applicants: MERCK & CO. INC.
Application year: 1980
Main classification: C07D501
IPC codes: C07D463, C07F5, C07D501, C07D487, C07D505, C07D213