ANTIBIOTIC beta -LACTAMS CONTAINING A PYRIDONE CARBOXYLIC ACID OR ACID DERIVATIVE

Abstract: This invention presents novel 2-azetidinone compounds of formula (I), wherein R80 is -CO2R5 or -CONR6R7; wherein R5 is hydrogen or (C1-C4) alkyl; and wherein R6 and R7 are the same or different and are hydrogen, (C1-C4) alkyl, or -OH with the proviso that when R6 is -OH, R7 is other than -OH. These compounds are useful as antibacterial agents to eradicate or control susceptible microbes. Intermediates and processes for making these compounds are also disclosed.

Description: ANTIBIOTIC 3-LACTAMS CONTAINING A PYRIDONE CARBOXYLIC ACID OR ACID DERIVATIVE FIELD OF THE INVENTION This invention encompasses novel 2-azetidinone compounds which have useful antimicrobial activity. INFORMATION DISCLOSURE Derivatives of 2-azetidinone which have antimicrobial and β- lactamase inhibitory activity are known in the art. European Patent Applications 0053815, 0053816, 0076758, and 0096297 disclose /3-lac- tams with various substituents at the C position of the ring. Euro¬ pean Patent Application 0053816 discloses 2-azetidinone compounds substituted at the C position with an organic residue. Abstracts from papers presented by Squibb Institute for Medical Research at the 25th and 26th Interscience Conferences on Antimicro- bial Agents and Chemotherapy disclose antibacterial compounds with a substituted-sulfonylaminocarbonyl group at the N-l position and a 2- (2-amino-4-thiazolyl) -2- (1-carboxy-1-methylethoxy) -iminoacetamido group at the C3 position. United States Patent No. 4,587,047, filed April 1, 1982, issued May 6, 1986, discloses substituted sulfonylaminocarbonyl-2-azetidin- ones. United States Patent Application Serial No. 444,771, filed November 26, 1982 and European Patent Application No. 0085291, filed March 1, 1983, published October 8, 1983, disclose substituted sulf¬ onylaminocarbonyl-2-azetidinones containing a terminal substituted heterocycle in the sulfonylaminocarbonyl activating group. U.K. Patent Application No. 8623151, filed September 26, 1986, and Belgium Patent 905502A disclose sulfonylaminocarbonyl-2-azetidinones contain¬ ing an imidazolidonylaminocarbony-l,4-dihydro-5-hydroxy-4-oxo-2-pyri- dinone in the activating group. SUMMARY OF THE INVENTION The present invention teaches novel 2-azetidinone analogs useful as microbial growth inhibitors. This invention includes enantiomers , diastereomeric and racemic mixtures of these compounds. Intermedi¬ ates and processes for preparing these compounds are also disclosed. Novel 2-azetidinone analogs within the scope of this invention are represented by Formula I and pharmacologically acceptable salts thereof; wherein R]_Q and R ] _g are the same or different and are hydro¬ gen, (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cyclo- alkyl, phenyl optionally substituted with between 1 and 3 substitu¬ ents selected from the group consisting of halogen, nitro, (C^-C^)- alkyl, and (C^-C^)alkoxy, benzyl optionally substituted with between 1 and 3 substituents selected from the group consisting of halogen, nitro, (C 1 -C 4 >alkyl, and (C1-C4)alkoxy, -CH 2 0C0CH 2 NHR , -CH 2 OCO 2 30. -CR " 2 F, or -CHF 2 ; wherein R4 is hydrogen, -COH or -CO-0-C(CH 3 ) 3 ; wherein R 30 is (C 1 -Cg)alkyl, -(CH 2 ) 2 NH 2 , -(CH 2 ) 2 NH(CH 3 ) , -(CH 2 ) 2 NH- C0-0-C(CH 3 ) 3 , -(CH 2 ) 2 N(CH 3 )-C0-0-C(CH 3 ) 3 , - (CH 2 ) 2 0C(0)NH 2 , -(CH 2 ) 2 C1, -(CH2) 2 0C H3 or -(CH2) 2 NHC0H; wherein Q is an acyl group derived from a carboxylic acid; wherein R 8 is -CO2R5 or -CON g y; wherein R5 is hydrogen or (0^-04) alkyl; and wherein Rg and R are the same or different and are hydrogen, .C-^-C^) alkyl, or -OH with the proviso that when Rg is OH, R7 is other than -OH. Novel compounds within the scope of this invention which are useful as intermediates to 2-azetidinone analogs having microbial growth inhibition include compounds of Formula I wherein R4 is -COH and -CO-0-C(CH 3 ) 3 ; and wherein R 30 is -(CH 2 ) 2 NH-C0-0-(CH 3 ) 3 and -(CH 2 ) 2 N(CH 3 )-CO-0-(CH 3 ) 3 . A detailed description of the acyl groups included in R Q is found in U.S. Patent 4,478,749, column 8, line 41 to column 12, line 50, as those terms are defined at column 7, line 34 through column 8, line 22, all of which is incorporated by reference herein. Preferred acyl groups of R Q include those which have been used to acylate 6-aminopenicillanic acid, 7-aminocephalosporic acid and their derivatives which can be found in "Chemistry and Biology of /3-Lactam Antibiotics, Vol. 1, R.B. Morin and M. Gorham, ed. , Academic Press, N.Y. (1982) and include the following list: 2-Cyano cetyl, Aminophenylacetyl, A ino(4-hydroxyphenyl)acetyl, α(Thien-2-yl)acetyl, α(Thien-3-yl)acetyl, Phenylacetyl, Hydroxyphenylacetyl, (Formyl- oxy) henylacety , [(Trifluoro ethyl)thio]acetyl, 2-(3,5-Dichloro- 4-oxo-l(4H)-pyridyl)acetyl, (IH-Tetrazol-l-yl)acetyl, (2-Amino-4- thiazolyl)-2-methoxyiminoacetyl, 2- [(Cyanomethyl)thio]acetyl, [ [ (4Ethyl-2 , 3-dioxo-1-piperizinyl)carbonyl] amino]phenylacetyl , . [ [ (4-Ethyl-2 , 3-dioxo-piperazinyl)carbonyl]amino] (4-hydroxyphenyl) - acetyl, 2-(Aminomethyl) henylacetyl, 4-(Carbamoylcarboxymethylene)- 1,3-dithiethane-2-carbonyl, 3-(o-Chlorophenyl) -5-methyl-4-isoxazole- carbonyl, 2-p-[(1,4,5,6-Tetrahydro-2-pyrimidinyl)phenyl]acetyl, Amino-1,4-cyclohexadien-l-yl-acetyl, Phenylsulfoacetyl, (2R) -2-amino- 2- (m-methanesulfonamidophenyl)acetyl, (2-Amino-4-thiazolyl)-2-(1- carboxy-l-methylethoxy)iminoacetyl, 2- (lH-Tetrazol-1-yl) cetyl, (2,3- Dihydro-2- imino-4-thiazolyl) (methoxyimino)acetyl, (2-Amino-4-thia- zol)carboxymethoxyiminoacetyl, (2-Aminopyridin-6-yl)methoxyiminoacet- yl, (2-Aminopyridin-6-yl)carboxymethoxyiminoacetyl, (4-Amino-2-pyr- imidyl)methoxyiminoacetyl, (5-Amino-1,2,4- hiadiazol-3-yl)-2-methoxy- iminoacetyl, (5-Amino-1, 2,4-thiadiazol-3-yl) -2-carboxymethoxyimino- acetyl, (5-Amino-l,2,4-thiadiazol-3-yl) -1-carboxy-l-methylethoxy) - iminoacetyl,D-α[ [ (Imidazolidin-2-on-l-yl)-carbonyl]amino]phenylacet- yl, D- [ [ (3-mesyl-imidazolidin-2-on-1-yl)carbonyl]amino]phenylacetyl, 2,6-Dimethylbenzoyl, (S)-2- (4-hydroxy-l,5-naphthyridine-3-carbox- amido-2-phenylacetyl. Preferred compounds within the scope of this invention include compounds wherein the organic acid derivative, R 2 o > i- s arι oximinoacyl moiety represented by Formula II; wherein R40 is -CH 3 , -CH 2 C0 2 R4 , or -C(CH3) 2 C0 2 R4 1( wherein R4 is hydrogen, (C ] _-C4) alkyl, -CHζCg^)^- CH (C H5), or a cation; wherein R50 is hydrogen, -C0-0-C(CH 3 ) 3 , -C0- 0-CH 2 -(C 6 H 5 ), or -C(C 6 H 5 ) 3 . Novel compounds within the scope of this invention containing an oximinoacyl moiety represented by Formula II which are useful as intermediates to 2-azetidinone analogs having microbial growth inhibition include compounds wherein R4 is (C-L-C4) alkyl, -CH- (C 6 H 5 )2, or -CH 2 (CgH5); and wherein R 50 is -C0-0-C(CH 3 ) 3 , -C0-0-CH 2 - (C 6 H 5 ), or -C(CgH 5 ) 3 . The compounds of this invention are identified in two ways: by descriptive name and by numerical identification which corresponds to the appropriate structure contained in the structure chart. In appropriate situations, the proper stereochemistry is represented in the structure charts as well. The various carbon moieties are defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n- hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n- decyl, n-undecyl, and n-dodecyl; Alkoxy refers to an alkyl radical which is attached to the remainder of the molecule by oxygen and includes branched or unbranched forms such as methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy; Alkenyl refers to a radical of an aliphatic unsaturated hydrocarbons having a double bond and includes both branched and unbranched forms such as ethenyl, 1-methyl-l-ethenyl, 1-propenyl, 2-propenyl, 1-but- enyl, 2-butenyl, 3-butenyl, 2- ethyl-1-butenyl, 1-pentenyl, 2-pent- enyl, 3-pentenyl, 4-pentenyl, l-methyl-4-pentenyl, 3-me hyl-1-pent¬ enyl, 3-methyl-2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hex- enyl, 1-me hyl-4-hexenyl, 3-methyl-l-hexenyl, 3-methyl-2-hexenyl, 1- heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyl-4-heptenyl, 3- methyl-1-heptenyl, 3-methyl-2-heptenyl, 1-octenyl, 2-octenyl, or 3- octenyl; Alkynyl refers to a radical of an aliphatic unsaturated hydrocarbons having a triple bond and includes both branched and un¬ branched forms such as ethynyl, 1-methyl-l-ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-4-pentynyl, 3- methyl-1-pentynyl, 3-methyl-2-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl, l-methyl-4-hexynyl, 3-me hyl-1-hexynyl, 3-methyl- 2-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-methyl- 4-heptynyl, 3-methyl-l-heptynyl, 3-methyl-2-heρtynyl, 1-octynyl, 2- octynyl, or 3-octynyl. Cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclσhexyl, cyclohept- yl, cyclooctyl or adamantyl. Halogen refers to a radical of fluorine, chlorine, bromine, or iodine. Unless otherwise indicated, in the above description and throughout this document, the parenthetical term (C^C^ is inclusive such that a compound of 0^-04) would include compounds of 1, 2, 3 and 4 carbons and their isomeric forms. It will be apparent to those skilled in the art that compounds of this invention may exist in different tautomeric forms. The scope of this invention includes all tautomeric forms in addition to those represented in the formulas used herein. It will be apparent to those skilled in the art that compounds of this invention may contain several chiral centers. The scope of this invention includes all enantiomeric or diastereomeric forms of Formula I compounds either in pure form or as mixtures of enantiomers or diastereomers. Specifically, the compounds of this invention have chiral carbon atoms at positions C 3 and C4 of the 3-lactam ring. The preferred form is cis at centers 3 and 4 and the preferred stereo¬ chemistry at C 3 and C4 is 3(S) and 4(S) . The phrase "cis at centers 3 and 4" means that the substituents at C-3 and C-4 are both oriented on the same side of the /3-lactam ring. The scope of this Invention includes the pharmacologically acceptable acid salts of the disclosed compounds . Acid salts are formed by reacting the compounds described herein with the appropri¬ ate acid in a suitable solvent. Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, hydrobromic, hydroiodic, acetic, lactic, citric, succinic, benzoic, salicylic, palmoic, cyclo- hexansulfamic, met anesulfonic, naphthalenesulfonic, p-toluenesulf- onic, maleic, fumaric, or oxalic. The scope of this invention includes the pharmacologically acceptable salts of the disclosed compounds. Such salts include the following cations but are not limited to these: alkali metal ions .such as potassium, sodium, lithium, alkaline earth metal ions such as magnesium or calcium and ammonium ions such as ammonium, tetralkylam- monium and pyridinium. Metal salts are formed by suspending the com¬ pounds in water or other suitable solvent and adding a dilute metal base such as sodium or potassium bicarbonate until the pH is between 6 and 7. The compounds of this invention and their respective pharmaco¬ logically acceptable salts have antibiotic activity against a variety of gram-negative bacteria including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The compounds are useful for treating bacterial infections in animals, including and most prefer¬ ably humans. Compounds of the invention are tested for in vitro antimicrobial activity using standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilu- tion as described in "Methods for Dilution Antimicrobial Susceptibil¬ ity Tests for Bacteria That Grow Aerobically" (M7-A) Published Decem¬ ber 1985 by the National Committee for Clinical Laboratory Standards, 771 East Lancaster Avenue, Villanova, PA 19084. Briefly, MIC values are determined in unsupplemented Mueller Hinton Agar (MHA) . The com- pounds tested are diluted serially into molten MHA at 47°C. The agar is poured into petri dishes and allowed to harden. The various bac¬ teria used for testing are grown overnight on MHA at 35°C and trans¬ ferred to Tryptiease Soy Broth (TSB) until a turbidity of 0.5 McFarland standard is obtained. The bacteria are diluted one to 20 in TSB and inoculated on the plates (1 μ ~ L using a Steers repli¬ cator). The plates are incubated at 35°C for 20 hours and the MIC is read to be the lowest concentration of drug that completely inhibits visible growth of the bacterium. The MIC test results of two typical compounds of this invention, Compound 14 which is (3S)-3-[2-(2-Amino- 4-thiazolyl)-Z-(2) -carboxyisopropyloxyimino)acetamido] -1- [(3-carboxy- 4-pyridon-6-yl)-carbonylamino-l-(2-imidazolidone-3-yl)sulfonylamino¬ carbonyl] -2-azetidiπone trisodium salt and Compound 17 which is (3S)- 3- [2- (2-Amino-4-thiazolyl) -Z- (2)-(carboxyisopropyloxyamino)acetam- ido] -1- [ (3-hydroxyaminocarbonyl-4-pyridon-6-yl)carbonylamino-l-(2- imidazolidone-3-yl)sulfonylaminocarbonyl] -2-azetidinone, are given in Table I. Various compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solu¬ tions or suspensions, eye drops, solutions or suspensions, and emul¬ sions containing suitable quantities of compounds of Formula I. For oral administration solid or fluid unit dosage forms can be prepared. For preparing solid compositions, the compounds of this Invention are mixed with conventional ingredients such as talc, mag¬ nesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulf te, starch, lactose, acacia, methylcellulose, and/or functionally similar pharmaceutical diluents or carriers. Capsules are prepared by mixing the compound with an Inert pharmaceutical dil¬ uent and filling the mixture into a hard gelatin capsule of appropri¬ ate size. Soft gelatin capsules are prepared by machine encapsula¬ tion of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other Inert oil. For preparing fluid compositions, the compounds of this inven¬ tion are dissolved in an aqueous vehicle together with sugar, aro¬ matic flavoring agents and preservatives to form a syrup. An elixir Is prepared by using a hydroalcoholic vehicle such as ethanol, suit¬ able sweeteners such as sugar and saccharin, and aromatic flavoring agents. Suspensions are prepared in an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, or methylcellulose. For parenteral administration, fluid unit dosage forms are pre¬ pared utilizing the compound and a sterile vehicle, water being pre- ferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In pre¬ paring solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophil- ized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethyl- ene oxide before suspending in the sterile vehicle. Advantageously, a -surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compounds of Formula I may also be administered in a carrier suitable for topical administration, such carriers include creams, ointments, lotions, pastes, jellies, sprays, aerosols, bath oils, or other pharmaceutical carriers which accomplish direct contact between the compound and the surface of the skin area to be treated. In general pharmaceutical preparations may comprise from about 0.01% to about 10%, and preferably from about 0.1% to about 5% ' by w/w of the active compound in the suitable carrier. Additionally, a rectal suppository can be employed to deliver the active compound. This dosage form is of particular interest where the mammal cannot be treated conveniently by means of other dosage forms, such as orally or by insufflation, as in the case of young children or debilitated persons. The active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethyl¬ ene glycols (carbowaxes) , polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melt- ing point or dissolution rate. These rectal suppositories can weigh from about 1 to 2.5 g. The term "unit dosage form", as used in the specification, refers to physically discrete units suitable as unitary dosages for hu an subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired pharma¬ ceutical effect in association with the required pharmaceutical dilu¬ ent, carrier or vehicle. The specifications for the novel unit dos- age forms of this invention are dictated by and directly dependent on the unique characteristics of the active material and the particular effect to be achieved and the limitations inherent in the art of com¬ pounding such an active material for use in humans and animals, as disclosed In detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, suppositor¬ ies, powder packets, wa ers, granules, cachets, drops, ampules, vials, aerosols with metered discharges, segregated multiples of any of the foregoing, and other forms as herein described. An effective quantity of the compound Is employed In treatment. The dosage of the compound for treatment depends on many factors that are well known to those skilled in the art. They Include for exam¬ ple, the route of administration and the potency of the particular compound. A dosage schedule for humans having an average weight of 70 kg is from about 50 to about 3000 mg of compound In a single dose. More specifically, the single dose is from about 100 g to 2000 mg of compound. Typically the dosages are given one to 4 times per day. The process for making compounds of Formula I is Illustrated in Charts A and B. The requirements for protecting groups in the pro¬ cesses of Charts A and B are well recognized by one skilled in the art of organic chemical synthesis and suitable protecting groups are used in the processes of Charts A and B. It is recognized that con¬ ditions for introduction and removal of protecting groups should not detrimentally alter any other groups in the molecule. Examples of suitable nitrogen protecting groups are- benzyl; triphenylmethyl (trltyl) ; trialkylsllyl, such as trimethylsIlyl or t- butyldimethylsilyl; t-butoxycarbonyl (t-BOC or BOC) ; benzyloxycar- bonyl (Cbz) ; trifluoroalkanoyl, such as trifluoroacetyl or tri- fluoropropionyl; or dlphenyl(me hyl)silyl. Introduction and removal of such nitrogen protecting groups are well known in the art of organic chemistry: See, for example, (1) J.F.W. McOmle, Advances in Organic Chemistry, :191-281 (1963); (2) R.A. Boissonas, Advances in Organic Chemistry, 3:159-190 (1963); (3) "Protective Groups in Organic Chemistry", J.F. . McOmie, Ed., Plenum Press, New York, page 74 (1973), and (4) "Protective Groups in Organic Synthesis", Theodora W. G eene, John Wiley and Sons, New York (1981). Under certain circumstances it may be necessary to protect two or more nitrogen atoms with different protecting groups allowing selective removal of one protecting group while leaving the remaining protecting groups in place. For example, the Cbz group can be selec¬ tively removed in the presence of the BOC group and vice versa. The compounds of this invention are prepared by the procedures outlined in Charts A and B. The substituents at the C4 position defined by R-J_Q and R- j _5 are prepared by procedures outlined in Chart A. The starting compound cis- (±) -4- (me hoxycarbonyl)-3- [ [ (benzyl- oxy)carbonyl]amino] -2-azetidinone, A-l, Is known. J. Org. Chem. , 2765-2767 (1982). The trans compound is known or is made by known methods. Thus compound A-l is either cis or trans with respect to the substituents on C3 and C4. It is recognized that alternative protecting groups could be used in place of the benzyloxycarbonyl group of compound A-l. See also, W. F. Huffman et al. , J. Am. Chem. Soc, 2352 (19770; D. B. Bryan et al. , J. Am. Chem. Soc, 2353 (1977). The C4-carbomethoxy group of compound, A-l, is reduced to the C4-hydroxymethyl group of compound, A-2, by use of metal hydride reducing reagents, such as sodium borohydride or zinc borohydride, In ether solvents, such as diethyl ether or tetrahydrofuran, at a tem¬ perature range of 0° to 80°C. The product is obtained after a normal aqueous work-up procedure followed by column chromatography on silica gel. The hydroxymethyl group of compound, A-2, reacts with H0 CCH - NHR4 wherein R is -COH or -BOC to produce compound A-4 using approx¬ imately equimolar quantities of the acid, 1-hydroxy-l-benzotriazole (HOBT) , and a carbodiimide, such as dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridIne. The choice of solvents is methylene chloride, dimethylformamide or a combination of both solvents and the reaction is carried out in general at the temperature range of 0°C to ambient temperature. The desired com¬ pound is obtained after filtration of precipitated dicyclohexylurea and removal of HOBT by washing with aqueous sodium bicarbonate solu- -lO- tion and then column chromatography on silica gel. To prepare compounds represented by A-3, the hydroxymethyl com¬ pound, A-2, reacts with a suitable protected chloroformate ester of formula ClC0 2 R 3 o where R 30 is (C 1 -C 8 )alkyl, -(CH 2 ) 2 NH-C0-0- (CH 3 ) 3 , - (CH 2 ) 2 N(CH 3 )-CO-0-(CH 3 ) 3 , -(CH 2 )2θC(0)NH 2 , -(CH 2 ) 2 C1, - * (CH 2 ) 2 OCH 3 or -(CH 2 ) 2 NHC0H, to give the compound, A-3. The reaction conditions involve the use of an Inert solvent such as methylene chloride, tetrahydrofuran, or dimethylformamide at -20°C to 30°C In the pres¬ ence of a slight excess of organic base, such as pyridine, 2,4-lutid- ine, or triethylamine. Following extractive workups involving suc¬ cessive washes with acid and base, the products are isolated by chromatography or crystallization. Some chloroformate esters are commercially available and others are be prepared according to the teaching of Huntress, "Organic Chlorine Compounds," John Wiley and Sons, Inc., New York, NY (1948); F. Stain et al. , J. Am. Chem. Soc, 72:1254 (1950), H. G. Ashburm et al. , J. Am. Chem. Soc, 60:2933 (1938) . Briefly, the process described in these references is to contact an alcohol with an excess of phosgene either neat or in an organic solvent. After workup, the product is usually isolated by vacuum distillation. An alternative process to prepare compounds represented by A-3, can be used when the desired chloroformate is unavailable. Compound A-2 is placed in a solvent such as methylene chloride, ethyl acetate, tetrahydrofuran, or acetonitrile containing a slight excess of an organic base, such as pyridine, triethylamine, or 2,4-lutidine, and is reacted at -20°C to 30°C with a solution of phosgene in an inert solvent, such as toluene, benzene or methylene chloride. The inter¬ mediate chloroformate thus formed is not isolated, but is treated with a molar equivalent of the suitably protected desired alcohol, R 3 QOH, where R 30 is (C 1 -C 8 )alkyl, -(CH 2 )2NH-C0-0-(CH 3 ) 3 , -(CH 2 ) 2 - N(CH 3 )-C0-0-(CH 3 ) 3 , -(CH 2 ) 2 0C(0)NH2, -(CH 2 ) 2 C1, -(CH 2 ) 2 0CH 3 or- (CH2)2NHC0H, in the presence of an organic base in an inert solvent at -20° C to 30° C to yield the compound, A-3. This alternative or reversed process is known in the field of steroid chemistry, G. Schu- bert et al. r Die Pharmazie, 35:453 (1980). To prepare compounds of this invention wherein R]_Q or R 5 are alkyl, alkenyl, alkynyl, cycloalkyl, substituted phenyl, substituted benzyl or fluoroalkyl, the hydroxyl substituent in compound A-2 is converted to an appropriate leaving group, Lg, by methods known in the art to give compound, A-5. The leaving group is displaced by known nucleophiles by methods known in the art to give compound A-6 wherein R' is alkyl, alkenyl, alkynyl, cycloalkyl, substituted phenyl, substituted benzyl or fluoroalkyl. To prepare compounds of this invention wherein R o or Rl5 are the same, a suitable amino acid derivative, A-7, is cyclized by known methods to give the substituted four membered ring, A-8, Slusarchyk, W. A., et al., Tetrahedron Letters, 2789-2792 (1986). Deprotection of the lactam nitrogen gives the hydroxy amide, A-9, which is reduced to the β-lactam by titanium trichloride in tetrahydrofuran and water, Miller, M. J., et al., J. Org. Chem., 1126 (1985), Miller, M. J., et al., J. Org. Chem., 410 (1980), Miller, M. J., et al., Tetrahedron, 2571 (1983). Other procedures to prepare substituted azetidinones are known in the art; see, for example, Teutsch, G., et al., Tetra¬ hedron, 2677-2684 (1986), Teutsch, G., et al., Tetrahedron Letters, 1561-1562 (1984), and U.S. Patent 4,478,749, column 19, lines 1-40. Optically active compounds of the Formula I of this invention are prepared by the use of the appropriate optically active form of compound, A-l, which is prepared by known methods, Takeda European patent application 8310461-3. The resolving agents are any of the known resolving agents such as optically active camphorsulfonic acid, bis-o-toluoyltartaric acid, tartaric acid, and diacetyl tartaric acid which are commercially available and which are commonly used for resolution of amines. See Organic Synthesis, Coll., V:932 (1978), which describes the resolution of R- (+) and S- (-) -α-phenylethylamine with (-) -tartaric acid. The preferred starting compound for making optically active com¬ pounds of Formula I, cis- (±) -1- [ (2' ,4' -dimethoxyphenyl)methyl] -4- (methoxycarbonyl) -3-phenylmethoxycarboxyamino-2-azetidinone, is known, Chem. Pharm. Bull., 2646-2659 (1984). The C 3 protecting group is removed by hydrogenolysis to produce the corresponding free amine. An .appropriate substituted tartaric acid enantiomer is then added such as (+) -di-p-toluoyl-D-tartaric acid and reaction condi- tions altered to facilitate precipitation of the appropriate azeti- dinone diastereomeric salt. The tartaric acid is removed by treating the compound with inorganic base such as aqueous sodium bicarbonate to produce the desired resolved amino-azetidinone. The acidic pyridone is prepared from the known compound, 4- hydroxy-6-methyl-2-pyrone, A-11, by forming the enamine, A-12, with N,N-dIme hylformamide in a suitable solvent such as dioxane. The enamine rearranges to the pyridinone, A-13, upon heating in 2-meth- oxyethanol in the presence of ammonia. The carboxylic acid moiety in compound A-13 is transformed to compounds containing moieties defined by RQQ , compound A-14, by methods known in the art. The methyl group in compound A-14 is oxidized to the acid with selenium dioxide in refluxing dioxane to give compound A-15. The carboxylic acid moiety obtained from the oxidation reaction reacts with aminoimidazolidinone in the presence of dimethylaminopyridine, dlcyclohexylcarbodiimide and 1-hydroxybenzotriazole in DMF to give the compound, A-16, which is attached to the β-lactam. Alternative procedures to complete the rest of the molecule are outlined in Chart B. As shown in Chart B, the benzyloxycarbonyl group of compound, B-l, is removed by catalytic hydro enolysis using palladium metal supported on carbon or palladium metal Itself under a hydrogen gas atmosphere In suitable solvents, such as alcoholic sol¬ vents, ether solvents or ethyl acetate, at ambient temperature. The compound, B-2, is obtained by removal of the solid catalyst and removal of the solvent under reduced pressure. The C 3 -amino group of compound, B-2, is acylated with a suitable carboxylic acid to produce compound, B-3. This conversion may be • carried out by any of a number of amide or peptide forming reaction sequences such as methods described in Methoden der Organischem Chemie, Vierte Auflage, Band XV/2, E. Wunch ed. , Georg Thieme Verlag, Stuttgart, p.l. A preferred acylation process is the use of approx¬ imately equimolar quantities of a desired acid, HOBT, and a carbodi- imide, such as DCC. The choice of solvents is methylene chloride, dimethylformamide or a combination of both solvents and the reaction is carried out in general at the temperature range of 0°C to ambient temperature. The desired compound is obtained after filtration of precipitated dicyclohexylurea, removal of HOBT by washing with aqueous sodium bicarbonate solution and column chromatography on silica gel if necessary. Also, the compounds can be made by other methods known in the art, see, for example, J. Am. Chem. Soc, 2401- 2404 (1973) . The amide, B-3, reacts with approximately 1.2 to 1.6 equivalents of chlorosulfonyl isocyanate at -20° to 0°C in organic solvents, such as methylene chloride, acetonitrile or a combination of both solvents to produce the activated azetidinone B-4 which is coupled to a silyl- ated aminoimidazolidinone prepared by reacting N-methyl-N-(trimethyl- silyl) -trifluoroacetamide or bis- (trimethylsilyl) -trifluoroacetamide with aminoimidazolidinone, A-16, in organic solvents, such as aceto¬ nitrile, methylene chloride or tetrahydrofuran, at ambient tempera¬ ture. The silylated aminoimidazolidinone reacts with compound B-4 in the presence of a tertiary amine base such as 2,6-lutldine at about 0°C, and the mixture is slowly warmed to room temperature over a period of one to 5 hours. The . crude product is obtained after a normal aqueous work-up procedure and followed by purification by appropriate methods, such as column chromatography, known to those skilled in the art. Removal of any remaining protecting groups by known methods gives the N-1-sulfonyl-aminocarbonyl compound, B-5. Alternatively, following the procedure outlined in Chart B, a methylene chloride solution of the B-l and 2,6-lutidine reacts with chlorosulfonyl isocyanate at 0° to give B-6. B-6 reacts with an acetonitrile solution of N-methyl-N-(trimethylsilyl) -trifluoroacet- amide and an aminoimidazolidinone, A-16, at ambient temperature to give B-7. The benzyl group at the C amino group is removed by known methods to give compound B-8 and the free amine is couple with a carboxylic acid in the presence of HOBT and DCC at ambient tempera¬ tures. Removal of any remaining protecting groups by known methods gives the N-1-sulfonyl-aminocarbonyl compound, B-5. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques . Example 1 cis- (±) -4- (Hydroxymethyl) -3- [((phenylmethoxy) -carbon¬ yl)amino] -2-azetidinone To a stirred solution of zinc chloride (23.2 g) in anhydrous tetrahydrofuran (300 ml) at 0°C is added sodium borohydride (13.8 g) and the mixture is allowed to warm to room temperature and is stirred overnight. To the mixture is added cis- (±)-4-(methoxycarbonyl) -3- [((phenylmethoxy)carbonyl)amino] -2-azetidinone (39.2 g) and the reac¬ tion mixture is slowly heated to 65°C and stirred at that temperature for 2 hours. The reaction mixture is cooled to 0°C and 6 N hydro¬ chloric acid (200 ml) is added dropwise with stirring. The mixture is poured into ethyl acetate (1 1) and the organic layer is taken. The aqueous layer is saturated with sodium chloride and re-extracted with ethyl acetate (200 ml) . The combined organic layer is washed with water (200 ml) and with 200 ml of brine twice and dried over anhydrous sodium sulfate. The solvent is " concentrated under reduced pressure to afford a yellow oil which is purified by column chromato¬ graphy on silica gel (ethyl acetate as eluent) to obtain 24.3 g of the title product. Physical characteristics are as follows: Melting point 98-100°C. Example 2 cis-(±)-3-[2[ (2-t-Butoxycarbonylamino-4-thiazolyl]2- [ (1-t-butoxycarbonylmethoxy)imino] ]acetamido-4-hydr- oxymeth l-2-azetidinone To a stirred solution of cis-(±)-4-(Hydroxymethyl)-3-[((phenyl- methoxy)-carbonyl)amino] -2-azetidinone (19.5 g) in methanol (150 ml) is added palladium black (7.6 g) slurried in ethanol (25 ml) and the reaction mixture is stirred under 1 atmosphere of hydrogen gas for 24 hours. Toluene (100 ml) is added to the reaction mixture and it is stirred for 15 minutes. The solid material is filtered and the fil- trate solution is concentrated under reduced pressure. The residue is dissolved in methylene chloride (200 ml) and dimethylformamide (500 ml) and cooled in the ice bath. To this cooled solution, 2-[(2- t-butoxycarbonylamino) -4-thiazolyl] - [ (1- -butoxycarbonylmethoxy)- imino]-carboxylic acid (23.8 g) is added followed by dicyclohexylcar- bodiimide (12.6 g) and 1-hydroxybenzotriazole (4.2 g) . The reaction mixture is stirred for 3 hours at 0°C. ■ The precipitated solid is filtered and the filtrate solution Is partitioned between ethyl acetate (2.5 1) and water (1 1). The organic layer is taken and the aqueous layer is washed with 500 ml of ethyl acetate twice. The combined organic layer is washed with aqueous sodium bicarbonate followed by brine and dried over anhydrous sodium sulfate. It is filtered and the filtrate solution is concentrated under reduced pressure and the residual material is chromatographed on silica gel eluting with 1:1: :hexane:ethyl acetate and ethyl acetate to obtain 14.1 g of the title compound. Physical characteristics are as follows: Melting point 195°C. (decomp.). Example 3 cis- (±) -3- [2 [ (2-t-Butoxycarbonylamino-4-thiazolyl]2- [ (1- t-butoxycarbonylmethoxy) imino] ]acetamido-4-N- formyl- lycinoyloxy ethyl-2-azetidinone To a mixture of cis- (±) -3- [2[ (2-t-Butoxycarbonylamino-4-thiazol¬ yl] 2- [ (1-t-butoxycarbonylmethoxy)imino] ]acetamido-4-hydroxymethyl-2- azetidinone (4.5 g) , 1-hydroxybenzotriazole (1.216 g) , dimethylamino- pyridine (122 mg) , N-formylglycine (1.62 g) and in the presence of a small amount of 4A molecular sieves in 60 ml of methylene chloride and 6 ml of dimethylformamide, dicyclohexylcarbodiimide (3.25 g) is added with stirring at room temperature. The reaction is complete in 2 hours. The precipitated solid is filtered off, washed with methyl¬ ene chloride (50 ml) and the filtrate solution is stirred with aque¬ ous sodium bicarbonate (1.89 g. sodium bicarbonate in 40 ml water) at room temperature for 15 minutes. The organic layer is taken, dried over sodium sulfate and concentrated under reduced pressure. The residue is passed through the medium pressure silica gel column eluting with 3:1:: hexane:ethyl acetate and ethyl acetate to obtain 3.6 g of the title compound. Physical characteristics are as follows: Melting point 108-110°C. Example 4 Alternative preparation of cis- (±) -4- (Hydroxy-methyl) - 3- [ ((phenylmethoxy)carbonyl)amino] -2-azetidinone A solution of 1.63 g of sodium borohydride in 25 ml of water is added dropwise to a well stirred solution of 3.0 g of cis-(±)-4- (methoxycarbonyl) -3- [ ((phenylmethoxy)carbonyl)amino] -2-azetidinone in 190 ml of tetrahydrofuran. The addition is made over a period of 10 minutes while stirring in an ice bath. " The reaction is stirred for 3 hours. Methylene chloride (250 ml) is added followed by anhydrous sodium sulfate. A clear solution is obtained by filtration. The solvent is removed and the residue is dissolved in acetone. The solution is clarified by filtration and concentrated to give 2.84 g of the title compound. Physical characteristics are as follows: 13 C NMR ( δ , CH 3 0H-d ): 55.9, 60.2, 61.6, 67.9, 128.7-129.3, 137.6, 158, 170.7. Example 5 cis- (±) -4- [Methoxycarbonyl)oxymethyl] -3- [ ((phenyl¬ methoxy) -carbonyl)amino] -2-azetidinone Methyl chloroformate (2.42 g) is added dropwise to a solution of 3.2 g of cis-(±) -4-(Hydroxy- ethyl)-3- [ ((phenylmethoxy)carbonyl)- amino] -2-azetidinone and 3.03 g of pyridine in 100 ml of methylene chloride while stirring at 0°C. After one hour an additional 0.5 g of methyl chloroformate is added. The reaction mixture is stirred an additional 0.5 hour and then washed successively with dilute mineral acid (e.g., HC1 or H2SO4) , water and potassium bicarbonate solution. Evaporation of the solvent and trlturatlon of the residue with ethyl acetate affords 2.48 g of the title compound. Physical characteris¬ tics are as follows: Melting point 155-158°C. According to the procedures of Example 5, the following com- pounds are also prepared: cis- (±) -4- [ (Formylaminoethoxycarbonyl)oxymethylJ-3-[((phenyl¬ methoxy)carbonyl)amino] -2-azetidinone; cis- (±) -4- [ (t-Butoxycarbonylaminoethoxycarbonyl)oxymethyl] -3- [((phenylmethoxy)carbonyl)amino] -2-azetidinone; cis- (±)-4- [(Aminocarbonyloxyethoxycarbonyl)oxymethyl] -3-[((phen¬ ylmethoxy)carbonyl)amino] -2-azetidinone; and cis-(±)-4- [(Chloroethoxycarbonyl)oxyme hyl] -3- [((phenylmethoxy) - carbonyl)amino] -2- zetidinone. Example 6 cis-(±)-1-[(Chlorosulfonyl)aminocarbonyl] -4- [(methoxy- carbonyl)oxymethyl] -3- [ ( (phenylmethoxy)carbonyl) - amino] -2-azetidinone Chlorosulfonyl isocyanate (175 mg) is added dropwise to a sus¬ pension of 382 mg of cis-(±)-4- [Methoxycarbonyl)oxymethyl] -3-[((phen¬ ylmethoxy)-carbonyl)amino] -2-azetidinone in 8 ml of methylene chlor- ide while stirring in an ice bath. The bath is removed after 20 minutes and the mixture stirred at ambient conditions. Evaporation of the solvent under vacuum leaves the title compound as a glass which is used without purification. According to the procedure of Example 6, the following chloro- sulfonyl compounds are also prepared: cis-(±)-1-[(Chlorosulfonyl)aminocarbonyl] -4-[ (formylaminoethoxy- carbonyl) -oxymethyl] -3- [((phenylmethoxy)carbonyl)amino] -2-azetidin¬ one; cis-(±)-l-[ (Chlorosulfonyl)aminocarbonyl] -4- [ (t-butoxycarbonyl- aminoethoxycarbonyl) -oxymethyl] -3- [ ((phenylmethoxy)carbonyl)amino] - 2-azetidinone; cis-(±)-l-[ (Chlorosulfonyl)aminocarbonyl] -4- [ (aminocarbonyloxy- ethoxycarbonyl) -oxymethyl] -3 - [ ( (phenylmethoxy) carbonyl)amino] -2- azetidinone; and cis- (±) -1- [ (Chlorosulfonyl)aminocarbonyl] -4- [ (chloroethoxycar- bonyl)oxymethyl] -3- [ ((phenylmethoxy)carbonyl)amino] -2-azetidinone. Example 7 3-(Dimethylaminomethylene) -4-oxo-6-methyl-2-pyrone N,N-dimethylformamide dimethyl acetal (150 ml) is added dropwise to a mixture of 4-hydroxy-6-methyl-2-pyrone (100 g) in dioxane (400 ml) at 0°C over 20 minutes. The mixture is warmed to room tempera¬ ture and stirred an additional 4 hours. The precipitated solid is filtered, washed with isopropanol and dried to give 85.0 g of the title compound. The filtrate is concentrated and isopropanol (300 ml) is added to the residue. This mixture is kept at 0°C overnight to give an additional 18.8 g .of the title compound. Physical charac¬ teristics are as follows: Melting point 152-153°C. Example 8 6-Methyl-4- (1H) -pyridone-3-carboxylic acid A mixture of 3-(dimethylaminomethylene)-4-oxo-6-methyl-2-pyrone (85.0 g) and ammonium hydroxide (500 ml) is slowly heated to 70°C with the condenser outlet open. The mixture is heated at 70-80°C for 3 hours , concentrated to a volume ' of about 100 ml and acidified with 3N HC1 to pH 5. The product is filtered and washed with water and diethyl ether to give 38.6 g of the title compound. Physical charac¬ teristics are as follows: Melting point 266-268°C (dec). Example 9 6-Methyl-4- (1H)-pyridone-3-carboxylic acid benzyl ester A mixture of 6-methyl-4- (1H)-pyridone-3-carboxylic acid (L6.0 g) and carbonyldiimdazole (23.0 g) in DMF (150 ml) is heated at 55-60°C for 2 hours. The mixture is cooled to room temperature, filtered and washed with THF (50 ml) to give 20.5 g of intermediate product. The intermediate product is mixed with benzyl alcohol (20 ml) in DMF (100 ml) and cooled to 0°C. Sodium hydride (5.4 g of 50% NaH dispersed in oil) is added to the cooled mixture and the mixture is slowly warmed to room temperature. ' After 30 minutes at room temperature, acetic acid (0.5 ml) is added and the solvent is removed. The residue is partitioned between methylene chloride (500 ml) and water (100 ml) , the organic layer is dried over sodium sulfate and concentrated. Trlturatlon of the residue with diethyl ether gives 19.0 g of the title compound. Physical characteristics are as follows: IR (KBr) 1728, 1648 cm '1 . Example 10 4-0xymethoxymethyl-6-methyl-3-carboxylic acid pyridine benzyl es er Sodium hydride (2.3 g of 50% NaH dispersed in oil) is added in several portions to a slurry of 6-methyl-4- (IH)-pyridone-3-carboxylic acid benzyl ester (lO ' .O g) in DMF (70 ml) at 0°C. After 5 minutes, chloromethyl methyl ether (3.42 ml) is added to the mixture. After one hour the solvent is removed and the residue is partitioned between methylene chloride (200 ml) and water (50 ml) . The organic layer is dried over sodium sulfate, concentrated and the residue is triturated with diethyl ether to give 6.1 g of the title compound. Physical characteristics are as follows: Melting point 86-87°C. Example 11 3-Benzyloxycarbonyl-4-(IH)-pyridone-6-carboxylic acid A mixture of 4-oxymethoxymethyl-6-methyl-3-carboxylic acid pyri¬ dine benzyl ester (8.3 g) and selenium dioxide (120 ml) is heated at reflux for 2 hours. The hot reaction mixture is filtered and the solid is washed with dioxane (40 ml) . Upon cooling the filtrate solution to room temperature, the title compound precipitates to give 3.0 g. The filtrate solution is concentrated and DMF (50 ml) is added to the residue. This solution is heated briefly and filtered. The remaining solution is concentrated and ethyl acetate (100 ml) is added to the residue. Upon standing at room temperature more solid precipitates which is filtered and dried to obtain an additional 3.8 g of the title compound. Physical characteristics are as follows: Melting point 201-204° dec. Example 12 3-Benzyloxycarbonyl-4-pyridon-6-yl-3-carbonylamino-2- imidazolidinone 3-Benzyloxycarbonyl-4-(IH)-pyridone-6-carboxylic acid (400 mg) , aminoimidazolidinone (148 mg) , DMAP (50 mg) , HOBT (200 mg) and DCC (333 mg) are mixed in DMF (25 ml) at room temperature. After 16 hours the precipitated solid is filtered and the filtrate solution is concentrated under reduced pressure. The residue is washed with H 2 0/ CHC1 3 . After concentrating, the organic layer is passed through a column of silica gel eluting with 4% methanol/chloroform to obtain 320 mg of the title compound. Physical characteristics are as follows: Melting point 168-170°. Example 13 (3-Carboxy-4- yridon-6-yl)-3-carbonylamino-2-i idazo1- idinone To a solution of 3-benzyloxycarbonyl-4-pyridon-6-yl-3-carbonyl- amino-2-imidazolidinone (800 mg) in DMF (30 ml) is added Pd-black (200 mg) under one atmosphere of H gas. After one hour a small amount of toluene (5 ml) is added to the mixture and stirred for 10 minutes. The solid is filtered and the filtrate solution is concen¬ trated. The residue is triturated with ethyl acetate to obtain 500 mg of the title compound. Physical characteristics are as follows: Melting point 291-294° dec. Example 14 Compound 14, (3S) -3- [2- (2-Amino-4-thiazolyl) -Z- (2)- carboxyisopropyloxyimino)acetamido] -1- [ (3-carboxy-4- pyridon-6-yl) -carbonylamino-1- (2-imidazolidone-3- yl)sulfonylaminocarbonyl] -2-azetidinone trisodium salt Chlorosulfonylisocyanate (55 μl) is added to a heterogeneous mixture of (3S)-3-[2-(2-t-butoxycarbonylamino] -4-thiazolyl) -Z-(2-t- butoxycarbonylisopropyloxyimino)acetamido]azetidin-2-one (250 mg) in freshly distilled methylene chloride (5 ml) at -40°C. The mixture is slowly warmed to about -10°C over 30 minutes and stirred for one hour. A mixture of (3-carboxy-4-pyridon-6-yl)-3-carbonylamino-2- imidazolidinone (135 mg) and N-methyl-N- (trimethylsilyl)trifluoro¬ acetamide (0.35 ml) In anhydrous THF (4 ml) is stirred at room tem¬ perature for one and one-half hours, then the CSI adduct is added at 0°C. After 3 hours the mixture is concentrated and methylene chlor- Ide (4 ml) and cold trifluoroacetic acid (4 ml) are added. The mix¬ ture is warmed to room temperature and after one and one-half hours the mixture is concentrated and the residue is dissolved in water (60 ml) by adjusting pH of the solution to about 5.5 with aqueous sodium bicarbonate. After lyophilizing the aqueous solution, the product is purified by column chromatography on XAD-16 resin eluting with water followed by 6% acetonitrile/water to give the title compound. Physi¬ cal characteristics are as follows: IR (neat) 3180 (broad), 1770, 1726 cm -1 . Example 15 (3-Benzyloxyaminocarbonyl-4-pyridon-6-yl)-3-carbonyl- amino-2-Imidazolidinone A slurry of (3-carboxy-4-pyridon-6-yl) -3-carboxylamino-2-imida¬ zolidinone (1 g) In DMF (40 ml) Is heated at 70°C to dissolve and then cooled to about 3Q°C. Carbonyldilmidazole (670 mg) is added and the mixture is allowed to warm to ambient temperature over 2.5 hours. Benzylhydroxyamine (550 mg) is added to the mixture at room tempera¬ ture and stirred for 2 hours. The solvent is removed and the residue is shaken with methylene chloride (100 ml)/2N HCl (30 ml), filtered and dried to obtain 560 mg of the title compound. Physical charac¬ teristics are as ollows: Melting point 250-253° . Example 16 (3-Hydroxyaminocarbonyl-4-pyridone-6-yl)-3-carbonyl- amino-2-imidazolidinone (3-Benzyloxyaminocarbonyl- -pyridon-6-yl) -3-carbonylamino-2- imidazolidinone (550 mg) is mixed in DMF with Pd-black (150 mg) under one atmosphere of H 2 gas. The mixture is filtered and the filtrate solution is concentrated under reduced pressure. Trituration of the residue with methanol produces the title compound. Physical charac- teristics are as follows: Melting point 266-269°. Example 17 Compound 17, (3S)-3-[2-(2-Amino-4-thiazolyl)-Z-(2)- (carboxyisopropyloxyamino)acetamido] -1- [(3-hydroxy- aminocarbony1-4-pyridon-6-yl)carbonylamino-l--(2- imidazolidone-3-yl)sulfonylaminocarbonyl].-2-azetidin- one To a slurry of (3S) -3- [2-(2-t-butoxycarbonylamino] -4-thiazolyl)- Z-(2-t-butoxycarbonyllsopropyloxyimino)acetamido]azetidin-2-one (350 mg) in methylene chloride (5 ml) at -40°C is added chlorosulfonyliso- cyanate (77 μ ~ L) . The mixture is slowly warmed to 0°C over 2 hours. A mixture of (3-hydroxyaminocarbonyl-4-pyrldon-6-yl) -3-carbonylamino- 2-imidazolidinone (190 mg) and N-methyl-N-(trimethylsilyl)trifluoro¬ acetamide (0.5 ml) in THF (4 ml) is stirred for 2 hours at room tem¬ perature. This silylated compound is added to the CSI adduct at 0°C and the mixture is stirred for one hour. The mixture is concentrated under reduced pressure and the residue is dissolved in water by adjusting pH of the solution to about 6.1 with an aqueous sodium bicarbonate. After lyophilizing, the crude product is partially purified by XAD-16 column chromatography. The crude product is acidified by adding methylene chloride (15 ml) and trifluoroacetic acid (2 ml) and purified by means of HP-20 column chromatography eluting with H 2 0 followed by 3% acetonitrile/water and then 6% acetonitrile/water to obtain 70 mg of the title compound. Physical characteristics are as follows: IR (neat) 3200 (broad), 1782, 1723, 1666 cm -1 . Following the procedures outlined in Example 17 but using 3- aminocarbonyl-4-pyridone-6-yl) -3-carbonyl-amino-2-imidazolidinone gives Compound 18: (3S)-3-[2- (2-amino-4-thiazolyl) -2- (2)- (carboxyisopropyloxyamino- )acetamido] -1- [ (3-aminocarbonyl-4-pyridon-6-yl)carbonyl(amino-1- (2- imidazolidone-3-yl)sulfonylaminocarbonyl] -2-azetidinone. Physical characteristics are as follows: M/C (μg/ml) (pseudomonas aeruginosa Culture No. 231) 8. FORMULAS Formula I Formula II 0 STRUCTURE CHART Compound No. 17 H C(CH 3 ) 2 C0 2 H CONHOH H 14 H C(CH 3 ) 2 C0 2 Na C0 2 Na Na 18 H C(CH 3 ) 2 C0 2 C0NH 2 H CHART A A-l Cbz Lg A-5 A-2 A-3 Cbz H 2 OC(0)CH 2 NHR4 A-6 A-4 CHART A (continued) CbzONH-CO-CH(NHBOC)-C(R 10 ) (R 15 )OH A-7 A-8 A-9 A-10 CHART A (continued) A-13 A-15 A-14 CHART B B-5 CHART B (continued) B-l B-6 T B-5 TABLE I Minimum Inhibitory Concentraion ( g/ml) Culture Organism Number Compound 17 Compound!^ Staphylococcus A.ureus 9218 >128 >128 S aphylococcus Aureus 3665 >128 >128 Staphylococcus Aureus 6685 >128 >128 Streptococcus Faecalis 694 >128 >128 Streptococcus Pneumoniae 41 64 64 Streptococcus Pyogenes 152 4 4 Citrobacter Freundli 3507 0.25 0.25 Enterobacter Cloacae 9381 64 64 Enterobacter Cloacae 9382 2 0.5 Escherichia Coll 9379 0.5 0.25 Escherichia Coli 9380 0.5 0.125 Escherichia Coli 9451 0.25 0.125 Klebsiella Oxytoca 9383 4 4 Klebsiella Oxytoca 9384 0.5 0.25 Klebsiella Pneumoniae 58 0.5 0.5 Proteus Vulgaris 9679 0.125 0.06 Serratia Marcescens 6888 2 0.5 Pseudomonas Aeruginosa 231 4 0.5 Pseudomonas Aeruginosa 9191 4 1 Compound 14 is (3S) -3- [2-(2-Amino-4-thiazolyl)-Z-(2) -carboxyisoprop- yloxyimino)acetamido] -1-[(3-carboxy-4-pyridon-6-yl) -carbonylamino-1- (2-imidazolidone-3-yl)sulfonylaminocarbonyl] -2-azetidinone trisodium salt Compound 17 is (3S)-3- [2-(2-Amino-4-thiazolyl) -Z-(2) -(carboxyisoprop- yloxyamino)acetamido] -1-[(3-hydroxyaminocarbonyl-4-pyrldon-6-yl)car- bonylamino-1-(2-imidazolidone-3-yl)sulfonylaminocarbonyl] -2-azetidin¬ one

Claims: CLAIMS 1. A compound of Formula I and pharmacologically acceptable salts thereof; wherein R ø and R 5 are the same or different and are a) hydrogen, b) (Cχ-C 8 ) alkyl, c) (C 2 -C 8 ) alkenyl, d) (C 2 -C 8 ) alkynyl, e) (C 3 -C 8 ) cycloalkyl, f) phenyl optionally substituted with between 1 and 3 substit¬ uents selected from the group consisting of halogen, nitro, C -C )- alkyl, and (C -C4)alkoxy, g) benzyl optionally substituted with between 1 and 3 substit¬ uents selected from the group consisting of halogen, nitro, (C -C4)- alkyl, and (0 -C4)alkoxy, h) -CH 2 OCOCH 2 NHR4, i) -CH 2 OC0 2 R 30 , j) -CH 2 F, or k) -CHF 2 ; wherein R4 is a) hydrogen, b) -COH, or c) -CO-0-C(CH 3 ) 3 ; wherein R 30 is (C 1 -C 8 )alkyl, -(CH 2 ) 2 NH 2 , - (CH 2 ) 2 NH(CH 3 ) , -(CH 2 ) 2 NH- CO-0-C(CH 3 ) 3 , -.(CH 2 ) 2 N(CH 3 )-C0-0-C(CH 3 ) 3 , -(CH 2 ) 2 OC(0)NH 2 , -(CH 2 ) 2 C1, -(CH 2 ) 2 OCH 3 or -(CH 2 ) 2 NHCOH; wherein R 2 Q I S an acyl group derived from a carboxylic acid; wherein R 80 is -CO2R5 or -C0NRgR 7 ; wherein R5 is hydrogen or ( ^ - C^ ) alkyl; and wherein Rg and R7 are the same or different and are hydrogen, (Cγ - C^ ) alkyl, or -OH with the proviso that when Rg is OH, Ry is other than -OH. 2. A compound of claim 1 wherein R 2Q is a oximino-acyl moiety of Formula II ; wherein OR 40 40 is a) -CH 3 , b) -CH 2 C0 2 R4 , or c) -C(CH 3 ) 2 C0 2 R 41 , wherein 4 is a) hydrogen, b) (C -C4) alkyl, c) -CH(CgH 5 ) 2 , d) -CH 2 (CgH 5 ), or e) a cation; wherein R 50 is a) hydrogen, b) -C0-0-C(CH 3 ) 3 , c) -CO-0-CH 2 -(CgH 5 ), or d) -C(CgH 5 ) 3 . - 3. A compound of claim 2; wherein R o and R 5 are hydrogen, whereln R4 is hydrogen or a cation, and wherein R50 is hydrogen. 4. A compound of claim 3; wherein R g0 is C0 2 H, CONHOH or C0NH 2 . 5. A compound of claim 4; (3S) -3- [2- (2-Amino-4- thiazolyl) -Z- (2) - carboxyisopropylox imino) acetamido] -1- [ (3-carboxy-4-pyridon-6-yl) - carbonylamino -1- (2 -imidazolidone -3 -yl) sulfonylaminocarbonyl] -2- azetidinone trisodium salt, (3S) -3- [2- (2 -Amino -4 -thiazolyl) -Z-(2) - (carboxyisopropylox amino) acetamido] -1- [ (3-hydroxyaminocarbonyl-4- pyridon- 6-yl) carbonylamino -1- (2 -imidazolidone -3 -yl)sulf onylaminocar- bonyl] -2-azetidinone, or (3S) -3- [2- (2-Amino-4- hiazolyl) -Z- (2)- (carboxyisopropyloxyamino) acetamido] -1- [ (3-aminocarbonyl-4-pyridon-6- yl) carbonylamino -1- (2- imidazolidone-3-yl)sulfonylaminocarbonyl] -2- azetidinone .

Inventors: KIM KYOUNG S, KIM, KYOUNG, S.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1988
Main classification: C07D417
IPC codes: A61K31, A61P31, C07D205, C07D213, C07D401, C07D417