EP0221954A1 - Monobactames substitues par du carbonate servant d'antibiotiques - Google Patents

Monobactames substitues par du carbonate servant d'antibiotiques

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Publication number
EP0221954A1
EP0221954A1 EP19860903066 EP86903066A EP0221954A1 EP 0221954 A1 EP0221954 A1 EP 0221954A1 EP 19860903066 EP19860903066 EP 19860903066 EP 86903066 A EP86903066 A EP 86903066A EP 0221954 A1 EP0221954 A1 EP 0221954A1
Authority
EP
European Patent Office
Prior art keywords
oxymethyl
amino
thiazolyl
silyl
azetidinone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19860903066
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German (de)
English (en)
Inventor
Barney J. Magerlein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0221954A1 publication Critical patent/EP0221954A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • This invention concerns novel 2-oxoazetidine analogs (monobactams) having antimicrobial activity, novel processes to make monobactams and novel intermediates.
  • Analogs of 2-oxoazetidine derivatives having antimicrobial activity are known in the art. Takeda, European Patent Applications 53-815 and 53-816. Squibb, U.S. Patent 4,478, 749 and European Patent Application 76-7582A. Among the known monobactam analogs are those containing an 0-substituted 2-aminothiazolyl-2-hydroxyiminoacetamido group on the C-3 position of the monobactam ring. Roussel UCLAF, European Patent Application 114-128-A. Various substituents have been described for the C-4 position of the monobactam ring. Takeda Patent Application EP 53-816. However, no publication, patent or patent application known to applicant describes or suggests the substituted monobactams disclosed herein.
  • the present invention concerns novel carbonate substituted 2-oxo ⁇ azetidine analogs and their use as microbial growth inhibitors. Novel intermediates and processes are also disclosed.
  • the present invention provides for both “racemic” mixtures and optically active isomers of compounds of Formula I wherein: R 1 is an acyl group derived from a carboxylic acid;
  • A is either sulfo, phosphono or a trisubstituted silyl group substituted with (C 1 -C 4 ) alkyls or phenyl; and, R 2 is selected from the group consisting of: a. (C 1 -C 8 ) alkyl, b. (C 2 -C 8 ) alkenyl, c. (C 3 -C 8 ) alkynyl, d. (C 3 -C 8 ) cycloalkyl, e. (C 6 -C 8 ) aryl, f. (C 6 -C 12 ) aralkyl, and g.
  • each member (a) through (g) may be substituted by 1 to 4 substituents selected from the group consisting of methoxy, hydroxy, halogen, nitro, and -N(R 10 )(R 11 ) wherein R 10 is hydrogen or alkyl (C 1 -C 4 ) and R 11 is hydrogen, alkyl (C 1 -C 4 ) or alkoxy (C 1 - C 4 ) provided that when R 11 is alkoxy, R 10 must be hydrogen; and, h.
  • substituents selected from the group consisting of methoxy, hydroxy, halogen, nitro, and -N(R 10 )(R 11 ) wherein R 10 is hydrogen or alkyl (C 1 -C 4 ) and R 11 is hydrogen, alkyl (C 1 -C 4 ) or alkoxy (C 1 - C 4 ) provided that when R 11 is alkoxy, R 10 must be hydrogen; and, h.
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 4 ) alkyl, (C 2 -C 3 ) alkoxyalkyl, and (C 2 -C 4 ) alkylcarbonyl or X is (C 2 -C 4 ) alkylcarbonyl ⁇ araino.
  • acyl groups included in R 1 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 ⁇ -Lactam Antibiotics, Vol. 1, R.B. Morin and M. Gorham, ed., Academic Press, N.Y. 1982 and include the following list: 2-Cyanoacetyl,
  • R 1 substituents are the substituted aminothiazolyl oxime carbonyl substituents shown in formula II wherein:
  • R 4 is selected from the group consisting of: (C 1 -C 4 ) alkyl, (C 2 -C 3 ) alkenyl, (C 3 -C 4 ) alkynyl or substituted (C 1 -C 4 ) alkyl such that substituted refers to 1 to 3 members of the following groups, amino, bromo, carboxy, chloro, cyano, fluoro, hydroxy, (C 2 -C 4 ) alkoxy carbonyl, aminocarbonyl,
  • R 5 is selected from the group consisting of: hydrogen, t-butoxy ⁇ carbonyl, phenylmethoxycarbonyl, and triphenylraethyl.
  • the preferred compounds are the C-3 and C-4 cis isomers of: 3-[2-(2-amino-4-thiazolyl)-(Z)-2-carboxymethoxyiminoacetamido]-4-[(methoxycarbonyl)oxymethyl]-2-oxo-1-azetidinesulfonic acid and the potassium salt thereof;
  • isomers of the above eleven compounds wherein the absolute configuration with respect to carbon centers 3 and 4 is 3(S) and 4(S).
  • Alkyl refers to an aliphatic hydrocarbon radical either branched or unbranched such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or the like.
  • Alkoxy refers to an alkyl radical which is attached to the remainder of the molecule by oxygen such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or the like.
  • Alkenyl refers to a radical of an aliphatic unsaturated hydrocarbons having a double bond and includes both branched and unbranched forms such as vinyl, allyl, isoproponyl, 2-methallyl, 2-butenyl, 3-butenyl or the like.
  • Alkynyl refers to a radical of an aliphatic unsaturated hydrocarbons having a triple bond and includes both branched and unbranched forms such as 1-propynyl, 2-propynyl, or the like.
  • Aralkyl refers to a radical in which an aryl group is substituted for a hydrogen atom of an alkyl such as benzyl, phenylethyl, phenyl ⁇ propyl, diphenylmethyl, fluorenylmethyl and the like.
  • Aryl refers to a radical derived from an aromatic hydrocarbon by removal of one hydrogen atom such as phenyl, ⁇ -naphthyl, 13-naphthyl, biphenyl, anthryl and the like.
  • Cycloalkyl refers to a radical of a saturated hydrocarbon in a ring structure such cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and the like.
  • Heterocyclic radical refers to 5 to 8-membered heterocyclic rings having one to a few hetero-atoms such as nitrogen (inclusive of N-oxide), oxygen and sulfur, as well as fused rings corresponding thereto, which have an available bonding site at a carbon atom thereof.
  • heterocyclic group which are usually advantageous include 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolidinyl, 2-, 3- or 4-pyridyl, N-oxido-2-, 3- or 4-pyridyl, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyranyl, pyrazinyl, 2-, 4- or 5- thiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, piperazinyl, 4- or 5-(1,2,3-thiadiazolyl), 3- or 5-(1,2,4-thiadiazolyl), 1,3,-4-thiadiazolyl, 1,2,5-thiadiazolyl, 4- or
  • the scope of this invention includes the pharmaceutically 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, tetralkylammonium and pyridinium.
  • MIC minimum inhibitory concentration
  • MFT Method for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically
  • the various bacterium used for testing are grown overnight on MHA at 35°C and transferred to Trypticase soy broth (TSB) until a turbidity of 0.5 McFarland standard is obtained .
  • the bacterium are diluted one to twenty in TSB and inoculated on the plates (1 ⁇ l using a Steers replicator ) .
  • 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 compounds of this invention are found in Table 1 .
  • the starting compound, cis-( ⁇ )-4-(methoxycarbonyl )-2-oxo-3-[[(phenyl ⁇ methoxy ) car bonyl]amino]-1 -azeti dine ( 1 ) is known . J . Org . Chem . 47 :2765-2767, 1982. It may be cis or trans wi th respect to the substituents on positions 3 and 4.
  • Step 1 the nitrogen at position 1 is protected.
  • Silylation is preferred.
  • Silylating agents (B 2 ) well known in the art may be used.
  • a trialkylsilyl chloride or an arylalkylsilyl chloride in the presence of an organic base is used.
  • the reaction is conducted at a temperature of about 0 to 25° C for a period of about 1 to 5 hours in any of several anhydrous solvents , e .g .
  • Step 2 the protected amino azetidinone (2) is reduced to give the compounds (3) .
  • the reaction is conducted in the presence of a metal hydride at a temperature range of 0° to room temperature for times of 2 to 5 hours .
  • the preferred method is to treat compounds (2) with lithium borohydride in anhydrous tetrahydrofuran under cold conditions for several hours .
  • Compounds ( 3) can be obtained from the reaction mixture by conventional methods such as crystallization, or column chromatography, and combinations thereof .
  • Compounds (3) can be directly used in Steps 1 or 3 of Chart 2.
  • the benzyloxycarbonyl substituent of compounds (3) can be hydrogenolysed and replaced with alternative blocking groups B 1 to yield compounds (4) .
  • These alternative steps become preferred when removal of the benzyloxycarbonyl is not practical by hydrogenolysis because other substituents will be simultaneously and undesirably reduced or when a substituent may poison the hydrogenolysis catalyst.
  • Step 3 of Chart 1 hydrogenolysis of the C-3 acyl amino substituent (eg. benzyloxycarbonyl) of compounds (3) is carried out in the presence of palladium-black or palladium on a support such as carbon under hydrogen gas to give a 3-amino compound.
  • These amino compounds are then acylated with blocking groups , B 1 , to obtain compounds (4) .
  • the acylation with B 1 can be achieved by the use of the various organic reagents known in the art , such as di-t-butyldicarbonate , t-butoxycarbonyl, or 9-fluorenylmethoxycarbonyl .
  • acylation is preferably achieved by use of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole at cold temperature .
  • compounds (2) may be acylated before reduction such that steps 2 and 3 of Chart 1 are reversed.
  • Step 1 the alcohol compounds (3) or (4) from Chart 1 are treated with a chlorof ormate ester of the formula CICOOR 2 where R 2 is def ined as above to give the carbonate compounds ( 6) .
  • This is the preferred route to compounds (6) .
  • the reaction conditions involve the use of an. inert solvent such as methylene dichloride , tetrahydrof uran , or dimethylformamide at -20°C to 30°C in the presence of a slight excess of organic base, such as pyridine, 2,4-lutidine, or triethyl amine.
  • organic base such as pyridine, 2,4-lutidine, or triethyl amine.
  • Steps 2 and 3 an alternative process to compounds (6) is presented. This process is helpful when the desired chloroformate is unavailable.
  • compounds (3) or (4) are placed in a solvent such as methylene dichloride, ethyl acetate, tetrahydrofuran, or acetonitrile containing a slight excess of an organic base, such as pyridine, triethylamine, or 2,4-lutidine.
  • a solvent such as methylene dichloride, ethyl acetate, tetrahydrofuran, or acetonitrile containing a slight excess of an organic base, such as pyridine, triethylamine, or 2,4-lutidine.
  • the solution is treated at -20°C to 30°C with a solution of phosgene in an inert solvent, such as toluene, benzene or methylene chloride.
  • Step 4 carbonate compounds (6) are unblocked to an intermediate amine.
  • the preferred process is dependent upon the blocking group (B 1 ) that is present.
  • the substrate is dissolved in a suitable solvent such as tetrahydrofuran, ethyl acetate, dimethyl formamide, methanol, or ethanol.
  • Hydrogenolysis in the presence of a hydrogenation catalyst, such as palladium black or palladium on a support, such as carbon is accomplished by shaking or stirring in an atmosphere of hydrogen, preferably of less than 3 atm.
  • a hydrogenation catalyst such as palladium black or palladium on a support, such as carbon
  • the catalyst is removed by filtration and the filtrate contains a solution of amine (7).
  • B 1 is t-butoxycarbonyl
  • this blocking group must be removed by acid , such as trifluoroacetic acid , and the amine isolated by evaporation of the reaction mixture.
  • B 1 is 9-fluorenylmethoxycarbonyl
  • the amine may be obtained by treatment with an organic base , such as piperidine or morpholine. Isolation of amine (7) then may require chromatography. Amines (7) need not be isolated.
  • the total reaction product can be used for conversion to carbonate (8) in Step 5. In Step 5, amines (7) are converted to the amides (8) where R 1 is as defined above .
  • This conversion may be carried out by any of a number of amide or peptide forming reaction sequences such as described in Methoden der Organischem Chemie , Vsammlung Auflage , Band XV/2, E. Wunch ed. , Georg Thieme Verlag, Stuttgart , p 1 .
  • a preferred acylation process is the use of approximately molar quantities of a desired acid, 1-hydroxy ⁇ benzotriazole, and a carbodiimide , such as dicyclohexylcarbodiimide .
  • These reagents are added to the solution of the amine in a solvent, such as tetrahydrof uran , dimethylformamide , or acetonitrile.
  • a temperature of 0°C - 60°C is operative , with 20-35 °C preferred.
  • the time of reaction is variable from 0.5-24 hr being required, although usually 3-4 hr is sufficient.
  • a precipitate of dieyclohexylurea is formed during the reaction. This is removed by filtration.
  • the amides (8) are isolated from the f iltrate by extractive procedures and chromatography.
  • R 1 may require blocking groups such as t-butoxycarbonyl , t-butyl , or triphenylmethyl to avoid formation of undesirable sulfonates during Step 6.
  • the amides ( 8) are sulfonated at N-1 .
  • the amides (8) are dissolved or suspended in a suitable solvent such as dimethylformamide or methyl ene dichloride and 1 -3 equivalents of a sulfonating agent added.
  • the preferred reagent is dimethylformamide-sulfur trioxide complex usually used as an approximately 1 molar solution in dimethyl formami de , K . Hofman and G . Simchen , Synthes is , 699-700 ( 1 979) . Pyridine-SO 3 complex is also operative .
  • reaction mixture is diluted with water or phosphate buffer , n-tetra ⁇ butylammonium bisulfate added, and the sulfonated azetidine (9) is extracted with a water immiscible solvent , such as methylene dichloride .
  • a water immiscible solvent such as methylene dichloride .
  • any blocking groups on R 1 are generally removed by treatment with acid .
  • an excess of trifluoroacetic acid is added to a solution of the substrate while stirring in an ice bath.
  • the residue resulting from evaporation of the sol vent af f ords the n-tetrabutylammonium salt whi ch is dissolved in water (a small volume of methanol may be added to hasten solution) and passed through a column of Dowex-50 resin in the K+ form.
  • This eluant now as the potassium salt , is passed over a column of HP-20 resin (Mitsubishi Chemical Industries ) . This column is eluted and combined as described in the experimental section resulting in the obtention of monobactam (9) .
  • Optically active isomers of the disclosed compounds are resolved by methods known in the art . Takeda European patent application 8310461 -3. Typically the separation of enantiomers is carried out by forming salts with enantiomers of a tartaric acid and taking advantage of the difference In solubility between the resulting diastereomers .
  • the starting compound, cis-( ⁇ )-1 [ (2,4-dimethoxyphenyl )methyl] -4- (methoxycarbonyl )-3-benzyl ⁇ oxycarboxyamido-2-azetidinone is known. Chem . Pharm. Bull . 32 :2646-2659 (1 984) .
  • the protecting group of the nitrogen bonded to C-3 is removed by hydrogenolysis to the corresponding free amine .
  • An appropriate substituted tartaric acid enantiomer is added such as. ( + )-di-p-toluoyl- D-tartaric acid and reaction conditions altered to facilitate precipitation of the appropriate azetidinone enantiomer salt .
  • the tartaric acid is removed by treating the compound with inorganic base such as sodium bicarbonate to obtain the C-3 free amino azetidinone which is then used as a starting material in the processes represented by Charts 1 and 2.
  • the compounds of Formula I have broad spectrum antimicrobial activity. They are useful as surface sterilants and as additives to products where microbial populations are sought to be limited, e .g. , animal feed .
  • the compounds of Formula I are also effective for treating bacterial infections in mammals , including humans .
  • 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 solutions or suspensions , eye drops , solutions or suspensions , and water-in-oil emulsions containing suitable quantities of compounds of Formula I .
  • unit dosage forms are prepared util izing the compound and a sterile vehicle , water being preferred.
  • the compound depending on the vehicle and concentration used , can be either suspended or dissolved in the vehicle.
  • the compound in preparing solutions the compound can be dissolved in water for inj ection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after f illing into the vial and the water removed under vacuum.
  • the dry lyophilized 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 ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the coraposition 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.
  • 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.
  • 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 suitable carrier.
  • 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, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate. These rectal suppositories can weigh from about 1 to 2.5 gm.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals, as disclosed in detail in this specification, these being features of the present invention.
  • suitable unit dosage forms in accord with this invention are tablets, capsules, pills, suppositories, powder packets, wafers, granules, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampoules, 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 example, 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, administered parenterally or in the compositions of this invention, are effective for treating bacterial infections. More specifically, the single dose is from about 100 mg to 2000 mg of compound.
  • the rectal dose is from about 100 mg to about 4000 mg in a single dose. More specifically, the single dose is from about 100 mg to about 2000 mg of compound. It is expected that the dosages can be given one to four times per day.
  • Preparation 1 provides methods for placing various substituted silyl groups (B 2 ) on compound (1), cis( ⁇ )-4-methoxycarbonyl-3-[[(phenylmethoxy)-carbonyl]amino]-2-azetidinone.
  • the precipitated solid is filtered and the filtrate solution is concentrated under reduced pressure.
  • the residue is dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the title compound (2).
  • the crude solid product is used directly for the next step without any further purification.
  • the reaction mixture is washed successively, diluted with methylene dichloride and with dilute hydrochloric acid, water and potassium bicarbonate solution. After drying over sodium sulfate, the solution is evaporated to yield a crude product.
  • the crude product is purified by chromatography over 40 g of silica gel (Skellysolve-B-ethyl acetate, 4:1) to yield the title compound which forms a crystalline mass.
  • Lithium borohydride (1.47 g) is added with stirring to a solution of cis-(+)-1-t-(butyldimethyl)silyl-4-methoxycarbonyl-3-[[2-(phenylmethoxy)carbonyl]amino]-2-azetidinone (2), (6.907 g, 17.5 mmol) in 50 ml of anhydrous tetrahydrof uran at 0°C. The reaction mixture is stirred at 0°C for 4 hours and then is quenched by adding acetic acid (16 ml) dissolved in 50 ml ethyl acetate followed by an aqueous sodium bicarbonate solution.
  • Method A Methyl chloroformate (2.0 ml, 25.8 mmol) is added dropwise while cooling in an ice bath to a solution of 1.092 g (3 mmol) of cis-( ⁇ )-1-(t-butyldimethyl))silyl-4-hydroxymethyl-3-[[(phenylmethoxy)-carbonyl]amino]-2-azetidinone (3) in 25 ml of methylene dichloride and
  • Phosgene in toluene (0.87 ml of a 1.26 M solution of phosgene in toluene) (1.10 mmol) is added dropwise while stirring in an ice bath to a solution of 58 mg (0.58 mmol) of triethylamine and 200 mg (0.55 mmol) of cis-( ⁇ )-3-amino-1-(t-Butyldimethyl)silyl-4-hydroxyraethyl-2-azetidinone (4) is 5 ml of tetrahydrof uran.
  • Thin layer chromatography on silica gel shows the absence of carbonate (6) and the appearance of a more polar, ninhydrin positive spot, i.e., cis-( ⁇ )-3-amino-1-(t-butyldimethyl)silyl-4-[(methoxycarbonyl)oxymethyl]-2-azetidinone (7).
  • the catalyst is removed by filtration.
  • Triphenylmethylchloromethane (742 mg, 2.66 mmol) is added, while stirring in an ice bath, to a solution of 1.45 g (2.42 mmol) of cis- ( ⁇ )-1-(t-butyldlmethyl)silyl-4-[(methoxycarbonyl)oxymethyl]-3-[2-(2-amino-4-thiazolyl)-(Z)-2-[1-methyl-1-(t- butoxycarbonyl)]ethoxyimino ⁇ acetamido]-2-azetidinone, from preparation 5, compound (b), in 10 ml of pyridine. After 2 hours the pyridine is evaporated in vacuo.
  • Example 1 cis-( ⁇ )-3-[2-(2-Amino-4-thiazolyl)-(Z)-2-carboxymethoxyiminoacetamido]-4-[(methoxycarbonyl)oxymethyl]-2-oxo-1- azetidinesulfonic Acid, Potassium Salt.
  • the reaction mixture is poured into 480 ml of 0.5 M monobasic potassium bi phosphate solution. Tetrabutyl' ammonium bisulfate (1.75 g, 5.15 mmol) is added.
  • the aqueous solution is extracted four times with 125 ml of methylene dichloride.
  • the combined extracts are washed with water, dried, and evaporated.
  • the residue is dissolved in 36 ml of 70% formic acid. After 45 minutes at ambient temperature the solution is evaporated under vacuum. Water is added to the residue and the solvent is evaporated again. The residue is warmed for a few minutes with 38-5 ml of water.
  • the solution is filtered to remove a small amount of gummy residue.
  • Example 2 Additional amounts of Example 2 are obtained by passing the mother liquors from the filtration of crystals through a column of 190 ml of HP-20 resin. The resin is eluted with 570 ml of water followed by 380 ml portions of 10% aqueous acetone and 380 ml of 20% aqueous acetone.
  • optically active title compound is obtained by resolving the enantiomers of cis-( ⁇ )-3-benzyloxycarboxamido-4-methoxycarbonyl-1-(2,4-dimethoxybenzyl)-2-azetidinone. Chem. Pharm. Bull. 32:2646-2659 (1984).
  • 1 UC is a registered trademark of The Upjohn Company.
  • 2Compound A is cis-( ⁇ )-3-[2-(2-amino-4-thiazolyl)-(Z)-2-carboxymethoxy iminoacetamido]-4-[(methoxycarbonyl)oxymethyl]2-oxo-1-azetidinesulfonic acid, potassium salt; and
  • Compound B is cis-( ⁇ )-3-[2-(2-amino-4-thiazolyl)- (Z)-2-methoxyiminoacetamido]-4-[(methoxycarbonyl)oxymethyl]-2-oxo-1-azetidinesulfonic acid, potassium salt.
  • FORMULAS cis-( ⁇ )-3-[2-(2-amino-4-thiazolyl)-(Z)-2-carboxymethoxy iminoacetamido]-4-[(methoxycarbonyl)oxymethyl]2-oxo-1-azetidines

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  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention se rapporte à des composés analogues de 2-oxoazétidine (monobactames) présentant une activité antimicrobienne, à des procédés nouveaux et à des produits intermédiaires nouveaux utiles dans la fabrication de monobactames. Les composés de la présente invention comprennent des composés de la formule (I) ou un sel pharmaceutiquement acceptable desdits composés, où R1 est un groupe acyle dérivé d'un acide carboxylique; A est un groupe sulfo, phosphono ou silyle trisubstitué, substitué avec (C1-C4) alkyles ou phényle; R2 est un hydrocarbure aliphatique, un hydrocarbure alicyclique ou un radical hétérocyclique pouvant être tous les trois substitués ultérieurement.
EP19860903066 1985-05-09 1986-04-25 Monobactames substitues par du carbonate servant d'antibiotiques Withdrawn EP0221954A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73246585A 1985-05-09 1985-05-09
US732465 1985-05-09

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EP0221954A1 true EP0221954A1 (fr) 1987-05-20

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EP19860903066 Withdrawn EP0221954A1 (fr) 1985-05-09 1986-04-25 Monobactames substitues par du carbonate servant d'antibiotiques

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EP (1) EP0221954A1 (fr)
JP (1) JPS62502825A (fr)
WO (1) WO1986006722A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990003376A1 (fr) * 1988-09-27 1990-04-05 The Upjohn Company Monocarbames a substitution dihydroxyaryle en position 4 pour utilisation en tant qu'antibiotiques

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE24726T1 (de) * 1981-10-05 1987-01-15 Squibb & Sons Inc 4-aether-derivate von 2-azetidinon-1-sulfonsaeuren.
FR2515182B1 (fr) * 1981-10-23 1986-05-09 Roussel Uclaf Nouveaux produits derives de l'acide 3-amino 2-oxo azetidine 1-sulfamique, leur procede de preparation, leur application comme medicaments et les produits intermediaires necessaires a leur preparation
EP0096297B1 (fr) * 1982-06-03 1988-06-15 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé de préparation de dérivés de 1-sulfo-2-oxoazétidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8606722A1 *

Also Published As

Publication number Publication date
JPS62502825A (ja) 1987-11-12
WO1986006722A1 (fr) 1986-11-20

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