EP0368908A1 - $g(b)-LACTAMES D'UTILITE THERAPEUTIQUE - Google Patents

$g(b)-LACTAMES D'UTILITE THERAPEUTIQUE

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Publication number
EP0368908A1
EP0368908A1 EP88906676A EP88906676A EP0368908A1 EP 0368908 A1 EP0368908 A1 EP 0368908A1 EP 88906676 A EP88906676 A EP 88906676A EP 88906676 A EP88906676 A EP 88906676A EP 0368908 A1 EP0368908 A1 EP 0368908A1
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EP
European Patent Office
Prior art keywords
amino
compound
hydroxy
methyl
hydrogen
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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.)
Pending
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EP88906676A
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German (de)
English (en)
Inventor
Kyoung Soon Kim
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • This invention encompasses novel 2-azetidinone compounds containing chiral aminopyrazolidinones which have useful antimicrobial activity.
  • European Patent Application 0053816 discloses 2-azetidinone compounds substituted at the C 4 position with an organic residue.
  • Patent 905502A disclose sulfonylaminocarbonyl-2-azetidinones containing an imidazolidonylaminocarbonyl-2-(1,4-dihydro-5-hydroxy-4-oxo)pyridine in the activating group. None of the above documents discloses a substituted sulfonylaminocarbonyl-2-azetidinone which has a chiral aminopyrazolidmone in the activating group.
  • the present invention teaches novel 2-azetidinone analogs containing chiral aminopyrazolidinones which are useful as microbial growth inhibitors.
  • This invention includes enantiomers, diastereomeric and racemic mixtures of these compounds. Intermediates 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 pharmaceutically acceptable salts thereof; wherein R 1 and R 2 are the same or different and are a) hydrogen, b) (C 1 -C 12 ) alkyl, c) (C 2 -C 8 ) alkenyl, d) (C 2 -C 8 ) alkynyl, e) (C 3 -C 10 ) cycloalkyl, f) phenyl optionally substituted with from one to 3 substituents selected from the group consisting of halogen, hydroxy, amino, nitro, (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy, g) benzyl optionally substituted with from one to 3 substituents selected from the group consisting of halogen, hydroxy, amino, nitro, (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy, h) -CH
  • 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 R 4 is -CHO and -CO-O-C(CH 3 ) 3 ; wherein R 5 is -(CH 2 ) 2 -NH-CO-O-C(CH 3 ) 3 , -(CH 2 ) 2 -
  • acyl groups Included In R 3 is found in United States 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 3 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.
  • Preferred compounds within the scope of this invention include compounds wherein the organic acid derivative, R 3 , is an oximinoacyl moiety represented by Formula III; wherein R 8 is a) -CH 3 , b) -CH 2 -CO 2 -R 9 , c) -C(CH 3 ) 2 -CO 2 -R 9 , d) - CH(CH 3 ) -CO 2 -R 9 , e) -C (CH 2 ) -CO 2 -R 9 , f) X 1 -CO 2 -R 9 , g) - CH 2 -CO-NHOH, or h) -C (CH 3 ) 2 -CO-NH0H; wherein X 1 is 1,1-cyclopropylidene; 1,2-cyclopropylene, 1,1-cyclobutylidene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,1,-cyclopentylidene, 1,2,-cyclopenty
  • Novel compounds within the scope of this invention containing an oximinoacyl moiety represented by Formula III which are useful as intermediates to 2-azetidinone analogs having microbial growth inhibition include compounds wherein R 9 is (C 1 -C 4 ) alkyl, -CH(C 6 H 5 ) 2 , or -CH 2 (C 6 H 5 ); and wherein R 10 is -CO-O-C(CH 3 ) 3 , -CO-O-CH 2 - (C 6 H 5 ), or -C(C 6 H 5 )3.
  • the compounds of this invention are identified in two ways: by the descriptive name and by numerical Identification which corresponds to the appropriate structure contained in the structure charts. In appropriate situations, the proper stereochemistry Is represented in the structure charts as well.
  • 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-propenyl, 2-propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 2-methyl-1-butenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3 -methyl-1-pentenyl, 3- methyl-2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1- methyl-4-hexenyl, 3-methyl-1-hexenyl, 3-methyl-2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyl-4-heptenyl, 3-methyl-1-hexenyl, 3-methyl-2-hexen
  • Alkynyl refers to a radical of an aliphatic unsaturated hydrocarbons having a triple bond and includes both branched and unbranched forms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 2-methyl-1-butynyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3 -methyl-1-pentynyl, 3- methyl-2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1- methyl-4-hexynyl, 3-methyl-1-hexynyl, 3-methyl-2-hexynyl, 1-heptynyl, 2-he ⁇ tynyl, 3-heptynyl, 4-heptynyl, 1-methyl-4
  • Aryl refers to a radical derived from an aromatic hydrocarbon atom such as phenyl, methylphenyl, dimethylphenyl, ⁇ -naphthyl, ⁇ - naphthyl, biphenyl, or anthryl.
  • Cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or adamantyl.
  • Halogen refers to a radical of fluorine, chlorine, bromine, or iodine.
  • the preferred orientation is cis at centers 3 and 4 and the preferred stereochemistry at C 3 and C 4 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 ⁇ -lactam ring.
  • the scope of this invention includes the pharmaceutically acceptable acid salts of the disclosed compounds. Acid salts are formed by reacting the compounds described herein with the appropriate acid in a suitable solvent.
  • Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, hydrobromic, hydroiodic, acetic, lactic, citric, succinic, benzoic, salicylic, palmoic, cyclohexansul- famic, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, or maleic.
  • 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, tetralkyl- ammonium and pyridinium.
  • Metal salts are formed by suspending the compounds 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 pharmaceutically 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 preferably 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 methods described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically" (M7-A) Published December 1985 by the National Committee for Clinical Laboratory- Standards, 771 East Lancaster Avenue, Villanova, PA 19084.
  • MIC minimum inhibitory concentration
  • MIC values are determined in unsupplemented Mueller Hinton Agar (MHA).
  • MHA Mueller Hinton Agar
  • the compounds tested are diluted serially into molten MHA at 47°C.
  • the agar is poured into petri dishes and allowed to harden.
  • the various bacteria used for testing are grown overnight on MHA at 35°C and transferred to Tryptiease Soy Broth (TSB) until a turbidity of 0.5 McFarland standard is obtained.
  • the bacteria 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 four typical compounds of this invention, Compounds 60(b), 60(d), 60(m) and 60(p) are given in Tables I and II.
  • 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 emulsions containing suitable quantities of compounds of Formula I.
  • solid or fluid unit dosage forms can be prepared.
  • the compounds of this invention are mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and/or functionally similar pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
  • the compounds of this invention are dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholic vehicle such as ethanol, suitable 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.
  • fluid unit dosage forms are prepared utilizing 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 injection 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 filling 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 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.
  • 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 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.
  • 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 g.
  • 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 the unique characteristics of the active material and the particular effect to be achieved and 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, table- spoonfuls, 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 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.
  • the single dose is from about 100 mg to 2000 mg of compound.
  • the dosages are given one to four times per day.
  • Charts A, B, and C The requirements for protecting groups in the processes 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 disclosed herein. It is recognized that conditions for introduction and removal of protecting groups should not detrimentally alter any other groups in the molecule. Examples of suitable nitrogen protecting groups are:
  • trialkylsilyl such as trimethylsilyl or t-butyldimethylsilyl
  • t-BOC or BOC t-butoxycarbonyl
  • Cbz benzyloxycarbonyl
  • trifluoroalkanoyl such as trifluoroacetyl or trifluoropropionyl
  • diphenyl(methyl)silyl
  • the Cbz group can be selectively 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, B, and C.
  • the substituents at the C 4 position in the ⁇ -lactam ring defined by R 1 and R 2 are prepared by procedures outlined in Chart A.
  • the starting compound cis-( ⁇ )-4-(methoxycarbonyl)-3-[[(benzyloxy)carbonyl]amino]-2-azetidinone, A-1 is known. J. Org. Chem., 2765-2767 (1982).
  • the trans compound is known or is made by known methods.
  • compound A-1 is either cis or trans with respect to the substituents on C 3 and C 4 .
  • the C 4 -carbomethoxy group of compound, A-1 is reduced to the C 4 -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 temperature range of 0° to 80°C.
  • metal hydride reducing reagents such as sodium borohydride or zinc borohydride
  • ether solvents such as diethyl ether or tetrahydrofuran
  • the hydroxymethyl group of compound, A-2 reacts with HO 2 CCH 2 - NHR 4 , wherein R 4 is -CHO or -BOC, to produce compound A-4 using approximately equimolar quantities of the acid, 1-hydroxy-1-benzotriazole (HOBT), and a carbodiimide, such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC) and a catalytic amount of 4- dimethylaminopyridine.
  • HOBT 1-hydroxy-1-benzotriazole
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • 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 a
  • 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 presence of a slight excess of organic base, such as pyridine, 2 ,4-lutidine, or triethylamine.
  • organic base such as pyridine, 2 ,4-lutidine, or triethylamine.
  • 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.
  • 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
  • the intermediate chloroformate thus formed is not isolated, but is treated with a molar equivalent of the suitably protected desired alcohol, R 5 OH, where R 5 is -(C 1 - C 8 )alkyl, - (CH 2 ) 2 NHBOC, -(CH 2 ) 2 -N(CH 3 )BOC, -(CH 2 ) 2 OC(O)NH 2 , -(CH 2 )- 2 Cl, -(CH 2 ) 2 OCH 3 or - (CH 2 ) 2 NHCHO, in the presence of an organic base in an inert solvent at -20°C to 30°C to yield the compound, A-3.
  • R 5 is -(C 1 - C 8 )alkyl, - (CH 2 ) 2 NHBOC, -(CH 2 ) 2 -N(CH 3 )BOC, -(CH 2 ) 2 OC(O)NH 2 , -(CH 2 )- 2 Cl, -(CH 2 ) 2
  • R 1 or R 2 are alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted phenyl or 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 a known nucleophiles by methods known in the art to give compound A-6 wherein R' Is alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted phenyl or benzyl or fluoroalkyl.
  • 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 ⁇ -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.
  • Optically active compounds of Formula I are prepared by the use of the appropriate optically active form of compound, A-1, 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-toluoyl- tartaric acid, tartaric acid, and diacetyl tartaric acid which are commercially available and which are commonly used for resolution of amines. See Organic Synthesis, Coll. Vol. V., p. 932 (1978) which describes the resolution of R-(+) and S-(-)- ⁇ -phenyl-ethylamine with (-)-tartaric acid.
  • the preferred starting compound for making optically active compounds 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 conditions altered to facilitate precipitation of the appropriate azetidinone 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.
  • Pyrazolidinones represented by A-20 are prepared from serine when R 6 or R 7 are hydrogen or from threonine when one of R 6 or R 7 is methyl as outlined in Chart C.
  • the stereochemistry at the C 4 position of the pyrazolidinone ring is determined by the use of either D or L, serine or threonine, as the starting material.
  • the amino acid is protected with a t-butoxycarbonyl group using procedures well known in the art to give compound C-2.
  • the protected amino acid reacts with tosyl chloride in pyridine to give the tosyl ester, C-3, which cyclizes in the presence of hydrazine to give the desired pyrazolidinone, A-20, which is purified by column chromatography, recrystallization or methods known to those skilled in the art.
  • Chart B Alternative procedures to complete the rest of the molecule are outlined in Chart B.
  • the benzyloxycarbonyl group of compound B-1 is removed by catalytic hydrogenolysis using palladium metal supported on carbon or palladium metal itself under a hydrogen gas atmosphere in suitable solvents, such as alcoholic solvents, ether solvents or ethyl acetate, at ambient temperature.
  • suitable solvents such as alcoholic solvents, ether solvents or ethyl acetate
  • 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, Vsammlung Auflage, Band XV/2 , E. Wunch ed., Georg Thieme Verlag, Stuttgart, p.l.
  • a preferred acylatlon process is the use of approximately equimolar quantities of a desired acid, HOBT, and a carbodiimide, such as DCC or DIC.
  • 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 HBOT by washing with aqueous sodium bicarbonate solution and column chromatography on silica gel if necessary.
  • 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 0oC
  • organic solvents such as methylene chloride, acetonitrlle or a combination of both solvents to produce the activated azetidinone B-4 which is coupled to a silylated intermediate prepared by reacting N-methyl-N-(trimethylsilyl)- trifluoroacetamlde or bis-(trimethylsilyl)-trifluoroacetamide with a suitable pyrazolidinonylaminocarbonylheterocycle, A-23, in organic solvents, such as acetonitrlle, methylene chloride or tetrahydrofuran, at ambient temperature.
  • the silylated intermediate reacts with compound B-4, optionally in the presence of a tertiary amine base such as 2,6-lutidine, at about 0°C and the mixture is stirred at 0° or slowly warmed to room temperature over a period of one to 5 hours.
  • a tertiary amine base such as 2,6-lutidine
  • Example 1 cis-( ⁇ )-4-(Hydroxymethyl)-3-[((phenylmethoxy)-carbonyl)amino]-2-azetidInone
  • zinc chloride 23.2 g
  • sodium borohydride 13.8 g
  • Example 3 cis-( ⁇ )-3-[2[(2-t-Butoxycarbonylamino-4-thiazolyl]2- [(1-t-butoxycarbonylmethoxy)imino]]acetamido-4-N- formyl-glycinoyloxymethyl-2-azetidinone
  • 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 tetrahydrofuran (190 ml).
  • the addition is made over a period of 10 minutes while stirring in an Ice bath.
  • Example 5 cis-(+)-4-[Methoxycarbonyl)oxymethyl]-3-[((phenylmethoxy)-carbonyl)amino]-2-azetidinone
  • Methyl chloroformate (2.42 g) is added dropwise to a solution of 3.2 g of cis-( ⁇ )-4-(Hydroxy-methyl)-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.
  • reaction mixture is stirred an additional 0.5 hour and then washed successively with dilute mineral acid (e.g., HCl or H 2 SO 4 ), water and potassium bicarbonate solution. Evaporation of the solvent and trituration of the residue with ethyl acetate affords 2.48 g of the title compound. Physical characteristics are as follows: m.p.: 155-158°C.
  • dilute mineral acid e.g., HCl or H 2 SO 4
  • Example 5 According to the procedures of Example 5, the following compounds are also prepared: cis-( ⁇ )-4-[(Formylaminoethoxycarbonyl)oxymethyl]-3-[((phenylmethoxy)carbonyl)amino]-2-azetidinone; cis-( ⁇ )-4-[(t-Butoxycarbonylaminoethoxycarbonyl)oxymethyl]-3- [((phenylmethoxy)carbonyl)amino]-2-azetidinone; cis-( ⁇ )-4-[(Aminocarbonyloxyethoxycarbonyl)oxymethyl]-3-[((phenylmethoxy)carbonyl)amino]-2-azetidinone; and cis-( ⁇ )-4-[(Chloroethoxycarbonyl)oxymethyl]-3-[((phenylmethoxy)- carbonyl)amino]-2-azetidinone.
  • 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 suspension of 382 mg of cis-( ⁇ )-4-[Methoxycarbonyl)oxymethyl]-3-[((phenylmethoxy)carbonyl)amino]-2-azetidinone in 8 ml of methylene chloride 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.
  • chlorosulfonyl compounds are also prepared: cis-( ⁇ )-1-[(Chlorosulfonyl)aminocarbonyl]-4-[(formylaminoethoxy- carbonyl)oxymethyl]-3-[((phenylmethoxy)carbonyl)amino]-2-azetidinone; cis-( ⁇ )-1-[(Chlorosulfonyl)aminocarbonyl]-4-[(t-butoxycarbonyl- amlnoethoxycarbonyl)oxymethyl]-3-[((phenylmethoxy)carbonyl)amino]-2- azetidinone; cis-( ⁇ )-1-[(Chlorosulfonyl)aminocarbonyl]-4-[(aminocarbonyloxy- ethoxycarbonyl)oxymethyl]-3-[((phenylmethoxy)carbonyl)amino]-2
  • Trifluoroacetic acid (15 ml) is added to (3-benzyloxy-4-pyridon-
  • Chlorosulfonylisocyanate (220 ml) is added to a heterogeneous mixture of 3(S)-3-[2-(2-t-butyloxycarbonylamino-4-thiazoyl)-Z-(2)-t- butyloxycarbonylisopropyloxyimino)acetamido]azetidine-2-one (1.0 g) in. methylene chloride (15 ml) at -40°C and the mixture is slowly warmed to 0°C over 90 minutes.
  • N-methyltrifluorosllyl acetamide (1.5 ml) is added to a mixture of (3-benzyloxy- 4-pyridon-6-yl)-1-carbonyl-4(S)-aminopyrazolidinone (660 mg) in tetrahydrofuran (15 ml) at room temperature. After 1.5 hours, the silylated reaction mixture is added to the chlorosulfonyl isocyanate reaction mixture at -20°C and the resulting mixture is slowly warmed to 0°C. After 5 hours, methanol (30 ml) is added and the solvent is removed.
  • 60(b) is 3(S)-3-[2-(2-amino-4-thiazoyl)-Z-(2)-(carboxylsopropyloxyimino)acetamido]-1-[(3-hydroxy-4-pyridon-6-yl)-1-carbonyl-pyrazolidinone-4(S)-amino]-sulfonylaminocarbonyl-2-azetidlnone.
  • 60(d) is 3(S)-3-[2-(2-amino-4-thiazoyl)-Z-(2)-(carboxylsopropyloxyimino)acetamido]-1-[(3-hydroxy-4-pyridon-6-yl)-1-carbonyl-pyrazolidi- none-4(R)-amino]-sulfonylaminocarbonyl-2-azetidinone.

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Abstract

Cette invention concerne des composés nouveaux de 2-azétidinone de formule (1), dans laquelle R1 et R2 sont identiques ou différents et représentent l'hydrogène, (C1-C12)alkyl, (C2-C8) alkényle, (C2-C8) alkényle, (C3-C10) cycloalkyle, un phényle éventuellement substitué par 1 à 3 substituants sélectionnés dans le groupe comprenant un halogène, un hydroxy, un amino, un nitro, (C1C4) alkyle, et (C1-C4) alcoxy, benzyl éventuellement substitué par 1 à 3 substituants sélectionnés dans le groupe comprenant un halogène, un hydroxy, un amino, un nitro, (C1-C4) alkyle, et (C1-C4) alcoxy, -CH2-O-CO-CH2-NHR4, -C2-O-CO2-R5, -CH2F, ou -CHF2; où R4 représente un hydrogène, -CHO ou -CO-O-C(CH3)3; où R5 représente -(C1-C8)alkyle, -(CH2)2NH-CO-O-C(CH3)3, -CH2)2N(CH3)-CO-O-C(CH3)3, -(CH2)2OC(O)NH2,-(CH2)2Cl); où R3 est un groupe acyle dérivé d'un acide carboxylique; où R6 représente un hydrogène ou un méthyle; où R7 représente un hydrogène ou un méthyle; où R11 représente un hydroxy ou -O-CH2-(C6H5); à condition que R6 et R7 ne représentent pas tous deux un méthyle. Ces composés ont un groupe d'activation qui contient une fraction de pyrazolidinone chirale et sont utiles en tant qu'agents antibactériens.
EP88906676A 1987-07-22 1988-07-06 $g(b)-LACTAMES D'UTILITE THERAPEUTIQUE Pending EP0368908A1 (fr)

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US7650287A 1987-07-22 1987-07-22
US76502 1987-07-22

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EP0368908A1 true EP0368908A1 (fr) 1990-05-23

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EP88306142A Withdrawn EP0300636A1 (fr) 1987-07-22 1988-07-06 Bêta-lactames utiles en thérapeutique
EP88906676A Pending EP0368908A1 (fr) 1987-07-22 1988-07-06 $g(b)-LACTAMES D'UTILITE THERAPEUTIQUE

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EP88306142A Withdrawn EP0300636A1 (fr) 1987-07-22 1988-07-06 Bêta-lactames utiles en thérapeutique

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EP (2) EP0300636A1 (fr)
JP (1) JPH02504272A (fr)
KR (1) KR890701588A (fr)
AU (1) AU2125188A (fr)
WO (1) WO1989000569A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2539128A1 (fr) * 1983-01-10 1984-07-13 Roussel Uclaf Nouveaux derives de la 3-amino 2-oxoazetidine comportant en position 1 un radical heterocyclique azote, leur procede de preparation, leur application comme medicaments et les produits intermediaires necessaires a leur preparation
EG18314A (en) * 1985-09-26 1993-02-28 Squibb & Sons Inc Process for preparing of 2-oxo-1((substituted sulfonyl)amino)carbonyl)-azitidines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8900569A1 *

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WO1989000569A1 (fr) 1989-01-26
EP0300636A1 (fr) 1989-01-25
KR890701588A (ko) 1989-12-21
JPH02504272A (ja) 1990-12-06
AU2125188A (en) 1989-02-13

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