WO2000063213A1 - Composes inhibant la beta-lactamase - Google Patents

Composes inhibant la beta-lactamase Download PDF

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Publication number
WO2000063213A1
WO2000063213A1 PCT/US2000/009929 US0009929W WO0063213A1 WO 2000063213 A1 WO2000063213 A1 WO 2000063213A1 US 0009929 W US0009929 W US 0009929W WO 0063213 A1 WO0063213 A1 WO 0063213A1
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Prior art keywords
compound
heterocycle
alkyl
alkanoyloxy
halo
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PCT/US2000/009929
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English (en)
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John D. Buynak
A. Srinivasa Rao
Greg C. Adam
Sirishkumar D. Nidamarthy
Venkata Ramana Doppalapudi
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Research Corporation Technologies, Inc.
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Priority to MXPA01010409A priority Critical patent/MXPA01010409A/es
Priority to CA002371389A priority patent/CA2371389A1/fr
Priority to JP2000612303A priority patent/JP2002542249A/ja
Priority to EP00922157A priority patent/EP1169323A1/fr
Priority to AU42386/00A priority patent/AU773013B2/en
Publication of WO2000063213A1 publication Critical patent/WO2000063213A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • 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
    • A61P31/04—Antibacterial agents

Definitions

  • ⁇ -lactamase enzymes have been organized into four molecular classes: A, B, C, and D based on amino acid sequence.
  • Class A which includes RTEM and the ⁇ -lactamase of Staphylococcus aureus
  • class C which includes the lactamase derived from P-99 Enterobacter cloacae
  • class D are serine hydrolases.
  • Class A enzymes have a molecular weight of about 29 kDa and preferentially hydrolyze penicillins.
  • the class B lactamases are metalloenzymes and have a broader substrate profile than the proteins in the other classes.
  • Class C enzymes include the chromosomal cephalosporinases of Gram-negative bacteria and have molecular weights of approximately 39 kDa.
  • the recently recognized class D enzymes exhibit a unique substrate profile which differs significantly from both class A and class C.
  • the class C cephalosporinases are responsible for the resistance of gram negative bacteria to a variety of both traditional and newly designed antibiotics.
  • the Enterobacter species which possesses a class C enzyme, is now the third greatest cause of nosocomial infections in the United States.
  • This class of enzymes often has poor affinities for inhibitors of the class A enzymes, such as clavulanic acid, a commonly prescribed inhibitor, and to common in vitro inactivators, such as 6- ⁇ -iodopenicillanate.
  • One strategy for overcoming this rapidly evolving bacterial resistance is the synthesis and administration of ⁇ -lactamase inhibitors. Frequently, ⁇ - lactamase inhibitors do not possess antibiotic activity themselves and are thus administered together with an antibiotic.
  • AUGMENTIN amoxicillin, clavulanate potassium
  • A is thio (S), sulfinyl (SO), or sulfonyl (SO 2 ); each n is independently 0, 1, or 2; each R j , is independently hydrogen, or (C r C 10 )al-kyl; each R b and R c is independently hydrogen, (C,-C 10 )alkyl, (C r C 10 )alkoxy, phenyl, benzyl, phenethyl, or (C r C 10 )alkanoyl; each R d is independently (C 1 -C 10 )alkyl, (C..-C ⁇ 0 )alkanoyl, aryl, heterocycle, aryl(C 1 -C 6 )alkyl, heterocycle, or heterocycle(C ] -C 6 )a---kyl; wherein any (C,-C, 0 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C, 0
  • the invention also provides a compound of formula IV:
  • R 10 is hydrogen
  • A is thio, sulfmyl, or sulfonyl; each n is independently 0, 1, or 2; each R e is independently hydrogen, or (C,-C, 0 )alkyl; each R- f and R g is independently hydrogen, (C.--C-.
  • each R h is independently (C r C 10 )alkyl, phenyl, aryl(C r C 6 )alkyl, heterocycle, or heterocycle(C,-C 6 )alkyl;
  • -R j is hydrogen or (C,-C 6 )alkyl;
  • C 10 )alkoxycarbonyl of R 7 , R 8 , R j and R k is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, cyanato, nitro, mercapto, oxo, aryl, heterocycle, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C r C 6 )alkoxy, (C,--C 6 )alkanoyl, (C.--C 6 )alkanoyloxy, aryl(C,- C 6 )alkanoyloxy, halo(C 1 -C 6 )alkanoyloxy, heterocycle(C !
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or IV, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, as well as such a pharmaceutical composition that further comprises a ⁇ -lactam antibiotic.
  • the invention also provides a method comprising inhibiting a ⁇ - lactamase by contacting (in vitro or in vivo) the ⁇ -lactamase with an effective amount of a compound of formula I or IN; or a pharmaceutically acceptable salt thereof.
  • the invention also provides a therapeutic method comprising inhibiting a ⁇ -lactamase in a mammal in need of such therapy, by administering an effective inhibitory amount of a compound of formula I or IN; or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method comprising enhancing the activity of a ⁇ -lactam antibiotic, by administering the ⁇ -lactam antibiotic to a mammal in need thereof, in combination with an effective ⁇ -lactamase inhibiting amount of a compound of formula I or IN; or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method comprising treating a ⁇ - lactam resistant bacterial infection in a mammal, by administering an effective amount of a ⁇ -lactam antibiotic in combination with an effective ⁇ -lactamase inhibiting amount of a compound of formula I or IN; or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula l or IN for use in medical therapy (preferably for use in inhibiting a ⁇ -lactamase in a mammal, or for treating a ⁇ -lactam resistant bacterial infection in a mammal), as well as the use of a compound of formula I or IN for the manufacture of a medicament useful for inhibiting a ⁇ -lactamase in a human.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing ⁇ -lactamase inhibitors of formula I or IV.
  • Compounds of formula I and IN are useful as ⁇ -lactamase inhibitors for therapeutic applications. They are also useful as pharmacological tools for in vitro or in vivo studies to investigate the mechanisms of antibiotic resistance, to help identify other therapeutic antibiotic agents or ⁇ -lactamase inhibitors, to identify which ⁇ -lactamases are being expressed by a given microorganism, or to selectively inhibit one or more ⁇ -lactamases in a microorganism.
  • Figure 1 Illustrates the synthesis of compounds of formula I
  • Figure 2 Illustrates the synthesis of compounds of formula I
  • Figure 3 Illustrates the synthesis of compounds of formula IN
  • Figure 4 Illustrates the synthesis of compounds of formulae I and
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, etc. denote both straight and branched groups.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heterocycle denotes a 6-10 membered unsaturated or saturated mono- bi- or tri-cyclic ring system comprising carbon and 1, 2, 3, or 4 heteroatoms selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein each X is absent or is H, O, (C.-C 4 )alkyl, phenyl or benzyl.
  • heterocycle includes “heteroaryl,” which denotes a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein each X is absent or is H, O, (C ⁇ -C 4 )alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • enhancing the activity of a ⁇ - lactam antibiotic means improving or increasing the antibiotic activity of the compared in a statistically measurable and significant manner with respect to the activity demonstrated by the compound in the absence of a compound of the invention.
  • (C r C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 1 -C 10 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, or decyl;
  • (C 3 -C 8 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;
  • (C,-C 10 )alkoxy can be methoxy, ethoxy, propoxy, isoprop
  • alkenyl can be vinyl, 1- propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1- nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8- nonenyl, 1-decenyl, 1-
  • -C 6 )alkanoyloxy can be iodoacetoxy, bromoacetoxy, chloroacetoxy, fluoroacetoxy, trifluoroacetoxy, 3-chloropropanoyloxy, 3-fluoropropanoyloxy, perfluoropropanoyloxy, or 3,3,3-trifluoropropanoyloxy;
  • aryl can be phenyl, indenyl, or naphthyl;
  • heterocycle can be triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, mo ⁇ holinyl, quinolinyl, isoquinolinyl, indolyl, pyrimidinyl,
  • R j is aryl, heterocycle, or -COOR ⁇
  • R is 2-pyridyl, or -COOR,.
  • R 2 is hydrogen.
  • R 3 is hydrogen, carboxy, or -CH 2 M wherein M is hydrogen, halo, hydroxy, (C 3 -C 8 )cycloalkyl, (C r C 6 )alkoxy, aryloxy, aryl(C..- C 10 )alkoxy, mercapto, (C r C.- 0 )alkylthio, arylthio, heterocycle, (heterocycle)thio, (C C 10 )alkanoylthio, aminocarbonyloxy, or M ⁇ R... More specifically, M is hydrogen, halo, (C,-C, 0 )alkanoyloxy, or heterocycle.
  • R 3 is acetoxymethyl, phenylacetoxymethyl, (3,4- dihydroxyphenyl)acetoxymethyl, chloromethyl, formyl, or chloroacetoxymethyl.
  • R 3 is hydrogen, methyl, acetoxymethyl, or 1-methyl- lH-tetrazol-5-ylthiomethyl.
  • R 3 is vinyl, optionally substituted at the 2-position with halo, cyano, -COOR-,, trifluoromethyl, formyl, (C 3 -C 8 )cycloalkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, heterocycle, or NR b R c ;
  • R 3 is vinyl, optionally substituted at the 2-position with cyano, -COO-R ⁇ (C 2 -C 6 )alkenyl, or heteroaryl.
  • A is sulfonyl (-SO 2 -).
  • R 7 is aryl, heterocycle, or -COOR e .
  • R 7 is 2-pyridyl, or -COOR e .
  • R 8 is hydrogen.
  • R j and R k are each independently hydrogen, cyano, -
  • R is carboxy, 2-pyridyl, tert-butoxycarbonyl, or methoxycarbonyl.
  • R 3 is 2-cyanovinyl, 2-(methoxycarbonyl)vinyl, 2- (2-pyridyl-N-oxide)vinyl, or 1,3-butadienyl.
  • R 5 and R 6 are each individually hydrogen.
  • R 5 and R 6 are each individually methylthio.
  • R j and R k are each independently hydrogen, cyano, 2-(methoxycarbonyl), 2-pyridyl-N-oxide, or vinyl.
  • a specific compound is a compound of formula I wherein A is sulfonyl (-SO 2 -); R, is 2-pyridyl, carboxy or tert-butoxycarbonyl; R 2 is hydrogen; R 3 is hydrogen, methyl, acetoxymethyl or l-methyl-lH-tetrazol-5- ylthiomethyl; and R 5 and R 6 are the same and are each hydrogen or thiomethyl; or a pharmaceutically acceptable salt thereof.
  • a specific compound is a compound of formula IN wherein A is sulfonyl (-SO 2 -); R 7 is 2-pyridyl, carboxy or tert-butoxycarbonyl; R 8 is hydrogen; and R- j is 2-cyanovinyl, 2-(methoxycarbonyl)vinyl, 2-(2'-pyridyl- ⁇ - oxide)vinyl, or 1,3-butadienyl; or a pharmaceutically acceptable salt thereof.
  • a preferred compound of formula I or IN is a pharmaceutically acceptable salt formed from a carboxy lie acid of formula I or IN wherein R 4 or R 10 is hydrogen. Most preferred is a salt wherein R 4 or R 10 been replaced with a sodium or potassium ion.
  • pharmaceutically acceptable salts also includes poly salts (e.g. di- or tri-salts) of a compound of formula I or IN, particularly a dicarboxylic acid salt of a compound of formula I wherein R, is carboxy and R 4 is hydrogen, or a dicarboxylic acid salt of a compound of formula IN wherein R 7 is carboxy and R 10 is hydrogen
  • compositions of formula I wherein R 4 has been replaced with a pharmaceutically acceptable cation can conveniently be prepared from a corresponding compound of formula I wherein R 4 is hydrogen, by reaction with a suitable base, for example, as disclosed in Example 1 hereinbelow.
  • compositions of formula IV wherein R 10 has been replaced with a pharmaceutically acceptable cation can conveniently be prepared from a corresponding compound of formula IV wherein R 10 is hydrogen, by reaction with a suitable base.
  • a useful intermediate for preparing a compound of formula I or IV, wherein R 4 or R 10 is hydrogen, is a corresponding compound wherein R 4 or R 10 has been replaced with a suitable removable carboxy protecting group.
  • protecting groups are well known in the art, for example, see Greene, T.W.; Wutz, P.G.M. "Protecting Groups In Organic Synthesis” second edition, 1991, New York, John Wiley & Sons, Inc.
  • Preferred protecting groups include (C,- C 10 )alkyl, (C 2 - C 10 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 10 )alkynyl, aryl, benzyl, or benzhydryl.
  • R quarantin R 2 , R 3 , R 5 , and R 6 have any of the values, specific values, or preferred values defined herein, and wherein R 4 is (C,-C ]0 )alkyl, (C 2 -C 10 )alkenyl, (C 3 - C g )cycloalkyl, (C 2 -C 10 )alkynyl, aryl, benzyl, or benzhydryl.
  • the invention also provides compounds of formula IV wherein R 7 , R 8 , and R, have any of the values, specific values, or preferred values defined herein, and wherein R 10 is (C 1 -C ]0 )alkyl, (C 2 -C 10 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 2 - C I0 )alkynyl, aryl, benzyl, and benzhydryl.
  • Compounds of formula (I) can be prepared as shown in Figure I by esterifying 7-aminocephalosporanic acid (commercially available from Aldrich) with diphenyldiazomethane to produce benzhydyl 7- aminocephalosporinate compound 1.
  • the degree of purity can be enhanced by substituting isoamylnitrite with isopropylnitrite and rhodium(II)acetate with rhodium(II)octonate.
  • 7-Alkylidenecephalosporinates 3 can be prepared by treating benzhydryl 7-oxocephalosporinate with the requisite Wittig Reagent. Oxidation of the resulting compound for example with an excess amount of 70% m-CPBA in rnethylene chloride and phosphate 6.4 buffer, gives the corresponding sulfone 4 that can be treated with Eschenrnoser's salt in acetonitrile to give ester 5. Hydrolysis of the ester followed by salt formation under standard conditions, for example, as illustrated in the Examples hereinbelow and in Figure 2, gives a compound 6.
  • the invention also provides intermediates of formulae 2, 3, 4, and 5, wherein R quarantine R 2 , R 3 , R 5 , and R 6 have any of the values, specific values, or preferred values defined herein, and wherein "Bhl" is diphenylmethyl or is another suitable carboxy protecting group such as for example (C,-C 10 )alkyl, (C 2 - C 10 )alkenyl, (C 3 - C 8 )cycloalkyl, (C 2 -C ]0 )alkynyl, aryl, or benzyl, that are useful to prepare compounds of formula I.
  • compounds of formula IV can be prepared from compound 7, which is available from 2, using procedures similar to those described by J. D. Buynak et. al., J. Med. Chem. 38, 1022-1034, 1995.
  • 7 is isomerized to a 1:3 mixture of 7 and 8, respectively.
  • Compound 8 is separated and hydrolyzed to alcohol 9, which is oxidized to provide aldehyde 10. Reaction of 10 with a series of ylides provides compounds 11a through llf.
  • Compound 10 can also be condensed with nitromethane to produce nitroalkene llh ( Figure 4), or can be reacted with hydroxylamine hydrochloride to produce oxime 14 ( Figure 4), which itself can be reacted with thionyl chloride to generate nitrile 17. Oxidation of compounds lla-llf, llh, 14, and 17 yields the corresponding sulfones.
  • Compound 12e can also be reacted with Eschenmoser's salt to generate sulfone 20 ( Figure 4). Hydrolysis of the esters 12a-12f, 12h, 15, 18, and 20 (e.g.
  • a compound that is particularly useful for preparing a compound of formula IN is an aldehyde of formula V:
  • R 7 , R 8 , R 10 , and A have any of the values, specific values, or preferred values described herein.
  • the 7-alkanoylmethylene species may be made by forming the vinyl anion and reacting it with a desirable alkanoyl halide.
  • the vinyl anion may be made by a standard lithium-halogen (or magnesium-halogen) exchange reaction, for example, reaction of compound 4a with methyl lithium.
  • the lithium vinyl group may then be functionalized by reaction with an alkoxycarbonyl chloride.
  • R 3 is a halogen
  • ethyl xanthate EtOCS 2 K
  • Raney-Nickel desulfurization H 2 /Ra-Ni
  • PC1 5 may be used to convert the 3-OH group into a 3-C1 group.
  • Compounds wherein R 3 is a hydrogen may be formed by reduction of the aforementioned 3-hydroxy cephem to the corresponding 3- hydroxy cepha with sodium borohydride.
  • R 3 is 3-hydroxymethyl may be obtained by hydrolysis of a corresponding acetoxy group (e.g. with NaOH or an appropriate enzyme).
  • Compounds wherein R 3 is halomethyl may be formed by reaction of a corresponding 3-hydroxymethyl compound with a halogenating reagent.
  • PC1 5 may be used to form the 3 -chloromethyl species.
  • R 3 is alkoxymethyl, aryloxymethyl, or arylalkoxymethyl
  • R 3 is alkoxymethyl, aryloxymethyl, or arylalkoxymethyl
  • tosyl chloride displacement of the resultant tosylate with an oxide.
  • sodium methoxide may be used to obtain the 3-methoxymethyl species.
  • R 3 is mercaptomethyl
  • NaSH sodium sulfhydride
  • This compound may further be derivatized with an alkylhalide to form a alkylthio group, or an acylchloride to form an acylthio group, for example, as described in Jerry March "Advanced Organic Chemistry” John Wiley & Sons, 4 ed.1992, 407.
  • Gabriel Synthesis i.e., reaction of the corresponding 3 -chloromethyl compound with potassium phthalimide followed by hydrolysis of the product with acid to yield the 3-aminomethyl compound.
  • a compound of formula I wherein R 3 is hydroxymethyl may also be prepared from a corresponding compound of formula I wherein R 3 is chloroacetoxymethyl by treatment with thiourea in the presence of a suitable base, such as for example, pyridine (T. Greene, P. Wutz "Protective Groups in
  • a compound of formula I wherein R 3 is cyanomethyl can be prepared from a corresponding compound of formula I wherein R 3 is halomethyl using techniques that are well known in the art, for example techniques such as those described in Jerry March “Advanced Organic Chemistry” John Wiley &
  • a compound of formula I wherein R 3 is -CH j NR b R. can be prepared from a corresponding compound of formula I wherein R 3 is -CH 2 (halo) using techniques that are well known in the art, for example techniques such as those described in Jerry March "Advanced Organic Chemistry” John Wiley &
  • a compound of formula I wherein R 3 is formyl can be prepared from a corresponding compound of formula I wherein R 3 is hydroxymethyl by oxidation, using techniques which are well known in the art.
  • a compound of formula I wherein R 3 is a 1-alkenyl substituent can generally be prepared from a corresponding compound of formula I wherein
  • R 3 is formyl, by reaction with the requisite ylide or stabilized ylide, using techniques which are well known in the art.
  • a compound of formula I wherein R 3 is cyanatomethyl can be prepared from a corresponding compound of formula I wherein R 3 is hydroxymethyl by reaction with a cyanogen halide using techniques that are well known in the art, for example techniques such as those described in Jerry March "Advanced Organic Chemistry” John Wiley & Sons, 4 ed.1992, 387.
  • R 3 is aminocarbonylmethyl
  • cyanide e.g., KCN
  • a compound of formula I or IN wherein A is sulfonyl (-SO 2 -) can be prepared by oxidation of a corresponding compound of formula I or IN wherein A is thio (-S-), for example, by using met ⁇ -chloroperbenzoic acid (rnCPBA).
  • a compound of formula I or IN wherein A is sulfinyl (-SO-) can be prepared by oxidation of a corresponding compound of formula I or IV wherein A is thio (-S-), using one equivalent of an acceptable oxidizing agent, for example, mCPBA.
  • Ylides can be prepared using techniques that are well known in the art, for example techniques such as those described in Jerry March "Advanced Organic Chemistry” John Wiley & Sons, 4 ed.1992, 956-963. Suitable ylides are also disclosed in U.S. Patent Number 5,597,817, issued January 29, 1997; and U.S. Patent Number 5,629,306, issued May 13, 1997. Compounds of formula I and IV wherein A is -S- or -SO- are particularly useful as intermediates for preparing the corresponding compounds of formula I or IV wherein A is -SO2-.
  • salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, oc-ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal for example, sodium, potassium or lithium
  • alkaline earth metal for example, calcium
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to a selected route of administration, i.e., by oral, parenteral, intravenous, intramuscular, topical, or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • a polyol for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like
  • vegetable oils nontoxic glyceryl esters, and suitable mixtures thereof.
  • suitable mixtures thereof can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of the invention to the skin are disclosed in Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • compositions may also be prepared in suitable forms for absorption through the mucous membranes of the nose and throat or bronchial tissues and may conveniently take the form of powder or liquid sprays or inhalants, lozenges, throat paints, etc.
  • the preparations may be presented as individual capsules, in liquid or semi-solid form, or may be used as drops, etc.
  • Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, powders, etc.
  • composition may, for example, be formulated as an intramammary preparation in either long acting or quick-release bases.
  • Useful dosages of the compounds of the invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the concentration of the compound(s) of the invention in a liquid composition will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%.
  • concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
  • compositions per unit dosage may contain from 0.1% to 99% of active material (the present 7-vinylidene cephalosporins and optional antibiotic), the preferred range being from about 10- 60%.
  • the composition will generally contain from about 15 mg to about 1500 mg by weight of active ingredient based upon the total weight of the composition; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg.
  • the unit dosage is usually the pure compound in a slightly acidified sterile water solution or in the form of a soluble powder intended for solution.
  • Single dosages for injection, infusion or ingestion may be administered, i.e., 1-3 times daily, to yield levels of about 0.5 - 50 mg/kg, for adults.
  • the invention provides a pharmaceutical composition, comprising an effective amount of a compound of formula I or IV as described hereinabove; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I or IV as described hereinabove; or a pharmaceutically acceptable salt thereof; a ⁇ -lactam antibiotic; and a pharmaceutically acceptable carrier.
  • the present compositions are preferably presented in a form suitable for absorption by the gastro-intestinal tract.
  • ⁇ -lactam antibiotics which are well known in the art include those disclosed by R.B. Morin and M. Gorin, M.Eds.; Academic Press, New York, 1982; vol. 1-3.
  • Preferred ⁇ -lactam antibiotics, suitable for use in the pharmaceutical composition of the invention include ⁇ -lactam antibiotics which are preferentially deactivated by Class A and Class C ⁇ -lactamase enzymes, for example, amoxicillin, piperacillin, ampicillin, ceftizoxime, cefotaxime, cefuroxime, cephalexin, cefaclor, cephaloridine, and ceftazidime.
  • a compound of the invention to function as a ⁇ - lactamase inhibitor can be demonstrated using the test described below, or using other tests which are well known in the art.
  • Representative compounds of formula I were evaluated as inhibitors of the Class C ⁇ -lactamase of Enterobacter cloacae P- 99, a cephalosporinase, and TEM-1, a penicillinase, by relative IC 50 analysis.
  • the IC 50 value represents the concentration of inhibitor required to effect a 50% loss of activity of free enzyme.
  • the IC 50 value of each compound was determined as follows.
  • Compounds of formulae II and III are provided for comparison purposes.
  • Compounds of formula I generally possess activity as ⁇ -lactamase inhibitors, and, thus, are useful as therapeutic agents and as pharmacological tools as described herein.
  • Compounds of formulae II and III are generally less effective against P-99 than corresponding compounds of formula I.
  • compounds of formula I are more potent toward P-99 than is tazobactam, showing a 1 to 2000 fold increase in activity.
  • Many compounds of formula I are provided for comparison purposes.
  • Compounds of formula I generally possess activity as ⁇ -lactamase inhibitors, and, thus, are useful as therapeutic agents and as pharmacological tools as described herein.
  • Compounds of formulae II and III are generally less effective against P-99 than corresponding compounds of formula I.
  • compounds of formula I are more potent toward P-99 than is tazobactam, showing a 1 to 2000 fold increase in activity.
  • the present ⁇ -lactamase inhibitors of formulae I and IV are particularly useful in the treatment of infections associated with Enterobacter, Citrobacter, and Serratia. These bacteria have the ability to attach to the epithelial cells of the bladder or kidney (causing urinary tract infections) and are resistant to multiple antibiotics including amoxicillin and ampicillin.
  • the present ⁇ -lactamase inhibitors of formula I are also be useful in the treatment of infections associated with highly resistant Pneumococci.
  • diseases include otitis media, sinusitis, meningitis (both in children and adults), bacteremia, and septic arthritis.
  • Resistant pneumococcal strains have surfaced in many parts of the world. For example, in Hungary, 58% of S. pneumoniae are resistant to penicillin, and 70% of children who are colonized with S. pneumoniae carry resistant strains that are also resistant to tetracycline, erythromycin, trimethoprin/sulfamethoxazole (TMP/SMX), and 30% resistant to chloramphenicol.
  • Klebsiella pneumoniae resistant via the production of ⁇ - lactamase have caused hospital outbreaks of wound infection and septicemia.
  • Example 1 Sodium salt of 7-[(Z)-(2'-pyridyl)methylene]-2- (exomethylidene) cephalosporanic acid sulfone (6a).
  • ester 5a 1.0 g, 1.43 mmol
  • anisole 0 °C
  • TFA and anisole were removed in vacuo and the residue was dissolved in EtOAc and extracted into aqueous sodium bicarbonate. The aqueous layer was loaded onto reverse phase column and eluted with 5% ethanol/water to give compound 6a (0.58 g, 79%).
  • the intermediate ester 5a was prepared as follows.
  • Picolyl chloride (8.9 g, 70 mmol), triphenylphosphine (18.3 g, 70 mmol) and 1,4- dioxane (30 mL) were mixed and refluxed for 24 hours. The reaction mixture was washed with ether (2 x 30 mL) and the remaining solid was dried in vacuo to give a white solid (25.5 g, 94%).
  • a mixture of 2- picolyltriphenylphosphonium chloride (5.8 g, 15 mmol) and sodium amide (0.58 g, 15 mmol) in THF (15 mL) was stirred at room temperature for 30 minutes.
  • Example 2 Sodium salt of 7-[(Z)-(ter-t-butoxycarbonyl)methylene]-2- (exomethylidene)cephalosporinate Sulfone (6b).
  • the intermediate ester 5b was prepared as follows.
  • Example 3 Sodium Salt of 7-[(-Z)-(2"-Pyridmyl)methylene]-3 , -desacetoxy- 2-(exomethylidene)cephalosporinate Sulfone (6c).
  • the intermediate 5c was prepared as follows.
  • Benzhydryl 7-Oxo-3'-(desacetoxy)cephalosporinate (2b) To a solution of benzhydryl 7-amino-3'-(desacetoxy)cephalosporinate (15 g, 39.5 mmol) in ethyl acetate (300 mL) were added isopropyl nitrite (13.3 mL, 59.2 mmol, 40% solution in CH 2 C1 2 ) and trifluoroacetic acid (0.13 g, 1.18 mmol) and the reaction was allowed to stir for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and redissolved in benzene (75 mL).
  • Example 4 Sodium salt of 7-[(-Z)-(-tert-butoxycarbonyl)methylene]-3'- desacetoxy-2 (exomethylidene)cephalosporinate Sulfone (6d).
  • the intermediate 5d was prepared as follows.
  • Example 5 Sodium salt of Benzhydryl l-[(Z)-(tert- Butylcarboxy)methylene]- 3'-desacetoxy-2-exomethylidene-3'-[l"-methyl-l"£ -tetrazol- 5"- yl)thio] cephalosporinate Sulfone (6f).
  • the intermediate compound 5f was prepared as follows.
  • Example 6 Sodium [2-[(bisthiomethyl)exomethylene]-7-[(Z)-(2"- pyridinyl)methylene]-3'- desacetoxycephalosporinate (6g).
  • the intermediate compound 5g was prepared as follows.
  • Example 7 Disodium Salt of 7-[( )-(Carboxy)methylene]- 2- (exomethylidene)-cephalosporinate Sulfone (6h)
  • Example 8 Disodium Salt 7-[(Z)(carboxy)methylene]-3'-desacetoxy-2- (exo- methylidene)cephalosporinate Sulfone (6i).
  • Benzhydryl 3-(acetoxymethyl)-7Z-[(2'-pyridyl)methylidene]-3- cephem-4-carboxylate (7) was prepared from 2 using a procedure similar to that described by J. D. Buynak et. al. J. Med. Chem. 38, 1022-1034, 1995.
  • the EtOAc layer was extracted with aqueous NaHCO 3 (2 x 0.15 mmol in 4 mL H 2 O).
  • the combined NaHCO 3 layers were directly loaded on a column (high porous polymer, MCI gel, CHP20P, Mitsubishi Chemical Corp., White Plains, NY, approx. 75 to 150 mL of resin) and the product eluted with 5% EtOH in deionized (millipore) water. Yields were between 60 to 80%.
  • Example 20 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I or IN ('Compound X'), for therapeutic or prophylactic use in humans.
  • ⁇ -lactam antibiotic can be any compound possessing antibiotic properties (e.g. amoxicillin, piperacillin, ampicillin, ceftizoxime, cefotaxime, cefuroxime, cephalexin, cefaclor, cephaloridine, or ceftazidime).
  • antibiotic properties e.g. amoxicillin, piperacillin, ampicillin, ceftizoxime, cefotaxime, cefuroxime, cephalexin, cefaclor, cephaloridine, or ceftazidime.

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Abstract

La présente invention concerne des composés de formules (I) et (IV). Dans les formules, R1-R11 et A peuvent prendre n'importe quelle valeur parmi celles définies dans le descriptif. Ces composés ainsi que leurs sels pharmaceutiquement acceptables sont utiles pour inhiber les enzymes β-lactamase, pour améliorer l'activité des bêta-lactamines, et pour traiter chez un mammifère les infections bactériennes résistant aux bêta-lactamines. La présente invention concerne également des compostions pharmaceutiques, des procédés de préparation de composés de formule (I) et (IV) et de nouveaux intermédiaires utiles pour effectuer la synthèse de composés de formules (I) et (IV).
PCT/US2000/009929 1999-04-15 2000-04-14 Composes inhibant la beta-lactamase WO2000063213A1 (fr)

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MXPA01010409A MXPA01010409A (es) 1999-04-15 2000-04-14 Compuestos inhibidores de beta-lactamasa.
CA002371389A CA2371389A1 (fr) 1999-04-15 2000-04-14 Derives de l'acide 7-alkylidene-cephalosporanique inhibant la beta-lactamase
JP2000612303A JP2002542249A (ja) 1999-04-15 2000-04-14 β−ラクタマーゼ阻害化合物
EP00922157A EP1169323A1 (fr) 1999-04-15 2000-04-14 Composes inhibant la beta-lactamase
AU42386/00A AU773013B2 (en) 1999-04-15 2000-04-14 Beta-lactamase inhibiting compounds

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JP2002356427A (ja) * 2001-05-30 2002-12-13 Shionogi & Co Ltd β−ラクタマーゼ阻害剤
WO2003020732A2 (fr) * 2001-07-24 2003-03-13 Alamx, L.L.C. 7-alkylidene-3-substitues-3-cephem-4-carboxylates utilises en tant qu'inhibiteurs de $g(b)-lactamase
US6770759B2 (en) 1997-12-29 2004-08-03 Research Corporation Technologies, Inc. Penicillanic acid derivative compounds and methods of making
US6906054B2 (en) 1999-04-15 2005-06-14 Research Corporation Technologies, Inc. Compositions for inhibiting beta-lactamase
US7022691B2 (en) 2002-04-04 2006-04-04 John D. Buynak Inhibitors of serine and metallo-β-lactamases
CN102731530A (zh) * 2011-04-07 2012-10-17 天津市医药集团技术发展有限公司 新型头孢菌素化合物及其合成方法与应用
CN107021893A (zh) * 2017-05-05 2017-08-08 贵州师范学院 一类硫代酰铵盐离子液体及其制备方法

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US5760027A (en) * 1996-12-06 1998-06-02 Research Corporation Technologies, Inc. Use of 7-alkylidene cephalosporins to inhibit elastase activity

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WO1996017849A1 (fr) * 1994-12-09 1996-06-13 Research Corporation Technologies, Inc. Derives d'acide 7-alkylidene cephalosporanique et procedes d'utilisation de ce dernier
US5760027A (en) * 1996-12-06 1998-06-02 Research Corporation Technologies, Inc. Use of 7-alkylidene cephalosporins to inhibit elastase activity

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770759B2 (en) 1997-12-29 2004-08-03 Research Corporation Technologies, Inc. Penicillanic acid derivative compounds and methods of making
US7125986B2 (en) 1997-12-29 2006-10-24 Southern Methodist University Foundation For Research Penicillanic acid derivative compounds and methods of making
US6906054B2 (en) 1999-04-15 2005-06-14 Research Corporation Technologies, Inc. Compositions for inhibiting beta-lactamase
JP2002356427A (ja) * 2001-05-30 2002-12-13 Shionogi & Co Ltd β−ラクタマーゼ阻害剤
WO2003020732A2 (fr) * 2001-07-24 2003-03-13 Alamx, L.L.C. 7-alkylidene-3-substitues-3-cephem-4-carboxylates utilises en tant qu'inhibiteurs de $g(b)-lactamase
WO2003020732A3 (fr) * 2001-07-24 2003-05-22 Alamx L L C 7-alkylidene-3-substitues-3-cephem-4-carboxylates utilises en tant qu'inhibiteurs de $g(b)-lactamase
US6916801B2 (en) 2001-07-24 2005-07-12 Alamx, Llc 7-Alkylidene-3-substituted-3-cephem-4-carboxylates as β-lactamase inhibitors
US7488724B2 (en) 2001-07-24 2009-02-10 Southern Methodist University Foundation For Research 7-alkylidene-3-substituted-3-cephem-4-carboxylates as beta-lactamase inhibitors
US7022691B2 (en) 2002-04-04 2006-04-04 John D. Buynak Inhibitors of serine and metallo-β-lactamases
CN102731530A (zh) * 2011-04-07 2012-10-17 天津市医药集团技术发展有限公司 新型头孢菌素化合物及其合成方法与应用
CN102731530B (zh) * 2011-04-07 2016-05-04 天津市医药集团技术发展有限公司 头孢菌素化合物及其合成方法与应用
CN107021893A (zh) * 2017-05-05 2017-08-08 贵州师范学院 一类硫代酰铵盐离子液体及其制备方法

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DE60029023D1 (de) 2006-08-03
DE60029023T2 (de) 2007-01-18
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CA2371389A1 (fr) 2000-10-26
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