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WO1996038448A1 - ANTIBIOTIQUES DU TYPE β-LACTAME - Google Patents

ANTIBIOTIQUES DU TYPE β-LACTAME Download PDF

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Publication number
WO1996038448A1
WO1996038448A1 PCT/US1996/008141 US9608141W WO9638448A1 WO 1996038448 A1 WO1996038448 A1 WO 1996038448A1 US 9608141 W US9608141 W US 9608141W WO 9638448 A1 WO9638448 A1 WO 9638448A1
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WIPO (PCT)
Prior art keywords
compound
group
alkyl
arylthio
acylamido
Prior art date
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Ceased
Application number
PCT/US1996/008141
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English (en)
Inventor
Burton Christensen
Tomasz Glinka
Ving J. Lee
Scott Hecker
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Trine Pharmaceuticals Inc
Original Assignee
Microcide Pharmaceuticals Inc
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Filing date
Publication date
Priority claimed from US08/455,969 external-priority patent/US5698547A/en
Priority claimed from US08/457,673 external-priority patent/US5688786A/en
Application filed by Microcide Pharmaceuticals Inc filed Critical Microcide Pharmaceuticals Inc
Priority to AU59583/96A priority Critical patent/AU5958396A/en
Publication of WO1996038448A1 publication Critical patent/WO1996038448A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to ⁇ -lactam antibiotics. More particularly, the present invention includes novel ⁇ -lactam compounds and their pharmacologically acceptable salts and prodrugs, their methods of production and use. These compounds exhibit antibiotic activity against a wide spectrum of organisms, including organisms which are resistant to ⁇ -lactam antibiotics.
  • the ⁇ -lactams exhibit their antibacterial activity by inhibiting bacterial peptidoglycan biosynthesis, and have been extremely effective in treating a wide variety of bacterial infections.
  • ⁇ -lactams that are said to have antibacterial activity are described in U.S. Patent 3,992,377 and U.S. Patent 4,256,739.
  • Unfortunately the wide-spread and indiscriminant use of these antibiotics has led to a rapid increase in the number of bacterial strains which are resistant to these compounds. Most importantly, this resistance has emerged among clinically important microorganisms which threaten to limit the utility of presently available ⁇ -lactam antibiotics.
  • resistant strains of Salmonella, S. pneumonias, Enterobacteriacese, and Pseudomonas have emerged which threaten to undo many of the strides made in reducing mortality and morbidity from bacterial infections.
  • Bacterial resistance to ⁇ -lactams follows three major pathways: a) the development of ⁇ -lactamases capable of inactivating the ⁇ -lactam ring; b) decreased ⁇ -lactam penetration into the bacteria due to changes in bacterial cell wall composition; and c) poor binding to penicillin-binding proteins (PBPs) .
  • PBPs penicillin-binding proteins
  • the latter pathway is especially important, as the binding of ⁇ -lactams to PBPs is essential for inhibiting bacterial cell-wall biosynthesis.
  • Certain Gram-positive bacteria namely methicillin-resistant Staphylococcus aureus (“MRSA") and enterococci are highly resistant to ⁇ -lactam antibiotics .
  • Experimental compounds which may possess utility as anti-MRSA or anti-enterococcal bactericides include the glycylcyclines (see, e.g.. P.-E. Sum et al.. J. Med. Chem.. 37, (1994)) , FK-037 (see, e.g.. H. Ohki gt al., J. Antibiotics. 46:359-361 (1993)) , RP-59,500 (see. e.g... S.K. Spangler et. aJ - # Antimicro. Agents
  • the present invention includes compounds, compositions and methods effective to treat infections in mammals arising from ⁇ -lactam antibiotic resistant bacteria.
  • the present invention features compounds that have antibiotic activity against an organism resistant to a ⁇ -lactam antibiotic.
  • vi tro and in vivo data showing the effectiveness of these compounds is provided in U.S. applications Serial Nos. 08/413,712, 08/413,713, 08/413,714, 08/415,064, 08/413,065, and 08/413,069, filed March 29, 1995 and U.S. Serial No. unassigned, filed May 15, 1995, entitled "Cephalosporin Antibiotics” .
  • That data demonstrated potent activity for certain pharmacophores appended to selected ⁇ -lactam nuclei.
  • compounds having thio-linked aryl pharmacophores as illustrated in the compounds of Structures II, III, IV and V below were shown to have good effect :
  • ⁇ -lactam antibiotic compounds encompassed by the present invention are compounds having the thio linked aryl and heteroaryl pharmacophores shown above appended to other ⁇ -lactam nuclei as described in detail herein. Examples of several classes of such compounds are provided herein and techniques are presented for making such compounds and using them both in vi tro and in vivo . Such compounds preferably have a minimum inhibitory concentration (MIC) that is less that 50%, more preferably less than 10%, and most preferably less than 1% of the MIC of the Cefotaxime for a ⁇ -lactam resistant organism, such as those previously listed in Table 1 of of U.S. applications Serial Nos.
  • MIC minimum inhibitory concentration
  • Other preferred compounds are able to prevent or reduce mortality in mice infected with the ⁇ -lactam resistant organism to a greater extent that vancomycin or cefotaxime.
  • the present invention includes a compound of the formula selected from the group consisting of :
  • X is selected from the group consisting of CH 2 , S, and 0;
  • T is selected from the group consisting of CH 2 and 0;
  • U is selected from the group consisting of CH 2/ S, 0, and CH(alkyl) , where alkyl is C-* . to C 4 ;
  • Y is selected from the group consisting of H, OMe, and NHCHO;
  • R** is selected from the group consisting of H, Me, or Et;
  • R 1 is selected from the group consisting of -NHC(0)ZR 3 ;
  • -NR 4 R and where Z is selected from the group consisting of -CH 2 (X * ) m -, -C(NOR 6 )-, -CH(OR 7 )-, -C(CHC0 2 R 8 )- and -CH(NR 9 R 10 ) -,
  • X * is selected from the group consisting of 0 and S,
  • n is selected from the group consisting of 0 and 1;
  • R 3 is selected from the group consisting of cyano, alkyl, aryl, heterocycle, heteroaralkyl and (CH 2 ) n T*; n is 1 to 6
  • T* is selected from the group consisting of amino, amidino (C- or N- linked) , gaunidine, and isothiouseido, optionally substituted by alkyl, aryl, hydroxyl, or amino;
  • R 4"7 are independently selected from the group consisting of hydrogen, alkyl, aryl and acyl;
  • R 8 is selected from the group of hydrogen, alkyl and aryl
  • R 9 and R 10 are selected independently from the group consisting of hydrogen, alkyl, acyl, and heterocyclecarbonyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl, and trialkylsilyl;
  • R 8 is selected from the group of hydrogen, alkyl and aryl;
  • R 9 and R 10 are selected independently from the group consisting of hydrogen, alkyl, acyl, and heterocyclecarbonyl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl, and trialkylsilyl;
  • R 11 is selected from the group consisting of H, halogen, alkyl, hydroxyl, amino, cyano, hydroxyalkyl, carboxamidoalkyl, optionally substituted aminoalkyl or quaternary ammonium alkyl, and quaternary heteroaryliumalkyl;
  • p is 0 , 1 , or 2 q is 0 or 1 r is 1 , 2 or 3 , R 12 . is NR 13 R 14 ,
  • R 13 -R 16 are independently selected from the group consisting of H, hydroxy, amino, amidino, alkyl, cycloalkyl, acyl, and phosphoryl and taken together may form a 5- or 6-membered ring; and R 17 is H or alkyl .
  • p is 0 , 1 or 2 ;
  • R *** is selected from the group consisting of
  • R 11 is H or halogen
  • R 18 is cyano or an optionally substituted phenyl or heteroaryl
  • V is carbon or nitrogen
  • A, B and C are independently selected from the group consisting of CR 19 , nitrogen and sulphur, where R 19 is hydrogen, alkyl, hydroxyl, amino, cyano, hydroxymethyl, or mono- or dialkylaminomethyl; and
  • D, E, F, and G are independently selected from the group consisting of CR 19 or nitrogen, where R 19 is selected from the group consisting of hydrogen, alkyl, hydroxyl, amino, cyano, hydroxymethyl, and mono- or dialkylaminomethyl.
  • Preferred compounds include those compounds wherein the groups A-C, V and D-G are pyrazole, thiadiazole and pyridine, and R 18 is optionally-substituted phenyl, pyridyl, pyrazolyl, or cyano.
  • the present invention provides for compositions comprising an amount of the compound of Structures A, B, C and/or D effective to treat bacterial infections in mammals arising from bacteria resistant to ⁇ -lactam antibiotics and a pharmaceutically acceptable carrier or diluent.
  • the present invention includes methods for treating a bacterial infection in a mammal arising from bacteria resistant to ⁇ -lactam antibiotics comprising administering to a mammal suffering from such an infection a therapeutically effective amount of a compound of Structure A, B, C and/or D.
  • alkyl denotes branched or unbranched hydrocarbon chains containing between one and six, preferably one and four, carbon atoms, such as, e.g.. methyl, ethyl, ⁇ -propyl, iso-propyl, ⁇ -butyl, sec-butyl, iso-butyl, tert-butyl, and 2-methylpentyl.
  • These groups may be optionally substituted with one or more functional groups which are attached commonly to such chains, such as, e.g..
  • alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, 4-cyanobuty1, 2-guanidinoethyl, 3-N,N' -dimethylisothiouroniumpropyl, and the like.
  • alkenyl denotes an alkyl group as defined above having at least one double bond, e.g. , allyl, 3-hydroxy-2-buten-l-yl, 1-methyl-2-propen-1-yl and the like.
  • aryl denotes a chain of carbon atoms an which form an least one aromatic ring having preferably between about 6-14 carbon atoms, such as, e.g.. phenyl, naphthyl, indenyl, and the like, and which may be substituted with one or more functional groups which are attached commonly to such chains, such as, e.g..
  • heterocycle denotes a chain of carbon and at least one non-carbon atoms which together form one or more aromatic or non-aromatic rings having preferrably between about 6-14 atoms, such as, e.g.. furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl. These rings may be optionally substituted with one or more functional groups which are attached commonly to such rings, such as, e.g...
  • heteroaryl denotes an aromatic heterocycle as defined above.
  • heterotricycle denotes an aromatic heterocyclic substituent as defined above which comprises three aromatic rings.
  • heterocyclecarbonyl denotes the group -C(0)Het, where Het is heterocycle as defined above .
  • alkoxyl denotes the group -OR, where R is alkyl as defined above, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, trifluoromethoxy, 3-hydroxyhexyloxy, 2-carboxypropyloxy, 2-fluoroethoxy, carboxymethoxy and cyanobutyloxy and the like.
  • alkylthio denotes the group -SR, where R is alkyl as defined above, such as methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, sec-butylthio, iso-butylthio, tert-butylthio, trifluoromethylthio, 3-hydroxyhexylthio, 2-carboxypropylthio, 2-fluoroethylthio, carboxy ethylthio and cyanobutylthio and the like.
  • acyl denotes groups -C(0)R, where R is alkyl as defined above, such as formyl, acetyl, propionyl, or butyryl .
  • aryloxy denotes groups -OAr, where Ar is an aryl group as defined above.
  • aralkyl denotes groups -RAr, where R is alkyl and Ar is aryl, both as defined above.
  • heteroaryl denotes groups -RHetAr where R is alkyl and HetAr is heteroaryl as defined above.
  • trialkylsilyl denotes the group RR'R"Si-, where R, R' and R" are alkyl as defined above.
  • Trialkylammonium denotes the group [RR'R"N-] + , where R, R 1 and R" are alkyl as defined above.
  • amino denotes the group NRR' , where R and R' may independently be alkyl, aryl or acyl as defined above, or hydrogen.
  • amido denotes the group -C(0)NRR', where R and R' may independently be alkyl, aryl or acyl as defined above, or hydrogen.
  • cyanoamido refers to the group
  • ⁇ -lactam resistant bacteria refers to bacteria against which a ⁇ -lactam antibiotic has an minimum inhibitory concentration (MIC) greater than 32 mg/ml.
  • prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs may be easier to administer than the parent drug in some situations. For example, the prodrug may be bioavailable by oral administration but the parent is not, or the prodrug may improve solubility to allow for intravenous administration.
  • the present invention provides compounds, methods and compositions effective to treat bacterial infections, and, especially, infections arising from bacteria which have developed resistance to conventional ⁇ -lactam antibiotics. More importantly, the present invention provides compounds, methods and compositions effective to treat bacterial infections arising from bacteria which have developed resistance to conventional ⁇ -lactam antibiotics.
  • A. Preferred Embodiments of Structures A-D With respect to R 3 especially preferred embodiments are those compounds wherein R 3 is cyano, alkyl, aryl, heterocycle or heteroaralkyl. Other preferred embodiments include those wherein R 3 is hydroxyphenyl, preferably 4-hydroxyphenyl, heterocycle and heteroaralkyl.
  • Preferred heterocycle substituents include thienyl, furyl and thiazolyl, especially 2-thienyl, 2-furyl, and optionally substituted heterocycles such as 2-aminothiazol-4-yl.
  • preferred embodiments include those wherein Z is methylene, substituted oxyiminomethylene (-C(NOR)-), substituted oxymethylene (-CH(OR)-) , substituted (carboxymethylene)methylene (-C(CHC0 2 R) -) , and aminomethylene (-CH(NRR' ) -) .
  • Such groups include, e.g.. hydrogen, 2-fluoroethyl, cyclopropylmethyl, cyclopentyl, allyl, and dichloroallyl.
  • the present invention includes intermediates which are especially useful in the formation of the bactericides of the invention.
  • these intermediates include those embodiments of the invention wherein R 1 is -NRR' , where R and R' are hydrogen, and acyl.
  • R 1 is -NRR'
  • R and R' are hydrogen
  • acyl examples include, e.g.. t-butyloxycarbonyl and benzyloxycarbonyl.
  • the present invention also contemplates other R 2 substituents which are either easily hydrolyzed under biological conditions, i.e.. such groups which can be cleaved easily after injection or ingestion of a compound of the invention by a mammalian subject (see, e.g.. European Patent Application No. 527,686 Al to Tsushima, e£ aJL. , which is incorporated herein by reference) .
  • the present invention further contemplates substituents R 2 which are effective to protect the carboxyl group from unwanted reactions during synthesis of the compounds of the invention. Many such protective groups are well-known in the art (see, e.g...
  • R 13 -R 16 are H or lower alkyl.
  • Especially preferred compounds include those compounds wherein R 12
  • the compounds of the present invention may be readily prepared in accordance with the procedures described in the references provided in this section. However, it will be appreciated that other synthetic pathways for forming the compounds of the invention are available and that the following is offered merely by way of example, and not limitation. It will be further recognized that various protecting and deprotecting strategies will be employed which are standard in the art (see . e.g.. Green and Wuts) . Those of skill in the art will recognize that the selection of any particular protecting group (e.g. , a carboxy protecting group) will depend on the stability of the protected moiety with respect to subsequent reaction conditions.
  • ⁇ -lactams of the present invention may be achieved using well-known methods and readily available materials (see, e.g.. March; Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH Publishers, 1989) ; and G.I. Georg, THE ORGANIC CHEMISTRY OF ⁇ -lactams, (VCH 1992) , each of which is incorporated herein by reference) .
  • the substituent R 1 may be any of the groups described above and are either available commercially (e.g. , from Aldrich, Milwaukee, WI) or can be formed using known techniques and starting materials (see. e.g.. March; Larock) . These groups can be substituted for those present on the starting material by variety of well known techniques (see, e.g.. Barrett, J.C.S. Perkin I, 1629 (1979) or Chauvette, J. Org. Chem. 36:1259 (1971) , both of which are incorporated herein by reference) , such as by transamination of an existing substituent for the desired substituent, or hydrolytic removal of the existing substituent followed by reaction with a suitably reactive form of desired substituent, such as an acyl chloride. Again, the appropriate reagents and techniques will be apparent to those of skill in the art.
  • the carboxyl group R 2 may be those protecting groups amenable to reductive cleavage, such as benzyl, p- or o-nitrobenzyl, 2, 2, 2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl and the like.
  • R 2 may be a protecting group amenable to acidic cleavage, such as t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4 ' -dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, ⁇ - (trimethylsilyl) ethyl, benzyl, 4- (or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4, 6-trimethoxybenzyl, methoxymethyl, benzhydryl, or 3, 3-dimethylallyl .
  • a protecting group amenable to acidic cleavage such as t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4 ' -dimethoxytrityl, trimethylsilyl, t-butyldimethylsily
  • Preferred protecting groups are p-methoxybenzyl, p-nitrobenzyl, allyl and benzhydryl. Such groups may be attached to the unprotected carboxyl group of the ⁇ -lactam starting material using known reagents and techniques, such as those described in Green and Wuts.
  • Preferred amine protecting groups include trityl, formyl, phenoxyacetyl, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, urethane-type protecting groups [such as t-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-chloroallylcarbonyl, allyoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, (C 4 -C 6 ) -cycloalkanyloxycarbonyl or
  • Especially preferred protecting groups are trityl, allyoxycarbonyl, benzyloxycarbonyl, phenoxyacetyl, and t-butoxycarbonyl. These may be attached and removed using standard techniques (see Green and Wuts) .
  • the selection of the amine-protecting group to be employed will depend on the stability of the protected ⁇ -lactam to the subsequent reaction conditions.
  • a therapeutically or pharmaceutically effective amount of a ⁇ -lactam and particularly, a compound of Structures A-D is administered to a mammal suffering from an ⁇ -lactam resistant bacterial infection, especially resistant S. aureus, in an amount effective to at least partially relieve the infection.
  • infections resulting from ⁇ -lactam resistant strains having similar ⁇ -lactam resistant activity to strains such as S. aureus ATCC 29213, S. aureus ATCC 25913, S. aureus ATCC 31432, S. aureus col (Meth R ) (lac-) , S. aureus 76 (Meth R ) (lac + ) , S. aureus ColBA (Meth s ) (lac " ) , E. fsecium ATCC 35667, or E. fscalis ATCC 29212.
  • compositions containing the compound(s) of the invention can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from an infection, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the infection.
  • An amount adequate to accomplish this is defined as "therapeutically effective amount or dose.” Amounts effective for this use will depend on the severity and course of the infection, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds of the invention are administered to a patient susceptible to or otherwise at risk of a particular infection. Such an amount is defined to be a "prophylactically effective amount or dose.” In this use, the precise amounts again depend on the patient's state of health, weight, and the like.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, .treatment can cease.
  • a suitable effective dose of the compound of the invention will be in the range of 0.1 to 1000 milligram (mg) per recipient per day, preferably in the range of 1 to 100 mg per day.
  • the desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the day. These subdoses can be administered as unit dosage forms, for example, containing 5 to 1000 mg, preferably 10 to 100 mg of active ingredient per unit dosage form.
  • the compounds of the invention will be administered in amounts of between about 2.0 mg/kg to 250 mg/kg of patient body weight, between about one to four times per day.
  • the formulations of the present invention comprise at least one compound or inhibitor of this invention in a therapeutically or pharmaceutically effective dose together with one or more pharmaceutically or therapeutically acceptable carriers.
  • Solid carriers inlcude, e.g., starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, and optionally other therapeutic ingredients.
  • Liquid carriers include, e.g., sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut and sesame oils.
  • various adjuvants such as are commonly used in the art may be included. For example: flavoring agents, coloring agents, preservatives, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA.
  • Various other considerations are described, e.g., in Gilman et al.
  • pharmacological agents can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. The preferred form depends on the intended mode of administration and therapeutic application.
  • a pharmacologically acceptable salt of the compound will be used to simplify preparation of the composition.
  • Preferred salts include sodium, potassium, arginine, glycine, alanine, threonine. These are prepared, preferably, in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Such agents may be formulated and administered systemically or locally.
  • Techniques for formulation and administration may be found in Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Co., Easton, PA (1990) .
  • Suitable routes may include oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular subcutaneous, intramedullary injections, as well an intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, just to name a few.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Example 1 In Vi tro Antibacterial Evaluation
  • the compounds of the invention can be evaluated against several ⁇ -lactam resistant bacteria strains by determining the minimum inhibitory concentration (MIC, ⁇ g/ml) of each compound with respect to each strain.
  • MIC minimum inhibitory concentration
  • the MIC the lowest concentration of antibiotic which inhibits growth of the test organism, is determined by the agar dilution method.
  • the test compound is incorporated in a series of two-fold dilutions into liquified Mueller-Hinton agar. Upon solidification, a number of different bacterial strains are spot inoculated with a replicating device onto the agar surface. After overnight incubation, the MIC breakpoint is determined as the lowest drug concentration that completely inhibited growth, disregarding a single colony or a faint haze.
  • NCCLS National Committee for Clinical Laboratory Standards
  • phosphate buffered saline PBS
  • Tween 20 or DMSO is used as a solubilizing vehicle as needed. Standard methods of vortexing, sonicating and gentle heat are used to facilitate solubilizing the test agent.
  • concentration of the stock solution is 10X that of the highest drug concentration tested.
  • a 1.28 mg/mL stock solution is used with a subsequent highest working concentration of 128 ⁇ g/mL.
  • Serial two-fold dilutions are done through ⁇ 0.25 ⁇ g/mL. Each drug level is tested in duplicate. Two-fold drug dilutions are done in sterile 50 mL tubes with a final drug volume of 5 mL. Upon the addition of 45 mL of molten agar, a 10-fold dilution results. Two, 25 mL. plates are then poured into 15x150 mm square Petri plates with grids and allowed to harden.
  • a control plate with a reference drug either cefotaxime, vancomycin or imipenem, is used as the positive growth control.
  • Stock concentrations of reference antibiotics are prepared and frozen at -80°C Upon preparation, the control plates are sealed and stored in the refrigerator for up to 1 week prior to use; however, imipenem control plates have to be prepared just prior to use. All test plates are used within 24 hours of preparation.
  • the inoculum contained about 10 4 colony forming units (cfu) ⁇ 0.5 logs.
  • cfu colony forming units
  • a few isolated colonies are transferred to a tube of nutrient broth and allowed to grow 4-6 hours at 35-36°C to reach log-phase growth.
  • Dropwise addition of the broth culture to PBS is done to match a 0.5 McFarland turbidity standard equal to 10 8 cfu/mL. This is further diluted ten-fold in PBS to reach a working inoculum concentration of 10 7 cfu/mL.
  • a concentration of about 10 4 cfu per spot is obtained.
  • Disposable sterile l ⁇ L loops are used to inoculate test plates, with each isolate in a designated grid on the agar plate.
  • An alternate method of inoculation involves the use of a replica plater, a device with 48 steel pins allowing the simultaneous inoculation of multiple isolates. After the spots have dried, the plates are incubated at 35-36°C for 16-20 hours . Endpoints are assessed as the minimum inhibitory concentration (MIC) of antimicrobial agent.
  • mice Compounds with superior activity in vi tro when compared to reference antibiotics, are further evaluated in a murine model for lethal bacteremic peritonitis.
  • Groups of 5 female Swiss-Webster mice each are challenged by the intraperitoneal (IP) route with tenfold increments of a bacterial inoculum. This permits calculation of the mean lethal dose (LD 50 ) and the LD 100 .
  • IP intraperitoneal
  • mice are challenged IP with an LD 100 titer of bacteria.
  • mice In two equal doses administered at the time of bacterial challenge and 2 hours later, groups of 10 mice each are treated subcutaneously with two-fold increments of the test drug and an antibiotic of known efficacy in mice and humans (i.e., positive control) . Mice are observed for 72h. Those alive at 72h are considered long term survivors.
  • the total drug dose in mg/kg that protects 50% of mice in a group from death is termed the mean protective dose (PD 50 ) .
  • PD 50 s are similarly determined for several pathogens. The quantitative endpoints for the new drug are then compared with those obtained with reference antibiotics.
  • mice Six ten-fold dilutions of inoculum suspended in 0.5 mL of sterilized 7% hog gastric mucin (Sigma) are injected IP in groups of 5 mice each. A control group of 5 mice receive mucin alone. Mice are observed for 72h. Those alive at 72h are considered long term survivors. The mean lethal dose (LD 50 ) and 100% lethal dose (LD 100 ) are determined by the probit test . For antibiotic efficacy studies, mice are challenged IP with bacterial titers that will afford an LD 100 for the test strain.
  • mice In two equal doses administered at the time of bacterial challenge and 2 hours later, groups of 10 mice each are treated by the subcutaneous route (SC) with twofold increments of the test antibiotic; another group is treated similarly with a reference antibiotic of known efficacy in animals and man.
  • Drug doses can range from 0.01 to 512 mg/kg. If the drug is poorly soluble, Tween 20 or propylene glycol will be employed to solubilize the drug. Animals are observed for 72h.
  • the 50% protective dose (PD 50 ) is calculated in mg/kg by the probit method. The PD 50 is the same as the 50% effective dose (ED 50 ) and the 50% curative dose (CD 50 ) .
  • mice Most of these mice will die within 6 to 48 h. Those alive at 72h will be considered long term survivors.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention porte sur les composés des formules A-D. Dans ces formules, X est choisi dans le groupe constitué de CH2, S et O. T est choisi dans le groupe constitué de CH2 et O. U est choisi dans le groupe constitué de CH2, S, O et CH(alkyle), où alkyle correspond à C1 - C4; R*** est choisi dans le groupe constitué d'un hétérotricyclique; (a), (b) et (c). Ces composés présentent une activité antibiotique contre un spectre large d'organismes qui sont résistants aux antibiotiques du type β-lactame et ils sont utiles comme agents antibactériens.
PCT/US1996/008141 1995-05-31 1996-05-31 ANTIBIOTIQUES DU TYPE β-LACTAME Ceased WO1996038448A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59583/96A AU5958396A (en) 1995-05-31 1996-05-31 Beta-lactam antibiotics

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US08/455,969 US5698547A (en) 1994-04-01 1995-05-31 Cephalosporin antibiotics
US08/455,969 1995-05-31
US08/457,673 US5688786A (en) 1994-04-01 1995-06-01 β-lactam antibiotics
US08/457,673 1995-06-01
US542695P 1995-10-12 1995-10-12
US60/005,426 1995-10-12

Publications (1)

Publication Number Publication Date
WO1996038448A1 true WO1996038448A1 (fr) 1996-12-05

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PCT/US1996/008928 Ceased WO1996038450A1 (fr) 1995-05-31 1996-05-29 Cephalosporines
PCT/US1996/008141 Ceased WO1996038448A1 (fr) 1995-05-31 1996-05-31 ANTIBIOTIQUES DU TYPE β-LACTAME

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Application Number Title Priority Date Filing Date
PCT/US1996/008928 Ceased WO1996038450A1 (fr) 1995-05-31 1996-05-29 Cephalosporines

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WO (2) WO1996038450A1 (fr)

Cited By (4)

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Publication number Priority date Publication date Assignee Title
EP1082325A4 (fr) * 1998-05-28 2002-02-06 Merck & Co Inc Antibacteriens penemes, a base de naphtosulfamylmethyle
EP1199077A1 (fr) * 2000-10-19 2002-04-24 Amura Limited Compositions pharmaceutiques contenant des acides oxapénème-carboxyliques stabilisées par lyophilisation avec des excipients pharmaceutiques
WO2002032423A1 (fr) * 2000-10-19 2002-04-25 Amura Limited Compositions pharmaceutiques contenant des acides oxapenem-3-carboxyliques
CN112321606A (zh) * 2020-11-04 2021-02-05 福安药业集团重庆博圣制药有限公司 头孢唑肟钠及其中间体的制备方法

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AR029004A1 (es) * 1999-09-22 2003-06-04 Essential Therapeutics Inc Compuesto del acido 7-acilamino-3-heteroariltio-3-cefem carboxilico y su uso para la preparacion de una composicion antibacteriana

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EP0011173A1 (fr) * 1978-11-01 1980-05-28 Sanraku-Ocean Co., Ltd. Procédé pour la production de composés antibiotiques bêta-lactame
EP0074599A1 (fr) * 1981-09-09 1983-03-23 Takeda Chemical Industries, Ltd. Dérivés de 5,6-cis-carbapénème, leurs préparation et utilisation
EP0090366A1 (fr) * 1982-03-29 1983-10-05 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'acide 1-azabicyclo(3.2.0)hept-2-ène-2-carboxylique, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0113101A1 (fr) * 1982-12-30 1984-07-11 Merck & Co. Inc. Esters d'acides 6-(1-hydroxyéthyl)-2-SR8-1-méthyl-1-carbadéthiapén-2-ème-3-carboxyliques
EP0154253A1 (fr) * 1984-02-21 1985-09-11 Kyowa Hakko Kogyo Co., Ltd. Composé de carbacéphème 3-substitué et composition pharmaceutique le renfermant
EP0160391A1 (fr) * 1984-03-27 1985-11-06 Sankyo Company Limited Dérivés de carbapénème et compositions les contenant
EP0238285A2 (fr) * 1986-03-17 1987-09-23 Schering Corporation 2-Hétérocyclylthio-Pénèmes
EP0243686A2 (fr) * 1986-03-27 1987-11-04 Sumitomo Pharmaceuticals Company, Limited Dérivés de bêta-lactame et leur préparation
EP0405217A1 (fr) * 1989-06-24 1991-01-02 Bayer Ag 2-isocéphèmes et 2-oxa-isocéphèmes, procédé pour leur préparation et leur utilisation comme et dans des médicaments
EP0422596A2 (fr) * 1989-10-11 1991-04-17 Takeda Chemical Industries, Ltd. Dérivés de carbapénème tricycliques
US5077287A (en) * 1991-01-18 1991-12-31 Eli Lilly And Company 3-thiazolylthio carbacephem antibacterial agents
EP0502468A1 (fr) * 1991-03-07 1992-09-09 GLAXO S.p.A. Carbapénèmes condensés, antibactériens
EP0502465A1 (fr) * 1991-03-07 1992-09-09 GLAXO S.p.A. Esters de dérivés de carbapénème condensés, antibactériens
EP0507313A1 (fr) * 1991-04-05 1992-10-07 Takeda Chemical Industries, Ltd. Composés polycycliques de carbapénèmes, leur préparation et leur utilisation
EP0574940A1 (fr) * 1992-06-18 1993-12-22 Tanabe Seiyaku Co., Ltd. Procédé d'élimination du groupe protecteur de groupe carboxyle

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1082325A4 (fr) * 1998-05-28 2002-02-06 Merck & Co Inc Antibacteriens penemes, a base de naphtosulfamylmethyle
EP1199077A1 (fr) * 2000-10-19 2002-04-24 Amura Limited Compositions pharmaceutiques contenant des acides oxapénème-carboxyliques stabilisées par lyophilisation avec des excipients pharmaceutiques
WO2002032424A1 (fr) * 2000-10-19 2002-04-25 Amura Limited Compositions stables d'acides oxapeneme-3-carboxyliques par co-lyophilisation avec des excipients pharmaceutiques
WO2002032423A1 (fr) * 2000-10-19 2002-04-25 Amura Limited Compositions pharmaceutiques contenant des acides oxapenem-3-carboxyliques
US7247622B2 (en) 2000-10-19 2007-07-24 Amura Limited Pharmaceutical compositions containing oxapenem-3-carboxylic acids
CN112321606A (zh) * 2020-11-04 2021-02-05 福安药业集团重庆博圣制药有限公司 头孢唑肟钠及其中间体的制备方法

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AU5985596A (en) 1996-12-18
AU5958396A (en) 1996-12-18

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