WO1998046566A1 - ANTIBIOTIQUES DE β-LACTAME AMELIORES - Google Patents

ANTIBIOTIQUES DE β-LACTAME AMELIORES Download PDF

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WO1998046566A1
WO1998046566A1 PCT/US1998/007690 US9807690W WO9846566A1 WO 1998046566 A1 WO1998046566 A1 WO 1998046566A1 US 9807690 W US9807690 W US 9807690W WO 9846566 A1 WO9846566 A1 WO 9846566A1
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group
alkyl
prodrug
compound
salt
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PCT/US1998/007690
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English (en)
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In-Seop Cho
Scott J. Hecker
Tomasz W. Glinka
Ving J. Lee
Zhijia J. Zhang
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Microcide Pharmaceuticals, Inc.
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Priority to AU71261/98A priority Critical patent/AU7126198A/en
Publication of WO1998046566A1 publication Critical patent/WO1998046566A1/fr

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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
    • 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
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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
    • C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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 hetero atoms directly attached in position 7
    • C07D463/16—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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
    • C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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 hetero atoms directly attached in position 7
    • C07D463/16—Nitrogen atoms
    • C07D463/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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
    • C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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 hetero atoms directly attached in position 7
    • C07D463/16—Nitrogen atoms
    • C07D463/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D463/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D463/22—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by nitrogen 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
    • 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 generally to organic chemistry, pharmaceutical chemistry, biochemistry, biology and medicine. More particularly, the present invention relates to novel ?-lactam compounds and their pharmacologically acceptable salts and prodrugs. Furthermore, the use of the claimed compounds, their salts, prodrugs and pharmacological compositions containing them, as antibiotics with activity against a broad spectrum of organisms, especially organisms which are resistant to conventional ⁇ - lactam antibiotics is disclosed.
  • ?-lactams as bacteriocides involves the inhibition of bacterial peptidoglycan biosyn- thesis.
  • Bacterial resistance to ?-lactams occurs via 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
  • Pathway c) is particularly important in that 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 and that resistance has been shown to be due to the presence of high levels of an unusual PBP, PBP2a, which is insensitive, or binds poorly, to /?-lactam antibiotics.
  • MRSA methicillin-resistant Staphylococcus aureus
  • enterococci are highly resistant to ?-lactam antibiotics and that resistance has been shown to be due to the presence of high levels of an unusual PBP, PBP2a, which is insensitive, or binds poorly, to /?-lactam antibiotics.
  • the activity of ?-lactam antibiotics against PBP2a-containing organisms has been shown to correlate well with their binding affinity to PBP2a.
  • glycopeptides vancomycin and teicoplanin are primarily used for MRSA bacteremia.
  • the quinolone antibacterials and some carbapenems, such as imipenem, have been reported to be active against a few MRSA strains, but their use is already being restricted due to emerging resistant MRSA strains.
  • mice which may possess utility as anti-MRSA or anti-enterococcal bactericides
  • glycylcyclines see, e.g., P.-E. Sum et al., J. Med. Che . , 37, (1994)
  • FK-037 see, e.g., H. Ohki et al., J Antibiotics, 46:359-361 (1993)
  • RP-59,500 see, e.g., S.K. Spangler et al., Antimicro Agents Chemother., 36:856-9 (1992)
  • the everninomycin complex see, e.g., .E. Sanders et al., Antimicro.
  • the present invention relates generally to novel ⁇ - lactam compounds.
  • it relates to antibiotic ?-lactams.
  • this inven- tions relates to ?-lactams which have biocidal activity against microorganisms resistant to conventional /?-lactam antibiotics, especially methicillin and/or ampicillin resistant disease-causing bacteria.
  • the invention also relates to the preparation and use of pharmacological compositions of the disclosed compounds, their pharmacologically acceptable salts and prodrugs in the treatment of infections produced by disease-causing microorganisms.
  • the compounds of this invention preferably have a minimum inhibitory concentration (MIC) that is less that
  • Staphylococcal or Enterococcal organism more preferably a methicillin-resistant Staphylococcal or ampicillin-resistant
  • Enterococcal organism 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 compounds of this invention comprise an optionally substituted 4-membered ?-lactam ring fused through its nitrogen atom and the methylene group adjacent to the nitrogen to a five- or six-membered heteroalicyclic group.
  • the five- of six-membered heteroalicyclic group is substituted with an optionally-substituted carboxylic acid group and with a sulfur atom.
  • the sulfur atom is then bonded to a five- or six-membered heteroaromatic group (Q, below) .
  • the five- or six-membered heteroaromatic group is both optionally and mandatorily substituted.
  • the five- or six membered heteroaromatic group must be substituted with one or two groups comprising, first, an optionally present, optionally-substituted mono- or polymethylene spacer group (alki) which in turn is bonded to a lipophilicity-enhancing group (R 99 ) . If the spacer group is not present, the lipophilicity-enhancing group R 99 is bonded directly to the heteroaromatic ring.
  • the lipohili- city-enhancing group is bonded to another independent optionally-substituted mono- or polymethylene spacer group (alk 2 ) which, finally, is bonded to an end group (R 12 ) which is either formally positively charged or is capable of attaining a positive charge at normal biological pHs . Any positions remaining open on the heteroaryl groups may be optionally substituted with a wide variety of substituents, described below.
  • the present invention relates to a compound selected from the group comprising:
  • X is selected from the group including CH 2 , oxygen, sulfur, SO and S0 2 ;
  • T is selected from the group including CH 2 and oxygen
  • U is selected from the group including CH 2 , sulfur, oxygen and
  • Y is selected from the group including H, -OCH 3 , and -NHCHO;
  • R* is selected from the group including -CH(OH)CH 3 , C(OH) (CH 3 ) 2 ,
  • R** is selected from the group including H, -CH 3 , and -CH 2 CH 3 ,
  • Z is selected from the group including -CH 2 (X*) m -,
  • X* is selected from the group including oxygen and sulfur
  • n 0 or 1
  • R 3 is selected from the group including cyano, alkyl, aryl, heteroaryl, heteroaralkyl and-(CH 2 ) n W wherein: n is 1 - 6, inclusive; and,
  • R 4-7 are each independently selected from the group including hydrogen, alkyl, aryl and acyl;
  • R 8 is selected from the group including hydrogen, alkyl and aryl;
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, alkyl, acyl, and heterocyclecarbonyl ;
  • R 2 is selected from a group including hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and trialkylsilyl or R 2 is not present at all and the C0 2 group to which it would be attached bears a negative charge;
  • Q is a heteroaryl group selected from the group including:
  • A, B, D and E are selected from the group including carbon, nitrogen and sulfur and the specific juxtaposition of groups A, B, D, and E is limited to examples of heterocyclic groups known in the chemistry arts; and,
  • G, H, J, L and M are carbon, nitrogen or + NR n -(quaternary ammonium heterocycle) and the specific juxtaposition of groups G, H, J, L and M is limited to examples of heterocyclic groups known in the chemistry arts;
  • R 11 is selected from the group including hydrogen, halogen, alkyl, alkoxy, hydroxyl, amino, cyano, hydroxyalkyl, carboxamidoalkyl, optionally substituted aminoalkyl or quaternary ammonium alkyl and quaternary heteroaryliumalkyl; and,
  • R is - [ alk ⁇ ] p [R 9 3 9 3 -] q [ alk 2 ] r R ,12
  • alki and alk 2 are each independently selected from the group including optionally substituted methylene groups -(CR'R")-;
  • R' and R" are independently selected from the group including alkyl and aryl;
  • p 0, 1 or 2;
  • q is 0 or 1
  • r 0, 1, 2 or 3;
  • R 12 is selected from the group including NR 13 R 14 ,
  • R 13 -R 16 are independently selected from the group including hydrogen, hydroxy, amino, amidino, alkyl, cycloalkyl, acyl, aminoacyl and phosphoryl and, taken together, R 13 and R 14 or R 15 and R 16 may form a 5- or 6-membered nitrogen-containing heteroaryl or heteroalicyclic ring;
  • R .17 is selected from the group including hydrogen and alkyl
  • alk 2 and R 12 taken together may form an optionally substituted 5- or 6-membered heteroalicyclic group.
  • heteroaryl groups known in the chemistry arts include the following:
  • alkyl refers to a branched or unbranched hydrocarbon chain containing between one and eight, inclusive, preferably between one and four, inclusive, carbon atoms, such as, for example and without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and 2-methylpentyl.
  • the alkyl moiety may be optionally substituted with one or more functional groups including, for example and without limitation, hydroxyl, alkoxy, aryloxy, halo, mercapto, alkylthio, arylthio, cyano, aryl, heteroaryl, hetero- alicyclyl, carboxyl, alkoxycarbonyl, alkenyl, alkynyl, nitro, amino, amido, isothioureido, amidino, guanidino, and the like.
  • one or more functional groups including, for example and without limitation, hydroxyl, alkoxy, aryloxy, halo, mercapto, alkylthio, arylthio, cyano, aryl, heteroaryl, hetero- alicyclyl, carboxyl, alkoxycarbonyl, alkenyl, alkynyl, nitro, amino, amido, isothioureido, amidino, guanidino, and the like
  • alkyl groups formed pursuant to this definition: trifluoromethyl, 3-hydroxyhexyl, 2-carboxy- propyl, 2-fluoroethyl, carboxymethyl, 4-cyanobutyl, 2- guanidinoethyl, 3-N,N' -dimethylisothiouroniumpropyl, and the like.
  • alkenyl refers to an alkyl group as defined above having at least one double bond in the one to eight or one to four carbon atom branched or unbranched hydrocarbon chain; e.g., and without limitation, allyl, 3-hydroxy-2- buten-1-yl, l-methyl-2-propen-l-yl and the like.
  • alkynyl refers to an alkyl group as defined above having at least one triple bond in the one to eight or one to four carbon atom branched or unbranched hydrocarbon chain; e.g., and without limitation, acetylenyl, propynyl, 3-methyl-lbutynyl, 4-methyl-2-pentynyl and the like.
  • aryl refers to an all-carbon monocyclic or fused-ring group (i.e., rings which share adjacent pairs of carbon atoms) having a completely conjugated pi-electron system.
  • aryl groups are phenyl, naphthyl, indenyl, anthracenyl and the like.
  • the aryl group may be substituted or unsubstituted.
  • the substituted group (s) is preferably one or more selected from the group including, without limitation, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, cyanoamido, heteroaryl, heteroalicyclyl, carbonyl, carboxyl, alkoxy- carbonyl, nitro, amino, amido, and the like, to form aryl groups such as, without limitation, biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chloro- phenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetyl- phenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphen
  • heteroaryl refers to a monocyclic or fused-ring (i.e., rings which share two adjacent atoms) group having one or more atoms independently selected from the groups including nitrogen, oxygen and sulfur in the ring(s) and, furthermore, having a completely conjugated pi-electron system.
  • heteroaryl groups include, without limitation, furanyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl .
  • the heteroaryl group may be substituted or unsubstituted.
  • the substituted group (s) is preferably selected from a group including, without limitation, alkyl, aryl, hydroxyl, alkoxy, aryloxy, halo, mercapto, thioalkoxy, thioaryloxy, cyano, cyanoamido, heteroaryl, heteroalicyclyl, carboxyl, carbonyl, alkoxycarbonyl, nitro, amino, amido, and the like, to form rings such as, for example and without limitation, 2-aminothiazol-4-yl, 2,3-dioxo- piperazinyl, 4- alkylpiperazinyl, 2-iodo-3-dibenzfuranyl, 3-hydroxy-4- dibenzthienyl and the like.
  • heteroalicyclic refers to a monocyclic or fused-ring (i.e., rings which share two adjacent atoms) group having one or more atoms independently selected from the groups including nitrogen, oxygen and sulfur in the ring(s) wherein the ring system does not contain a fully conjugated pi-electron system.
  • carboxyheteroalicylic refers to a heteroalicyclic group substituted with a carboxylic acid or carboxylic acid ester group as defined herein.
  • alkoxy refers to an -0-alkyl group, alkyl being previously defined.
  • aryloxy refers to an -0-aryl group, aryl being previously defined.
  • thioalkoxy refers to an -S-alkyl group, alkyl being previously defined.
  • thioaryloxy refers to an -S-aryl group, aryl being previously defined.
  • aralkyl refers to an aryl-alkyl- group, aryl and alkyl being previously defined.
  • heteroarylkyl refers to a HetAr-alkyl- group, HetAr and alkyl being previously defined herein.
  • trialkylsilyl refers to an -Si (alkyl) 3 group, wherein each alkyl may be the same or an independently selected alkyl group as defined herein.
  • Trialkylammonium refers to an - + N (alkyl) 3 , group wherein each alkyl may be the same or an independently selected alkyl as defined herein.
  • amino denotes the group -NRR' , where R and R' are independently selected from the group including hydrogen, alkyl, aryl, heteroaryl, alicyclyl and heteroalicyclyl as each term is defined herein.
  • halo refers to fluorine, chlorine, bromine and iodine.
  • cyanamido refers to the -NR-CDN group where R is as previously defined herein.
  • lipophilicity enhancing refers to a group which increases the propensity for the molecule containing such a group to partition preferentially into an oily or fatty milieu over an aqueous one.
  • the measure of lipophilicity is termed the "octane/water partition coefficient", which is well- known to those of ordinary skill in the art.
  • R 2 the preferred embodiments of this invention are those in which R 2 is hydrogen since, in general, only those compounds in which R 2 is hydrogen are biologically active.
  • the present invention also contemplates other R 2 substituents which are 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 an organism, especially a mammal (see, e.g., European Patent Application No. 527,686 Al to Tsushima, et al., which is fully incorporated, including any drawings, 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.
  • 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., Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (Wiley 1991), which is incorporated herein by reference) .
  • Examples of such groups include allyl, t- amyl, benzhydryl, t-butyl, t-butyldimethylsilyl, benzyl, 2- chloroallyl, 3, 3-dimethylallyl, 2, 4-dimethoxybenzyl, 3,4- dimethoxybenzyl, 4, 41-dimethoxytrityl, 4-methoxybenzyl, 2- methoxybenzyl, 4-methoxytrityl, methoxymethyl, 4- nitrobenzyl, 2-nitrobenzyl, phenacyl, 2, 2, 2-trichloroethyl, trimethylsilyl, 2- (trimethylsilyl) ethyl, and trityl as well as the trifluoro-acetate, hydrochloride, hydrobromide and sulfate salts thereof.
  • R* is -CH(OH)CH3 or -C(OH) (CH3) 2
  • R** is hydrogen
  • Z is selected from the group including -CH2(X*) m - and
  • R 3 is selected from the group including cyano, aryl and heteroaryl
  • r is 1 , 2 or 3 ;
  • R 12 is selected from the group including -NR 13 R 14 ,
  • R i3 - i7 are selected from the group including hydrogen and alkyl; or,
  • alk 2 and R 12 combine to form an optionally substituted 5- or 6- membered heteroalicyclic group containing one nitrogen, examples of which, as preferred embodiments but without limitation, are:
  • R 3 is a heteroaryl group on which at least one of the substitutents is an amino group
  • p is 0 or 1;
  • r is 1 or 2;
  • R .99 is sulfur
  • R 12 is NR 13 R 14
  • R 13 and R 14 are hydrogen.
  • compositions .
  • the present invention provides for the administration of a pharmacological composition containing a therapeutically effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof to an organism suffering from infection by a disease-causing microorganism.
  • organism refers to any multicellular life form but preferably refers to mammals such as, without limitation, mice, rats, cats, dogs, horses, monkeys, pigs, goats, etc. Most preferably, the organism is a human being.
  • a “pharmacologically acceptable salt” refers to a salt including, but not limited to, sodium, potassium, arginine, glycine, alanine and threonine. These may be prepared in water mixed with a suitable surfactant such as hyroxypropyl- cellulose. Other salts, surfactants and methods of preparation are well known to those skilled in the art.
  • prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because,' in some situations, they may be easier to administer than the parent drug. They also may be bioavailable by oral administration whereas the parent may not be. The prodrug may also have improved solubility in a pharmacological composition over the parent.
  • the use of a bioreactive R 2 group is an example of a prodrug. That is, as noted previously, when R 2 is anything but hydrogen, the compound is generally biologically inactive. However, some types of R 2 groups can be removed in vivo, by naturally occurring biological processes, leaving the compound in the same (biologically active) form as if it had begun with R 2 being hydrogen. Such a compound, with R 2 being a biologically removable group, is an example of a "prodrug".
  • infection refers to the entrance, growth and multiplication, in the body of an organism, of a disease-causing microorganism, in particular, for the purposes of this invention, disease-causing bacteria and even more particularly, /?-lactam resistant disease-causing bacteria such as, for example and without limitation, MRSA and enterococci, discussed above.
  • a "disease-causing microorganism” refers to a virus, fungus, bacterium, paramecium, amoeba, etc. which, when it enters the body of an organism, causes a pathological condition in that organism.
  • ?-lactam resistant disease-causing bacteria refers to bacteria which, when they enter an organism, cause an infection and for which conventional ⁇ - lactam antibiotics such as, for example, methicillin or ampicillin have a minimum inhibitory concentration (MIC) greater than 32 mg/ml.
  • MIC minimum inhibitory concentration
  • a “therapeutically effective amount” refers to that amount of the compound being administered which will eliminate an infection or which will to some extent relieve one or more of its symptoms.
  • a "pharmaceutical composition” refers to mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Carriers may be solids or liquids.
  • Solid carriers include, 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.
  • an "excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents.
  • a pharmacological composition can assume a variety of forms. These include, for example, solid, semi-solid and liquid forms, such as tablets, pills, powders, capsules, liquid solutions or suspensions, liposomes and injectable and infusible solutions.
  • pharmacological compositions can be specifically prepared for administration systemically or locally.
  • the choice, and techniques for preparation, of pharmacological compositions may be found in Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Co., Easton, PA (1990) as well as in numerous other publications well known to those skilled in the art.
  • Routes for the administration of the compounds of this invention include oral, rectal, transdermal, vaginal, trans- mucosal, 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.
  • preferred routes of administration are oral or intravenous, intraperitoneal or intramuscular injection, ii. Dosage .
  • a therapeutically effective amount of one or more compounds of this invention is administered to a organism suffering from a ?-lactam resistant infection, including, but not limited to, methicillin-resistant, vancomycin-resistant or ampicillin- resistant bacterial infections in an amount effective to at least partially relieve the infection.
  • a suitable effective dose of a compound of this 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 may be administered in one dose or, preferably, in 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 one and four times per day.
  • a maintenance dose may be administered if desired by the treating physician. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the response of the patient, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment can cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of the disease symptoms.
  • Prophylactic use As well as being useful to treat patients with an ongoing infection, the compounds of this invention may be used in a prophylactic manner. That is, 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.
  • 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 the desired substituent, such as an acyl chloride.
  • a suitably reactive form of the desired substituent such as an acyl chloride.
  • 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 ' -dimethoxy- trityl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, S- (trimethylsilyl) ethyl, benzyl, 4- (or 2-methoxybenzyl, 2,4- di ethoxybenzyl, 3, 4-dimethoxybenzyl, 2, 4 , 6-trimethoxy- benzyl, methoxymethyl, benzhydryl, or 3, 3-dimethylallyl.
  • a protecting group amenable to acidic cleavage such as t- butyl, t-amyl, trityl, 4-methoxytrityl, 4, 4 ' -dimethoxy- trityl, trimethylsilyl, t-buty
  • 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
  • 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.
  • thiolate nucleophile 2 may be formed using known procedures and commercially available starting materials.
  • the following references, which are incorporated, including any drawings, by reference herein, provide experimental details for accomplishing the synthesis shown in Scheme I for compounds of types A, B and C:
  • Patents 4,782,145 and 4,782,146 (6) M. Sunagawa, H. Matsumura, T. Inoue and M. Fukasawa, J. Antibiotics, 45, 500 (1992); and (7) D. Phillips and B.T. O'Neill, Tetrahedron Letters, 31, 3291 (1990) .
  • this invention relates to novel ?-lactam antibiotics demonstrating activity superior to conventional ?-lactams such as methicillin, ampicillin and vancomycin against bacterial infections.
  • the following assays are employed to select those compounds demonstrating the optimal degree of the desired activity. i. In Vitro.
  • the compounds of the invention can be evaluated against ?-lactam resistant (for instance, but not limited to, methicillin-resistant , vancomycin-resistant and/or ampicillin-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 liquefied 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.
  • Disposable sterile 1 ⁇ 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.
  • MIC minimum inhibitory concentration
  • mice Groups of 5 female Swiss-Webster mice (Simonsen, Gilroy, CA) 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 LDioo.
  • mice are challenged IP with an LDioo titer of bacteria.
  • 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 quanti- tative endpoints for the new drug are then compared with those obtained with reference antibiotics.
  • mice are challenged IP with bacterial titers that will afford an LDioo for the test strain.
  • SC subcutaneous route
  • 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 5 o) and the 50% curative dose (CD 50 ) .
  • Samples of blood from the hearts of all animals that die and from half the mice that survive are cultured on brain-heart infusion agar. Animals that received a protective dosage of the test drug will be alive at 72h, although they may appear moderately ill to very ill during the observation period. Infected, placebo-treated control mice and those receiving non-effective i.e. lower dosages of the test drug will demonstrate a high rate of mortality. Most of these mice will die within 6 to 48h.

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Abstract

La présente invention concerne de nouveaux composés de bêta-lactame, leurs sels et leurs promédicaments pharmacologiquement acceptables, qui présentent une activité antibiotique contre de nombreux organismes, en particulier les bactéries résistant aux antibiotiques de bêta-lactame traditionnels, par exemple la bactérie d'origine staphylococcique résistant à la méthicilline, et la bactérie d'origine entérococcique résistant à l'ampicilline.
PCT/US1998/007690 1997-04-17 1998-04-15 ANTIBIOTIQUES DE β-LACTAME AMELIORES WO1998046566A1 (fr)

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AU71261/98A AU7126198A (en) 1997-04-17 1998-04-15 Improved beta-lactam antibiotics

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US08/842,915 1997-04-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5077287A (en) * 1991-01-18 1991-12-31 Eli Lilly And Company 3-thiazolylthio carbacephem antibacterial agents
US5538964A (en) * 1995-02-22 1996-07-23 Merck & Co., Inc. 3-thioheteroaryl 1-carba-1-dethiacephalosporin compounds, compositions and methods of use
US5541317A (en) * 1991-05-31 1996-07-30 Sankyo Company, Limited Azetidinone compounds useful in the preparation of carbapenem antibiotics and process for preparing carbapenem and penem compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5077287A (en) * 1991-01-18 1991-12-31 Eli Lilly And Company 3-thiazolylthio carbacephem antibacterial agents
US5541317A (en) * 1991-05-31 1996-07-30 Sankyo Company, Limited Azetidinone compounds useful in the preparation of carbapenem antibiotics and process for preparing carbapenem and penem compounds
US5538964A (en) * 1995-02-22 1996-07-23 Merck & Co., Inc. 3-thioheteroaryl 1-carba-1-dethiacephalosporin compounds, compositions and methods of use

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