WO2003090761A1 - Antibacteriens 9-oxime macrolide - Google Patents

Antibacteriens 9-oxime macrolide Download PDF

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Publication number
WO2003090761A1
WO2003090761A1 PCT/US2003/012478 US0312478W WO03090761A1 WO 2003090761 A1 WO2003090761 A1 WO 2003090761A1 US 0312478 W US0312478 W US 0312478W WO 03090761 A1 WO03090761 A1 WO 03090761A1
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alkyl
group
heteroaryl
aryl
heterocyclyl
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PCT/US2003/012478
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English (en)
Inventor
Xenia Beebe Searle
Stevan Djuric
Zhenkun Ma
Fan Yang
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Abbott Laboratories
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Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP03719894A priority Critical patent/EP1501519A1/fr
Priority to CA002483221A priority patent/CA2483221A1/fr
Priority to JP2003587394A priority patent/JP2006513976A/ja
Priority to MXPA04010558A priority patent/MXPA04010558A/es
Publication of WO2003090761A1 publication Critical patent/WO2003090761A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • TECHNICAL FIELD This invention is directed to compounds which are useful as antibacterials, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis or treatment of bacterial infections using the compounds .
  • a first embodiment of this invention is directed to compounds which are useful as antibacterials, and salts, prodrugs, and salts of prodrugs thereof, the compounds having formula ( I )
  • R 1 is alkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, -CH 2 R 5 , alkyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl, - (CH 2 ) alkenyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl; R is hydrogen, alkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl,
  • R is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl ;
  • R 8 and R are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl; or
  • R and R together are C 3 -C -alkylene or C 4 -C -alkylene interrupted with one moiety selected from the group consisting of an -0-, -NH-, -N (alkyl)-, -S-, -C(0) ⁇ , -S(0)-, and -S0 2 -; and
  • a second embodiment of this invention is directed to a process for making compounds having formula (I)-d
  • R 1 is alkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, -CH 2 R ⁇ , alkyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl, - (CH 2 ) alkenyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl;
  • R is alkyl interrupted with one or two or three moieties independently selected from the group consisting of -0-, -NH-, -N (alkyl)-, -S-, -S (0) -, and -S0 2 - or alkyl interrupted with one or two or three moieties independently selected from the group consisting of -0-, -NH-, -N (alkyl)-, -S-, -S(0)-, and -S0 2 - and substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl,
  • R is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
  • R 8 and R9 are iindependently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl; or
  • R 8 and R9 together are C 3 -C 7 -alkylene or C-C-alkylene interrupted with one moiety selected from the group consisting of -0-, -NH-, -N (alkyl)-, -S-, -C(0)-, -S(0)-, and -S0 2 -; and
  • X is hydrogen, the process comprising the steps of:
  • H 2 N-0R 2 (2) or salts thereof, a preferred embodiment of which is methoxylamine hydrochloride, with or without an additive, at a pressure between about 1.2 and 5 atm, to provide compounds having formula (I) -a
  • a third embodiment of this invention is directed to intermediates which are used in the second embodiment.
  • a fourth embodiment of this invention is directed to a process for making compounds having formula (I)-c
  • R 1 is alkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, -CH 2 R 6 , alkyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl, - (CH 2 ) alkenyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl;
  • R is acetyl or benzoyl
  • R is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
  • R and R are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent independently selected from the group consisting of aryl, heteroaryl, and heterocyclyl; or R 8 and R together are C 3 -C 7 -alkylene or C -C 7 -alkylene interrupted with one moiety selected from the group consisting of -0-, -NH-, -N (alkyl)-, -S-, -C(0)-, -S(0)-, and -S0 2 -, the process comprising the step of:
  • a sixth embodiment of this invention is directed to compositions which are useful for prophylaxis or treatment of bacterial infections in a fish or a mammal, the compositions comprising a therapeutically effective amount of one or more of the compounds of the first embodiment and an excipient.
  • a seventh embodiment of this invention is directed to use of one or more of the compounds of the first embodiment for the preparation of a medicament for prophylaxis or treatment of bacterial infections.
  • Alkenyl means monovalent, straight-chain and branched-chain hydrocarbon moieties, having two to eight carbon atoms and at least one carbon-carbon double bond.
  • Alkenyl moieties include but-1, 3-dienyl, butenyl, but-2-enyl, ethenyl, l-ethylhexen-2-yl, hex-3-enyl, 1-methylbutenyl, 2-methylbutenyl, l-methylbut-2-enyl, 1-methylbut-l, 3-dienyl, pentenyl, pent-2-enyl, and pent-3-enyl, propenyl .
  • Alkyl means monovalent, saturated, straight-chain and branched-chain hydrocarbon moieties, having one to six carbon atoms .
  • Alkyl moieties include butyl, 1, 1, -dimethylethyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, ethyl, 1-ethylpropyl, 2-ethylpropyl, hexyl, methyl, 2-methyl ⁇ ropyl, 3-methylbutyl, 1-methylpentyl, 2-methylpent-3-yl, and pentyl .
  • Alkylene means divalent, saturated, straight-chain and branched-chain hydrocarbon moieties, having one to eight carbon atoms .
  • Alkylene moieties include butylene, 1,1, -dimethylethylene, 1, 1-dimethylpropylene, 1, 2-dimethylpropylene, ethylene, 1-ethylpropylene, 2-ethylpropylene, hexylene, methylene, 2-methylpropylene, 3-methylbutylene, 1-methylpentylene, 2-methylpent-3-ylene, and pentylene.
  • Alkynyl means monovalent, straight-chain and branched-chain hydrocarbon moieties, having two to six carbon atoms and at least one carbon-carbon triple bond.
  • Alkynyl moieties include ethynyl (acetylenyl) , pentynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, l-methylbut-2-ynyl, 2-methylbut-3-ynyl, hexynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, l-methyl-pent-2-ynyl, l-methylenepent-3-ynyl, 1-methyl-pent-2, 4-diynyl, and prop-2-ynyl (propargyl) .
  • Aryl means monovalent, unsubstituted and substituted phenyl moieties, attached through a carbon atom, and unfused or fused with another phenyl moiety or a cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, naphthyl, or saturated part of an indanyl moiety.
  • Phenyl moieties fused with phenyl, naphthyl, or the saturated part of an indanyl moieties are unsubstituted and substituted naphthyl, anthracen- (1- to 4-)yl, or fluoren-(l- to 4-)yl, respectively.
  • Phenyl moieties fused with cycloalkyl moieties are unsubstituted and substituted indan-(4- to 7-)yl and 1, 2, 3, -tetrahydronaphth- (5- to 8-)yl.
  • Phenyl moieties fused with cycloalkenyl moieties are unsubstituted and substituted inden-(4- to 7-)yl, 1, 2-dihydronaphth- (5- to 8-)yl and 1, 2-dihydronaphth- (5- to 8-)yl.
  • Phenyl moieties fused with heteroaryl moieties include unsubstituted and substituted benzimidazol- (4- to 7-)yl, 1-benzofuran- (4- to 7-)yl, 1, 2-benzisothiazol- ( 4- to 7-)yl, benzthiazol- (4- to 7-)yl, 1-benzothiophen- (4- to 7-)yl, cinnolin-(5- to 8-)yl, indol-(4- to 7-)yl, isoquinolin- (5- to 8-)yl, phthalazin- (5- to 8-)yl, quinazolin- (5- to 8-)yl, quinolin-(5- to 8-)yl, and quinoxalin- (5- to 8-)yl.
  • Phenyl moieties fused with heterocyclyl moieties include unsubstituted and substituted 1, 3-benzodiox- (4- to 7-)yl, 1, -benzodiox- (5- to 8-)yl, 1, 3-dihydro-2-benzofuran- (4- to 7-)yl, 2, 3-dihydro-l-benzofuran- (4- to 7-)yl, 1, 3-dihydro-2-benzothiophen- (4- to 7-)yl,
  • Cycloalkyl means monovalent, unsubstituted and substituted, saturated cyclic hydrocarbon moieties, having three to six carbon atoms.
  • Cycloalkyl moieties are unsubstituted and substituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Cycloalkenyl means means monovalent, unsubstituted and substituted, cyclic hydrocarbon moieties having four to six carbon atoms and at least one carbon-carbon double bond.
  • Cycloalkenyl moieties are unsubstituted and substituted 1, 3-cyclohexadienyl, 1, -cyclohexadienyl, cyclohexenyl, cyclopentadienyl, and cyclopentenyl .
  • Halo means fluoro (-F) , chloro (-C1) , bromo (-Br) , and iodo (-1) moieties.
  • Heteroaryl means monovalent, aromatic, unsubstituted and substituted five-membered ring moieties having two double bonds and (a) one oxygen or one sulfur atom, (b) one, two, three, or four nitrogen atoms, or (c) one or two nitrogen atoms and one oxygen or one sulfur atom and the remaining atoms are carbon atoms, each of which is attached through a carbon atom or a nitrogen atom; and monovalent six-membered ring moieties having three double bonds and one, two, or three nitrogen atoms and the remaining atoms are carbon atoms, attached through a carbon atom; in which the foregoing heteroaryl moieties are unfused or fused with another heteroaryl moiety or an aryl moiety.
  • Five-membered heteroaryl moieties fused with aryl moieties include unsubstituted and substituted benzimidazol- (1- or 2-)yl, 1-benzofuran- (2- to 3-)yl, 1, 2-benzisothiazol-3-yl, benzthiazol-2-yl, 1- benzothiophen- (2- to 3-)yl, cinnolin-(3- or 4-)yl, indol-(l- to 3-)yl, isoquinolin- (1-, 3-, or 4-)yl, phthalazin- (1- or 4-)yl, quinazolin- (2- or 4-)yl, quinolin-(2- to 4-)yl, and quinoxalin- (2- or 3-)yl.
  • Five-membered heteroaryl moieties fused with other five-membered heteroaryl moieties include unsubstituted and substituted [1, 3] thiazolo [4, 5-d] [1, 3] oxazolyl, [1,3] thiazolo [4, 5-d] [1,3] thiazolyl, thieno [3, 2-d] [1, 3] oxazolyl, thieno [3, 2-d] [1, 3] thiazolyl, and thieno [2, 3-b] thiophenyl .
  • Five-membered heteroaryl moieties fused with six-membered heteroaryl moieties include unsubstituted and substituted furo [2, 3-b]pyridin- (2- or 3-)yl, 3H-imidazo [4, 5-b] pyridin- (2- or 3-)yl, [1,3] thiazolo [4, 5-b] pyrazin-2-yl,
  • heteroaryl moieties are unsubstituted and substituted pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, and 1, 3, 5-triazinyl .
  • heteroaryl moieties fused with aryl moieties include unsubstituted and substituted cinnolin-(3- or 4-)yl, isoquinolin- (1-, 3-, or 4-)yl, phthalazin- (1- or 4-)yl, quinazolin- (2- or 4-)yl, quinolin-(2- to 4-)yl, and quinoxalin- (2- or 3-)yl.
  • Six-membered heteroaryl moieties fused with five-membered heteroaryl moieties include unsubstituted and substituted furo [2, 3-b]pyridin- (4- to 6-)yl, 3H-imidazo [4, 5-b] pyridin- (5- to 7-)yl, [1, 3] thiazolo [4, 5-b] pyrazin- (5- or 6-)yl, [1, 3] thiazolo [4, 5-b] pyridin- (5- to 7-)yl, and thieno [2, 3-b]pyridin- (4- to 6-)yl.
  • Six-membered heteroaryl moieties fused with other six-membered heteroaryl moieties include unsubstituted and substituted 1, 5-naphthyridinyl, 1 , 7-naphthyridinyl,
  • Heterocyclyl means (a) monovalent, non-aromatic, unsubstituted and substituted four-membered ring moieties having one nitrogen, oxygen, or sulfur atom and the remaining atoms are carbon atoms, zero double bonds, attached through a carbon atom or a nitrogen atom, (b) monovalent, non-aromatic, unsubstituted and substituted five-membered ring moieties having one or two nitrogen, oxygen, or sulfur atoms and the remaining atoms are carbon atoms, and zero or one double bonds, attached through a carbon atom or a nitrogen atom, and (c) monovalent, non-aromatic, unsubstituted and substituted six-membered ring moieties having one, two, or three nitrogen, oxygen, or sulfur atoms and the remaining atoms are carbon atoms, and zero, one, or two double bonds, attached through a carbon atom or a nitrogen atom.
  • Five-membered heterocyclyl moieties include unsubstituted and substituted 1, 4-dioxanyl, 1, 3-dioxolanyl, imidazolidinyl, 2-imidazolinyl, 4 , 5-dihydroisoxazolyl, pyrazolidinyl, 2-pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, and 2H-pyrrolyl.
  • Six-membered heterocyclyl moieties include unsubstituted and substituted 1, 3-dithianyl, 1, 4-dithianyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, 2H-pyranyl, 4H-pyranyl, and thiomorpholinyl .
  • Substituted aryl and heteroaryl moieties are those moieties substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, -CN, -OH, -SH, -NH 2 , -NC-2, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -OCF 3 , -OCH2CF 3 , -OCF 2 CF 3 , -OR 30 , -SR 30 , -S(O) (alkyl) , -S0 2 (alkyl), -C(0)H, -C(O) (alkyl) , -C(0)OH, -C (0) O (alkyl) , -NH(alkyl), -N(alkyl) 2 , -C(0)NH 2 , -C (0) H (alkyl)
  • Substituted cycloalkyl, cycloalkenyl, and heterocyclyl moieties are those moieties substituted with one, two, or three substituents independently selected from the group consisting of alkyl, phenyl, halo, -CN, -OH, -NH 2 , -CF 3 , -OR 30 , -SR 30 , -S(O) (alkyl) , -S0 2 (alkyl), -C(0)H, -C(O) (alkyl) , -C(0)OH, -C (0) 0 (alkyl) , -NH (alkyl), -N(alkyl) 2 , -C(0)NH 2 , -C (0) NH (alkyl) , and -C (0) N (alkyl) 2 , in which the phenyl is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo
  • Hydroxyl protecting moiety means selectively introducible and removable moieties which protect -OH moieties against undesirable side reactions. Hydroxyl protecting moieties include 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, tert-butoxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 2,2, 2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl,
  • variable moieties may combine to provide an eighth embodiment of this invention, which embodiment is directed to compounds having formula (I) and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
  • R 1 is - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl;
  • R is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl ;
  • R 8 and R9 are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
  • X is hydrogen or fluoro; compounds having formula (I) , and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
  • R is - (CH 2 ) alkynyl or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl;
  • R is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl ;
  • R 8 and R9 are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
  • X is hydrogen or fluoro; compounds having formula (I) , and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
  • R is - (CH 2 ) alkynyl or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of aryl and heteroaryl;
  • R is hydrogen, alkyl, or alkyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl;
  • X is hydrogen or fluoro; compounds having formula (I) , and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
  • R is - (CH 2 ) alkynyl or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of aryl and heteroaryl;
  • R is hydrogen, alkyl, or alkyl substituted with phenyl
  • X is hydrogen or fluoro; compounds having formula (I), and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which R is - (CH 2 ) alkynyl or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of aryl and heteroaryl; R is alkyl; R is hydrogen or R P , in which R P is a hydroxyl protecting moiety; one of R4 and R5 is hydrogen and the other is -OH; or R 4 and R5 together are
  • R 1 is - (CH 2 ) alkynyl or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, thienyl, isoxazolyl, thiazolyl, pyridyl and pyrimidinyl, in which the thienyl, isoxazolyl, thiazolyl, pyridyl and pyrimidinyl are independently unsubstituted or substituted with one substituent selected from the group consisting of pyrimidinyl, pyridyl, thienyl, isoxazolyl, thiazolyl, 1H- tetraazol-5-yl, 2H-tetraazol-5-yl, l-methyl-lH-tetraazol-5- yl, and 2-methyl-2H-tetraazol-5-y
  • R 2 is alkyl
  • X is hydrogen or fluoro; compounds having formula (I), and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
  • R is prop-2-ynyl, 3- (quinolin-3-yl) prop-2-ynyl, 3- (1, 5-naphthyridin-3-yl) prop-2-ynyl, 3- (quinoxalin-6- yl)prop-2-ynyl, 3- (5- (2-methyl-2H-tetraazol-5-yl) thien-2- yl)prop-2-ynyl, 3- (5- (pyridin-2-yl) thien-2-yl) prop-2-ynyl, 3- (2- (pyrimidin-2-yl) thien-5-yl) prop-2-ynyl, 3- (2- (2-methyl- 2H-tetraazol-5-yl) 1, 3-thiazol-5-yl) prop-2-ynyl, 3- (2- (2-methyl-2H-tetraazol-5-yl) pyridin-6-yl) prop-2-ynyl, 3- (3- (pyridin-2-yl) isox
  • R is alkyl
  • R is hydrogen or R , in which R is a hydroxyl protecting moiety; one of R 4 and R5 are hydrogen and the other is -OH; or
  • X is hydrogen or fluoro; and compounds having formula (I), and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
  • R is - (CH 2 ) alkynyl or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of aryl and heteroaryl;
  • R is methyl
  • X is hydrogen or fluoro
  • R moieties are 3- (qumolm-3- yl) prop-2-ynyl, 3- (1, 5-naphthyridin-3-yl) prop-2-ynyl, 3- (quinoxalin-6-yl) prop-2-ynyl, 3- (5- (2-methyl-2H-tetraazol-5- yl) thien-2-yl) prop-2-ynyl, and 3- (5- (pyridin-2-yl) thien-2- yl)prop-2-ynyl.
  • R moiety is methyl
  • R 3 moiety is hydrogen
  • X moieties are hydrogen and fluoro;
  • R is - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of naphthyridinyl, quinolinyl, quinoxalinyl, and thienyl, in which the thienyl is substituted with one substituent selected from the group consisting of pyridyl and 2H-tetraazolyl, in which the 2H-tetraazolyl is substituted
  • R 4 and R5 taken together 0; and X1 is fluoro; compounds having formula (I) , and salts, prodrugs, and salts of prodrugs thereof, m whi .
  • Compounds of this invention contain asymmetrically substituted carbon atoms in the R or S configuration, in which the terms "R” and “S” are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl . Chem. (1976) 45, 13-10.
  • Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms .
  • Atoms with an excess of one configuration over the other are assigned the configuration which is present in the higher amount, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace all stereoisomers of the compounds including racemic mixtures, enantiomers, mixtures of enantiomers, diastereomers, and mixtures of diastereomers .
  • Individual stereoisomers of the compounds may be prepared I any one of a number of methods within the knowledge of the ordinarily skilled practioner. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, enzyme resolution, and conversion of enantiomers in an enantiomeric mixture to diastereomers and chromatographically separating the diastereomers and regeneration of the individual enantiomers .
  • Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers .
  • Diastereomeric mixtures of compounds resulting from a synthetic reaction can be separated by chromatographic technique, which are well-known to the ordinarily skilled practioner.
  • Chromatographic resolution of enantiomers can be accomplish, on chiral commercially available chromatography resins .
  • the racemate is placed in solution and loaded onto the column containing a chiral stationary phase.
  • the enantiomers arc then separated by high performance liquid chromatography.
  • Enzymes such as esterases, phosphatases and upases, may be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture.
  • an ester derivative of a carboxyl group of the compounds to be separated can be prepared.
  • Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
  • Resolution of enantiomers may also be accomplished by converting the enantiomers in the mixture to diastereomers by reacting of the former and chiral auxiliaries .
  • the resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries .
  • Compounds of this invention may also contain carbon-carbon double bonds or carbon-nitrogen double bonds in the Z or E configuration, in which the term “Z” represents the larger two substituents on the same side of a carbon-carbon or carbon-nitrogen double bond and the term “E” represents the larger two substituents on opposite sides of a carbon-carbon or carbon-nitrogen double bond.
  • the compounds may also exist as an equilibrium mixture of Z or E configurations .
  • prodrug-forming moieties may have attached thereto prodrug-forming moieties.
  • the prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed hydroxyl, amino, or carboxylic acid in vivo.
  • Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance.
  • Compounds of this invention may exist as acid addition salts, basic addition salts, or zwitterions .
  • Salts of the compounds are prepared during their isolation or following their purification.
  • Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid.
  • Excipients include encapsulating materials or formulation additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof.
  • Excipients for orally administered compounds in solid dosage forms include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, ethanol, ethyl acetate, ethyl carbonate, ethyl cellulose, ethyl laureate, ethyl oleate, gelatin, germ oil, glucose, glycerol, groundnut oil, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, olive oil, peanut oil, potassium phosphate salts, potato starch, propylene glycol, Ringer's solution, talc, tragacanth, water, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium lauryl sulfate, sodiumphosphate
  • Excipients for ophthalmically and orally administered compounds in liquid dosage forms include benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, ethyl acetate, ethyl carbonate, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, tetrahydrofurfuryl alcohol, water, and mixtures thereof.
  • Excipients for osmotically administered compounds include chlorofluorohydrocarbons, ethanol, isopropanol, water, and mixtures thereof.
  • Excipients for parenterally administered compounds include 1, 3-butanediol, castor oil, corn oil, cottonseed oil, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S. P. or isotonic sodium chloride solution, water, and mixtures thereof.
  • Excipients for rectally and vaginally administered compounds include cocoa butter, polyethylene glycol, wax, and mixtures thereof.
  • Compounds of this invention may be administered orally, ophthalmically, osmotically, parenterally (subcutaneously, intramuscularly, intrasternally, intravenously) , rectally, topically, transdermally, and vaginally.
  • Orally administered compounds in solid dosage forms may be administered as capsules, dragees, granules, pills, powders, and tablets.
  • Ophthalmically and orally administered compounds in liquid dosage forms may be administered as elixirs, emulsions, microemulsions, solutions, suspensions, and syrups.
  • Osmotically and topically administered compounds may be administered as creams, gels, inhalants, lotions, ointments, pastes, powders, solutions, and sprays.
  • Parenterally administered compounds may be administered as aqueous or oleaginous solutions or aqueous or oleaginous and suspensions, in which suspensions comprise crystalline, amorphous, or otherwise insoluble forms of the compounds .
  • Rectally and vaginally administered compounds may be administered as creams, gels, lotions, ointments, and pastes.
  • Therapeutically effective amounts of compounds of this invention depend on the recepient of treatment, the disorder being treated and the severity thereof, the composition comprising the compounds, the time of administration, the route of administration, the duration of treatment, the potency of the compounds, and the rate of excretion of the compounds .
  • the daily therapeutically effective amount of the compounds administered to a patient in single or divided doses range from about 0.1 to about 200 mg/kg body weight, preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions contain these amounts of the compounds or combinations of submultiples thereof.
  • Streptococcus pyrogenes PIU 2548 GG Streptococcus pneumoniae ATCC 6303 HH
  • Compounds of this invention displayed antibacterial activity in the range of about 0.008 ⁇ g/mL to greater than about 128 ⁇ g/mL against the microorganisms listed in Table 1. This antibacterial activity demonstrates the usefulness of the compounds as antibacterials.
  • DME 1, 2-dimethoxyethane
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • a particular carbonate resin employed in the synthesis of compounds of this invention is MP-carbonate (Argonaut Technologies, San Carlos, CA) .
  • Compounds having formula (1) may be prepared as described in commonly-owned U.S. Patents 5,866,549, 6,054,435, and 6,075,133.
  • Additives include camphorsulfonic acid, cesium fluoride, d-iisopropylethylamine, triethylamine, sodium acetate, boron trifluoride etherate, and carbonate resins.
  • the reaction is typically conducted at about 40°C to 120°C, over about 1 hour to about 14 days, at pressures of about 1 atm to 5 atm, in solvents such as methanol, ethanol, iso-propanol, dichloromethane, 1, 2-dichloroethane, 1,4-dioxane, and DME.
  • solvents such as methanol, ethanol, iso-propanol, dichloromethane, 1, 2-dichloroethane, 1,4-dioxane, and DME.
  • Compounds having formula (I) -a may be converted to compounds having formula (I)-b by reacting the former and an oxidant, with or without a first base.
  • Oxidants include N-chlorosuccinimide • dimethyl sulfide, dicyclohexyl carbodiimide • dimethylsulfoxide with pyridinium trifluoroacetate, and Dess-Martin periodinane.
  • First bases include diisopropylamine, and triethylamine. The reaction is typically conducted at about -20°C to about 0°C, over about 1 hour to about 2 hours, in solvents such as dichloromethane, chloroform, and 1, 2-dichloroethane .
  • Compounds having formula (I)-b may be converted to compounds having formula (I)-c by reacting the former, a fluoridating agent, and, optionally, a second base.
  • Fluorinating agents include 3, 5-dichloro-l-fluoropyridinium tetrafluoroborate, N-fluorobenzenesulfonimide, 3, 5-dichloro-l-fluoropyridinium triflate,
  • Second bases include sodium hydride, potassium hydride, lithium diisopropylamide, triethylamine, N,N-diisopropylethylamine, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide .
  • the reactions are typically conducted at about -78°C to about 0°C, over about 2 to about 24 hours, in solvents such as DMF, THF, and diethyl ether.
  • Fluoride-donating agents include tetrabutylammonium fluoride, polymer-bound ammonium fluoride, tetrabutylammonium fluoride, pyridine -hydrogen fluoride, and triethylamine • trihydrofluoride .
  • the reaction is typically conducted at about 0 °C to about 50 °C, over about 1 hour to about 24 hours, in solvents such as THF, and 1,4-dioxane.
  • EXAMPLE 2 A solution of N-chlorosuccinimide (90 mg) in dichloromethane (2.5 mL) at -10°C was treated with dimethylsulfide (56 ⁇ L) , stirred for 10 minutes, treated with a solution of EXAMPLE 1 (350 mg) in dichloromethane (2 mL) , stirred at -10°C to 0°C for 1.5 hours, treated with triethylamine (63 ⁇ L) warmed to room temperature, and washed with saturated sodium carbonate and water. The combined washings were extracted with dichloromethane, and the organics were combined, washed with water and brine, dried over anhydrous Na 2 S0 , filtered, and concentrated.
  • EXAMPLE 3 A solution of EXAMPLE 2 (313 mg) in methanol (20 mL) at 55°C was stirred for 18 hours and concentrated; and the concentrate was flash chromatographed on silica gel with 1-3% 2M NH 3 in methanol/dichloromethane.
  • EXAMPLE 4 A solution of EXAMPLE 3 (38.7 mg) , 3-bromoquinoline (11.8 ⁇ L) , triethylamine (5 mL) dichlorobis (triphenylphosphine) palladium (II) (2 mg) and copper iodide (0.1 mg) in acetonitrile (0.5 mL) was stirred at 80°C for 18 hours then cooled and concentrated; and the concentrate was flash chromatographed on silica gel with 2% 2M NH 3 in methanol/dichloromethane.
  • EXAMPLE 5 This example was prepared by substituting 3-bromo-l, 5-napthiridine for 3-bromoquinoline in EXAMPLE 4.
  • EXAMPLE 6 This example was prepared by substituting 6-bromoquinoxaline for 3-bromoquinoline in EXAMPLE 4.
  • EXAMPLE 7 This example was prepared by substituting 2-bromo-5- (3-methyltetrazole) thiophene for 3-bromoquinoline in EXAMPLE 4.
  • EXAMPLE 8 This example was prepared by substituting 2-bromo-5- (2-pyridine) thiophene for 3-bromoquinoline in EXAMPLE 4.
  • EXAMPLE 9 A solution of EXAMPLE 1 (781 mg) in DMF (5 mL) at -10°C was treated with 60% oily sodium hydride (81 mg) , stirred at -10°C for 45 minutes, treated with
  • N-fluorobenzenesulfonimide (352 mg) , stirred at -10°C for 3 hours, diluted with iso-propyl acetate, washed with water and brine, and dried (Na 2 S0 4 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 1.5% 2M NH 3 in methanol/dichloromethane.
  • Example 10 A solution of Example 9 (630 mg) in methanol (20 mL) at 55°C was stirred for 18 hours and concentrated; and the concentrate was flash chromatographed on silica gel with 4% 2M NH 3 in methanol/dichloromethane.
  • EXAMPLE 11 A solution of EXAMPLE 10 (120 mg) , 3-bromoquinoline (35 ⁇ L) , triethylamine (1.5 mL) , dichlorobis (triphenylphosphine) palladium (II) (6.2 mg) and copper iodide (0.3 mg) in acetonitrile (1.5 mL) at 80°C was stirred for 18 hours then cooled and concentrated; and the concentrate was flash chromatographed on silica gel with 4% 2M NH 3 in methanol/dichloromethane.
  • EXAMPLE 12 This example was prepared by substituting 2-bromo-5- (3-methyltetrazole) thiophene for 3-bromoquinoline in EXAMPLE 11.
  • EXAMPLE 10 13 C (CDCI 3 ) ⁇ 204.1, 166.1, 165.6, 158.0, 104.0, 97.9, 83.7, 81..0, 80.2, 79.8, 78.4, 73.1, 70.3, 69.5, 65.8, 61.3, 59.8, 50.1, 40.8, 40.2, 37.7, 32.5, 28.2, 26.1, 25.0, 22.4, 21.1, 20.6, 18.8, 16.6, 15.1, 13.5, 10.6.

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Abstract

L'invention concerne des composés antibactériens de formule générale (I), et des sels, des promédicaments, ainsi que des sels de ces promédicaments; des procédés de production desdits composés et de produits intermédiaires utilisés dans ces procédés; des compositions contenant lesdits composés; ainsi que des méthodes prophylactiques ou thérapeutiques d'infections bactériennes mettant en oeuvre lesdits composés.
PCT/US2003/012478 2002-04-25 2003-04-23 Antibacteriens 9-oxime macrolide WO2003090761A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP03719894A EP1501519A1 (fr) 2002-04-25 2003-04-23 Antibacteriens 9-oxime macrolide
CA002483221A CA2483221A1 (fr) 2002-04-25 2003-04-23 Antibacteriens 9-oxime macrolide
JP2003587394A JP2006513976A (ja) 2002-04-25 2003-04-23 ９−オキシムマクロリド抗菌薬
MXPA04010558A MXPA04010558A (es) 2002-04-25 2003-04-23 Antibacterianos de macrolida 9-oxima.

Applications Claiming Priority (3)

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US13185102A 2002-04-25 2002-04-25
US10/131,851 2002-04-25
US10/420,260 2003-04-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102146085A (zh) * 2010-02-09 2011-08-10 北京理工大学 一种9-肟醚酮内酯衍生物、制备方法及其药物组合物

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056800A1 (fr) * 1997-06-11 1998-12-17 Pfizer Products Inc. Derives de 9-oxime erythromycine
WO1999021871A1 (fr) * 1997-10-29 1999-05-06 Abbott Laboratories Derives ketolide a substitution 2-halo-6-o
WO2000071557A1 (fr) * 1999-05-24 2000-11-30 Pfizer Products Inc. Derives de 13-methyl-erythromycine
WO2000078773A2 (fr) * 1999-06-24 2000-12-28 Abbott Laboratories Methode de preparation de derives d'erythromycine substitues en 6-o
WO2001063539A2 (fr) * 2000-02-24 2001-08-30 Abbott Laboratories Agents anti-infectieux utiles contre des souches de bacteries resistant a l'action de plusieurs medicaments
WO2002046204A1 (fr) * 2000-12-06 2002-06-13 Ortho-Mcneil Pharmaceutical, Inc. Derives 6-0-carbamoylcetolide de l'erythromycine utiles comme antibacteriens

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056800A1 (fr) * 1997-06-11 1998-12-17 Pfizer Products Inc. Derives de 9-oxime erythromycine
WO1999021871A1 (fr) * 1997-10-29 1999-05-06 Abbott Laboratories Derives ketolide a substitution 2-halo-6-o
WO2000071557A1 (fr) * 1999-05-24 2000-11-30 Pfizer Products Inc. Derives de 13-methyl-erythromycine
WO2000078773A2 (fr) * 1999-06-24 2000-12-28 Abbott Laboratories Methode de preparation de derives d'erythromycine substitues en 6-o
WO2001063539A2 (fr) * 2000-02-24 2001-08-30 Abbott Laboratories Agents anti-infectieux utiles contre des souches de bacteries resistant a l'action de plusieurs medicaments
WO2002046204A1 (fr) * 2000-12-06 2002-06-13 Ortho-Mcneil Pharmaceutical, Inc. Derives 6-0-carbamoylcetolide de l'erythromycine utiles comme antibacteriens

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102146085A (zh) * 2010-02-09 2011-08-10 北京理工大学 一种9-肟醚酮内酯衍生物、制备方法及其药物组合物

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