Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• TECHNICAL FIELD This invention is directed to compounds which are useful as antibacterials, processes for making the compounds and intermediates useful in the process, 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 hydrogen, -OH, -OR 9 , -OC(0)OR 9 , -OC(0)NH 2 ,
• R 2 is hydrogen or RP, in which RP is a hydroxyl protecting moiety; one of R and R is hydrogen, and the other is -OH,
• R 7 is hydrogen and R 8 is -OH, -OR 25 , -0C(0)R 25 , -OC(0)OR 25 , -0C(0)NH 2 , -OC(0)NHR 26 , -0C (0) NR 26 R 27 , -OCH 2 R 28 , or -OC(0)OCH 2 R 28 ; or
• R and R together 0;
• R 9, R13 , R19, R20, and R25 are independently alkyl, cycloalkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl;
• R 10 , R 11 , R 15 , R 16 , R 21 , R 22 , R 26 , and R 27 are independently alkyl, cycloalkyl, - (CH 2 ) alkenyl,
• R is alkyl or alkyl substituted with one or two independently selected aryl substituents;
• R 17 and R are independently hydrogen or alkyl;
• R31 and R32 are independently alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH 2 , -NH (alkyl), and -N (alkyl) 2 ,
• a third embodiment of this invention is directed to a process for making the compounds of the first and second embodiments .
• a fourth embodiment of this invention is directed to intermediates which are useful in the second embodiment.
• a fifth embodiment of this invention is directed to compositions for the 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 or second embodiment and an excipient .
• a sixth embodiment of this invention is directed to use of a therapeutically effective amount of a compound of the first or second embodiment for 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, pent-3-enyl, and 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 (tert-butyl ) , 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, ethyl, 1-ethylpropyl, 2-ethylpropyl, hexyl, methyl, 2-methylpropyl, 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, l-methyl-pent-2, 4-diynyl, and prop-2-ynyl (propargyl).
• Aryl means monovalent, unsubstituted or substituted phenyl which is 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, 4-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 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-
• Phenyl moieties fused with heterocyclyl moieties include unsubstituted and substituted 1, 3-benzodioxa (4- to 7-)yl, 1, 4-benzodioxa (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, 4-cyclohexadienyl, cyclohexenyl, cyclopentadienyl, and cyclopentenyl .
• Halo means fluoro (-F) , chloro (-C1), bromo (-Br), and iodo (-1) .
• 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, [1, 3] thiazolo [4, 5-b] pyridin-2-yl, and thieno [2 , 3-b] pyridin- (2- or 3-)yl.
• Six-membered heteroaryl moieties are unsubstituted and substituted pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, and 1, 3, 5-triazinyl .
• Six-membered heteroaryl moieties fused with aryl moieties include unsubstituted and substituted cinnolin-(3- or 4-)yl, isoquinolin- ( 1-, 3-, or 4-)yl, phthalazin- ( 1- or
• 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,
• Six-membered heteroaryl moieties fused with other six-membered heteroaryl moieties include unsubstituted and substituted 1, 5-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, pteridinyl, pyridazino [4, 5-d] pyridazinyl, pyrido [2, 3-d] pyridazinyl, and pyrido [3, 4-d] pyridazinyl .
• 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.
• Four-membered heterocyclyl moieties are
• 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 , -N0 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -OCF 3 ,
• Substituted cycloalkyl, cycloalkenyl, and heterocyclyl moieties are those moieties substituted with one, two, or three substituents independently selected from the group consisting of alkyl, halo, -CN, -OH, -NH 2 , -CF 3 , -OR 30 ,
• -SR 30 -S(O) (alkyl) , -S0 2 (alkyl), -C(0)H, -C (0) (alkyl) , -C(0)0H, -C(0)0(alkyl) , -NH (alkyl), -N(alkyl) 2 , -C(0)NH 2 , -C(0)NH(alkyl) , -C (0) N (alkyl) 2 , and R 40 , in which the phenyl is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, -CN, -OH, -NH 2 , and -CF 3 .
• 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,
• variable moieties may combine to provide a seventh embodiment of this invention, which embodiment is directed to compounds having formula (I), formula (I)-f, formula (I)-g, formula (II), formula (I ⁇ )-f, and formula (II) -g, and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which R 1 is -OH, -OR 9 , -OC(0)OR 9 , -0C(0)NH 2 , -OC(0)NHR 10 , or -OC(O)NR 10 R 11 ;
• R 2 is hydrogen or RP, in which RP is a hydroxyl protecting moiety; one of R and R is hydrogen, and the other is -OH, -OR 13 , -OC(0)OR 13 , -NH 2 , -NHC (0) OR 14 , -NHR 15 , -NR 15 R 16 , -OC(0)NH 2 , -OC(0)NHR 15 , -OC (0) NR 15 R 16 , -N (R 17 ) C (0) NH 2 , -N(R 17 )C(0)NHR 15 , or -N (R 17 ) C (O) NR 15 R 16 ; or
• R 7 is hydrogen and R 8 is -OH, -OR 25 , -OC(0)R 25 , -OC(0)OR 25 , -0C(0)NH 2 , -OC(0)NHR 26 , or -OC (0) NR 26 R 27 ; or
• R 7 and R8 together 0;
• R 9 , R 13 , R 19 , R 20 , and R 25 are independently alkyl, cycloalkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl;
• R 10 , R 11 , R 15 , R 16 , R 21 , R 22 , R 26 , and R 27 are independently alkyl, cycloalkyl, - (CH 2 ) alkenyl,
• R is alkyl or alkyl substituted with one or two independently selected aryl substituents
• R 17 and R23 are independently hydrogen or alkyl
• R 31 and R32 are independently alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH 2 , -NH (alkyl), and -N (alkyl) 2 , - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH 2 , -NH (alkyl), and -N (alkyl) 2 , or
• R and R is hydrogen, and the other is -OH, -OR 13 , -OC(0)OR 13 , -NH 2 , -NHC (0) OR 14 , -NHR 15 , -NR 15 R 16 , -0C(0)NH 2 , -OC(0)NHR 15 , -OC (0) NR 15 R 16 , -N (R 17 ) C (0) NH 2 , -N(R 17 )C(0)NHR 15 , or -N (R 17 ) C (O) NR 15 R 16 ; or
• R 7 is hydrogen and R 8 is -OH, -OR 25 , -OC(0)R 25 , -0C(0)0R 25 , -0C(0)NH 2 , -OC(0)NHR 26 , or -OC (0) NR 26 R 27 ; or
• R and R together 0;
• R 9 , R 13 , R 20 , and R 25 are independently alkyl, cycloalkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl;
• R , R , R , R , R , and R are independently alkyl, cycloalkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, aryl, heteroaryl
• R is alkyl or alkyl substituted with one or two independently selected aryl substituents
• R 17 and R23 are independently hydrogen or alkyl
• R 31 and R32 are independently alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH 2 , -NH (alkyl), and -N (alkyl) 2 , - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH 2 , -NH (alkyl), and -N (alkyl) 2 , or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl, -NH 2 , -NH (alkyl), and -N (al
• X is hydrogen, fluoride, chloride, or bromide; compounds having formula (I), formula (I)-f, formula
• R 1 is -OH or -OR 9 ;
• R is hydrogen; one of R 3 and R4 is hydrogen, and the other is -OH,
• R3 and R4 together 0; one of R and R is hydrogen, and the other is -OH,
• R 7 is hydrogen and R 8 is -OH , -OR 25 , -OC ( 0) R 25 , -OC ( 0 ) OR 25 , -OC (0) NH 2 , -OC (0 ) NHR 26 , or -OC ( 0) NR 26 R 27 ; or
• R 9, R13, R20, and R25 are independently alkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl, - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl, or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
• R 15 , R 16 , R 21 , R 22 , R 26 , and R 27 are independently alkyl, cycloalkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, aryl, heteroaryl, heterocyclyl, alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, heterocyclyl
• R 14 is alkyl or alkyl substituted with phenyl;
• R 31 and R32 are independently alkyl, - (CH 2 ) alkenyl, - (CH 2 ) alkynyl, alkyl substituted with one substituent selected from the group consisting of aryl and heteroaryl, - (CH 2 ) alkenyl substituted with one substituent selected from the group consisting of aryl and heteroaryl, or - (CH 2 ) alkynyl substituted with one substituent selected from the group consisting of aryl and heteroaryl; and
• X is hydrogen, fluoride, chloride, or bromide; compounds having formula (I), formula (I)-f, formula (I)-g, formula (II), formula (II) -f, and formula (II) -g, and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
• R 1 is -OH or -OR 9 ;
• R is hydrogen; one of R 3 and R4 is hydrogen, and the other is -OH, -NH 2 , -NHR 15 , -NR 15 R 16 or -NHC (O) OR 14 ; or
• R 5 is hydrogen, and R 6 is -OH, -OC(0)NH 2 , -OC(0)NHR 21 , or -OC(0)NR 21 R 22 ;
• R 7 is hydrogen and R 8 is -OH, -OR 25 , -OC(0)R 25 , -OC(0)NH 2 , -OC(0)NHR 26 , or -OC (0) NR 26 R 27 ;
• R 21 and R 2 are independently methyl, ethyl, propyl, butyl, prop-2-enyl, or prop-2-ynyl, each of which is independently unsubstituted or substituted with one substituent selected from the group consisting of -NH 2 and
• R , R , R and R are independently methyl, ethyl, propyl, butyl, prop-2-enyl, prop-2-ynyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropyl substituted with phenyl, phenyl substituted with two independently selected halo substituents, or methyl, ethyl, propyl, butyl, prop-2-enyl, or prop-2-ynyl, each of which is substituted with one substitutent selected from the group consisting of (4, 5-dihydroisoxazol-5-yl) , phenyl, pyridyl, pyrimidinyl, thienyl, isoxazolyl, oxazolyl, quinolyl and isoquinolyl, in which substituent is unsubstituted or substituted with one substituent selected from the group consisting of -F, -Cl, -B
• R 9 and R 25 are independently methyl, ethyl, propyl, butyl, prop-2-enyl, or prop-2-ynyl, each of which is independently unsubstituted or substituted with one substituent selected from the group consisting of thienyl, isoxazolyl, , 5-dihydroisoxazol-5-yl, phenyl, pyridyl, pyrimidinyl, quinolyl, and isoquinolyl, in which each substituent is independently unsubstituted or substituted with one substituent selected from the group consisting of phenyl, pyridyl, pyrimidinyl, thienyl, isoxazolyl, quinolyl, isoquinolyl, and phenyl substituted with one substituent selected from the group consisting of methyl, -OH, (methyl) 0-, -F, -Cl, and -Br;
• R 14 is tert-butyl or phenylmethyl
• R is methyl, ethyl, or propyl, each of which is independently unsubstituted or substituted with one substituent selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, thienyl, pyrimidinyl, isoxazolyl, and oxazolyl, in which each substituent is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of -F, -Cl, -Br, -I, methyl, -OH, and (methyl) 0-; and
• X is hydrogen, fluoride, chloride, or bromide; and compounds having formula (I), formula (I)-f, formula (I)-g, formula (II), formula (II) -f, or formula (II) -g, and pharmaceutically acceptable salts, prodrugs, and salts of prodrugs thereof, in which
• R 1 is -OH, (methyl)O-, (ethyl)O-, (prop-2-ynyl) 0-, (prop-2-enyl) 0-, (phenylmethyl) 0-, (3- (5-pyridin-2-ylthien- 2-yl) prop-2-ynyl) 0-, (3- (quinolin-3-yl) prop-2-enyl) 0-, (3- (3- (pyridin-2-yl) isoxazol-5-yl) prop-2-ynyl) 0-, or (3- (5- (pyrimidin-2-yl) thien-2-yl) prop-2-ynyl) 0-;
• R is hydrogen
• R 3 is hydrogen, and R4 is -OH, -NH 2 , (tert-butyl)OC(0)NH-, (phenylmethyl) OC (0) NH-, (methyl) NH-,
• R 5 is hydrogen
• R 6 is (2-aminoethyl) NHC (0) 0-, (2- (dimethylamino) ethyl) NHC (O)O-, (3-aminopropyl) NHC (0) 0-, (4-aminobutyl)NHC(0)0-,
• R 7 is hydrogen
• R 8 is -OH, (methyl) 0-, (ethyl) 0-, (propyl) 0-, prop-2-ynyl) 0-, (prop-2-enyl) 0-, 3- (5- (pyridin-2-yl) thien-2-yl) prop-2-ynyl) 0- , 3- (quinolin-3-yl) prop-2-enyl) 0-,
• X is hydrogen or fluoride, chloride, or bromide.
• R moiety for the practice of this invention using compounds having formula (I), formula (I)-f, formula (I)-g, formula (II), formula (II) -f, or formula (I ⁇ )-g, is -OH.
• R moiety for the practice of this invention using compounds having formula (I), formula (I)-f, formula (I)-g, formula (II), formula (II) -f, or formula (I ⁇ )-g is hydrogen.
• (I ⁇ )-f, or formula (I ⁇ )-g are -NH 2 , (tert-butyl) OC (0) NH-, and (phenylmethyl) OC(0)NH-.
• R moiety for the practice of this invention using compounds having formula (I), formula (I)-f, or formula (I)-g is hydrogen.
• R moieties for the practice of this invention using compounds having formula (I), formula (I)-f, or formula (I)-g are (2- ( (1- (2-methoxyphenyl) ethyl) amino) ethyl) NHC (O)O-, (2-aminoethyl)NHC(0)0-,
• R moiety for the practice of this invention using compounds having formula (I), formula (I)-f, formula (I)-g, formula (II), formula (II) -f, or formula (II) -g is hydrogen.
• R is -OH; R is hydrogen; R is hydrogen and R is
• R is -OC(0)NHR 21
• R 21 is alkyl substituted with one substituent selected from the group consisting of -NH 2 and
• R31 is alkyl substituted with one substituent selected from the group consisting of phenyl and pyridyl, in which the phenyl is substituted with -0 (alkyl) and the pyridyl is unfused or fused with phenyl; and X is hydrogen;
• R 1 is -OH; R is hydrogen; R and R are hydrogen; R 4 is -NH 2 or -NHC (0) OR 14 ; R 8 is -OH, -OR 25 , -OC(0)R 25 , or
• R 14 is alkyl substituted with phenyl
• R 25 is alkyl or alkyl substituted with one substituent selected from the group consisting of pyridyl and 4, 5-dihydroisoxazolyl, in which the 4, 5-dihydroisoxazolyl is substituted with one substituent selected from the group consisting of pyridyl and phenyl, in which the phenyl is unsubstituted or substituted with one halo substituent
• R 26 is alkyl, cycloalkyl, cycloalkyl substituted with phenyl, phenyl substituted with two independently selected halo substituents, or alkyl substituted with one substituent selected from the group consisting of phenyl, pyridyl, and 4, 5-dihydroisoxazolyl, in which the phenyl is unsubstituted or substituted with one substituent selected from the group consisting of alkyl, halo
• R 1 is -OH; R , R and R are hydrogen; R is -NH 2 or
• R 8 is -OH, -OR 25 , -OC(0)R 25 or -OC(0)NHR 26
• R 14 is phenylmethyl
• R 25 is C 3 -alkyl or C ⁇ -C 2 ⁇ alkyl substituted with one substituent selected from the group consisting of pyridyl and 4 , 5-dihydroisoxazolyl, in which the 4, 5-dihydroisoxazolyl is substituted with one substituent selected from the group consisting of pyridyl and phenyl, in which the phenyl is unsubstituted or substituted with one halo substituent;
• R 26 is C 3 -alkyl, C 5 -C 6 -cycloalkyl, C -cycloalkyl substituted with phenyl, phenyl substituted with two independently selected halo substituents, or
• R 1 is -OH; R 2 , R 3 and R 7 are hydrogen; R 4 is -NH 2 ; R 8 is -OH, (propyl) 0-, (3-phenyl-4, 5-dihydroisoxazol-5-yl) methoxy, (3- (pyridin-2-yl) -4, 5-dihydroisoxazol-5-yl)methoxy, 3- (4-fluorophenyl) -4, 5-dihydroisoxazol-5-yl) methoxy,
• 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 racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers of the compounds thereof .
• 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. For example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persul
• 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 suspensions in which the 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 the 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.
• Representative compounds of this invention displayed antibacterial activity superior to the control, which control demonstrated no antibacterial activity. This antibacterial activity demonstrates the usefulness of the compounds as antibacterials . It is also meant to be understood that certain metabolites of compounds of this invention, which metabolites are produced by in vitro or in vivo metabolic processes, would also be useful as antibacterials and are meant to be embraced by this invention. It is still also meant to be understood that certain precursor compounds, which precursor compounds may be metabolized in vitro or in vivo to form compounds of this invention, are meant to be embraced by this invention. Compounds of this invention may also be prepared by synthetic chemical processes, examples of which synthetic chemical processes, and intermediates employed in the processes, are shown hereinbelow.
• N, N-dimethylformamide N, N-dimethylformamide
• EDCI 1- (3-dimethylaminopropyl) -3- carbodiimide hydrochloride
• THF tetrahydrofuran
• Compound having formula (I) -a may be prepared from erythromycin A as described in Bioorg. & Medicinal Chemistry Letters, Vol. 5, No. 12, 1307-1310.
• Compounds having formula (I) -a may be converted to compounds having formula (I)-b by reacting the former, an amino-protecting group precursor, and a first base.
• amino-protecting group precursors examples include benzyl chloroformate, dibenzyl dicarbonate, and N- (benzyloxycarbonyloxy) succinimide.
• first bases include pyridine, sodium bicarbonate, sodium carbonate, triethylamine, tributylamine, and diisopropylethylamine.
• the reaction is typically conducted over about 1 hour to about 3 days, at about -10°C to about 35°C, in solvents such as dichloromethane, methanol, tetrahydrofuran, ether, N, N-dimethylformamide, acetonitrile, ethyl acetate, acetone, 1, 2-dimethoxyethane, dimethylsulfoxide, dioxane, chloroform, and mixtures thereof.
• solvents such as dichloromethane, methanol, tetrahydrofuran, ether, N, N-dimethylformamide, acetonitrile, ethyl acetate, acetone, 1, 2-dimethoxyethane, dimethylsulfoxide, dioxane, chloroform, and mixtures thereof.
• Compounds having formula ( I ) -b may be converted to compounds having formula (I)-c by reacting the former, a hydroxyl-protecting group precursor, and the first base, with or without 4- (N, N-dimethylamino) pyridine .
• hydroxyl-protecting group precursors include acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, trimethylsilyl chloride, and triethylsilyl chloride.
• the reaction is typically conducted over about 1 hour to about 48 hours, at about -10°C to about 75°C, in solvents such as tetrahydrofuran, ether, N, N-dimethylformamide, acetonitrile, ethyl acetate, acetone, 1, 2-dimethoxyethane, dichloromethane, chloroform, and mixtures thereof.
• solvents such as tetrahydrofuran, ether, N, N-dimethylformamide, acetonitrile, ethyl acetate, acetone, 1, 2-dimethoxyethane, dichloromethane, chloroform, and mixtures thereof.
• Compounds having formula (I)-c may be converted to compounds having formula (I)-d by (a) reacting the former, a carbonylating agent, and a second base, with or without 4- (N, N-dimethylamino) pyridine, and (b) reacting the product of step (a) and 2-aminoethylamine .
• carbonylating agents examples include 1, 1 ' -carbonyldiimidazole, phosgene, diphosgene, triphosgene and disuccinimidyl carbonate.
• second bases examples include 1, 8-diazabicyclo (5.4.0) undec-7-ene, triethylamine, diisopropylethyl amine, pyridine, and lutidine.
• Step (a) is typically conducted at about -78°C to about 100°C, over about 1 hour to about 24 hours, in solvents such as toluene, ether, tetrahydrofuran, dichloromethane, N,N-dimethylformamids, benzene, pyridine and mixtures thereof .
• solvents such as toluene, ether, tetrahydrofuran, dichloromethane, N,N-dimethylformamids, benzene, pyridine and mixtures thereof .
• Step (b) is typically conducted at about 0°C to about 50°C over about 1 hour to about 4 days in solvents such as tetrahydrofuran, acetonitrile, dichloromethane, chloroform, toluene, benzene ether, and mixtures thereof.
• solvents such as tetrahydrofuran, acetonitrile, dichloromethane, chloroform, toluene, benzene ether, and mixtures thereof.
• Compounds having formula (I)-d may be converted to compounds having formula (I)-e by (a) reacting the former and a compound having formula R 31C(0)R', in which R' is hydrogen or alkyl, and (b) reacting the product of step (a) and a reducing agent, with or without a first acid.
• Examples of compounds having formula R 31C(0)R' in which R' is hydrogen include pyridine-2-carbaldehyde, pyridine-3- carbaldehyde, pyridine-4-carbaldehyde, pyrimidine-4- carbaldehyde, quinoline-3-carbaldehyde, quinoline-4- carbaldehyde, phenylacetaldehyde,
• Examples of compounds having formula R C(0)R' in which R' is alkyl include 1-phenylethanone, l-(3,4- dichlorophenyl) propan-1-one, 1- (2-methoxyphenyl) propan-1- one, 1- (2-methoxyphenyl) ethanone, 2,2, 2-trifluoro-1- (2-methoxyphenyl) ethanone, and 1- (3, 5-bis (trifluoromethyl) phenyl) ethanone .
• Examples of the reducing agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc and hydrochloric acid, iron pentacarbonyl and alcoholic potassium hydroxide, borane -pyridine, and formic acid.
• first acids include acetic acid, formic acid, and hydrochloric acid.
• Step (a) is typically conducted at about 25°C to about 150°C, over about 1 hour to about 24 hours, in solvents such as tetrahydrofuran, dichloromethane, toluene, benzene, dimethyl sulfoxide, acetonitrile, xylene, N, N-dimethylformamide, and mixtures thereof.
• Step (b) is typically conducted at about -10°C to about 50°C, over about 1 hour to about 24 hours, in solvents such as acetonitrile, methanol, ethanol, dichloromethane, toluene, benzene, N, -dimethylformaide, and mixtures thereof.
• solvents such as acetonitrile, methanol, ethanol, dichloromethane, toluene, benzene, N, -dimethylformaide, and mixtures thereof.
• Compounds having formula (I) -a may be converted to compounds having formula (II) -a by reacting the former and a second acid.
• second acids include hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid, and trifluoroacetic acid.
• the reaction is typically conducted at about -10°C to about 70°C, over about 1 hour to about 72 hours, in solvents such as dichloromethane, tetrahydrofuran, methanol, water, ethanol, isopropanol, butanol, and mixtures thereof.
• solvents such as dichloromethane, tetrahydrofuran, methanol, water, ethanol, isopropanol, butanol, and mixtures thereof.
• Compounds having formula (II) -a may be converted to compounds having formula (II) -b by using the same reagents and under the same conditions described for the conversion of compounds having formula (I) -a to compounds having formula (I)-b in SCHEME 1.
• Compounds having formula (II) -b may be converted to compounds having formula (II) -c by using the same reagents and under the same conditions described for the conversion of compounds having formula (I)-b to compounds having formula (I)-c in SCHEME 1.
• Compounds having formula (II) -c may be converted to compounds having formula (II) -d by reacting the former, a compound having formula R 25COOH, an acid activating agent, with or without the second base, and with or without 4- (N, N-dimethylamino) pyridine .
• acid activating agents examples include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1, 3-dicyclohexylcarbodiimide, and thionyl chloride.
• Examples of compounds having formula R 25COOH include 2-pyridylacetic acid, 3-pyridylpropanoic acid, phenylacetic acid, 3-quinolin-3-ylacrylic acid, 4- (5-pyridin-2-ylthien-2- yl) but-3-enoic acid, propanoic acid, and butanoic acid.
• the reaction is typically conducted at about -10°C to about 35°C, over about 1 hour to about 3 days, in solvents such as dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, and mixtures thereof.
• solvents such as dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, and mixtures thereof.
• Examples of compounds having formula R NCO include ethyl isocynante, isopropyl isocyanate, allyl isocyanate, cyclopentyl isocyanate, cyclohexyl isocyanate, phenyl isocyanate, 4-fluorobenzylisocyanate, 3, 5-dichlorophenyl isocyanate, trans-2-phenylcyclopropyl isocyanate, 2-methoxyphenyl isocyanate, 2-ethylphenyl isocyanate, 3, 4-dichlorophenyl isocyanate, and 1-naphthyl isocyanate.
• the reaction is typically conducted at about 25°C to about 150°C, over about 1 hour to about 4 days, in solvents such as toluene, benzene, xylene, dichloromethane, chloroform, tetrahydrofuran, and mixtures thereof.
• solvents such as toluene, benzene, xylene, dichloromethane, chloroform, tetrahydrofuran, and mixtures thereof.
• compounds having formula (II) -c may be converted to compounds having formula (II) -e by (a) reacting the former, the carbonylating agent, and the second base, with or without 4- (N, -dimethylamino) pyridine, and (b) reacting the product of step (a) and a compound having formula H 2 NR using the same reagents and under the same conditions described for the conversion of compounds having formula (I)-c to compounds having formula (I)-d in SCHEME 1.
• Examples of amines having formula H 2 NR include ethylamine, propylamine, (prop-2-ynyl) amine, (prop-2- enyl) amine, phenylmethylamine, (3-fluorophenyl) methylamine, ( 2-fluorophenyl ) methylamine, ( 4-methylphenyl ) methylamine, ( 4-methoxyphenyl ) methylamine, (pyridin-2-yl ) methylamine, (pyridin-3-yl) methylamine, (pyridin-4-yl) methylamine, 2- (pyridin-2-yl) ethylamine, 2- (pyridin-3-yl) ethylamine, and 2- (pyridin-4-yl) ethylamine .
• R is hydrogen, by reacting the former and a deprotecting agent .
• deprotecting agents include acids such as methanol, ethanol, acetic acid, and formic acid and bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and ammonia.
• the reaction is typically conducted at about 25°C to about 70°C, over about 1 hour to about 72 hours, in solvents such as water, methanol, ethanol, and mixtures thereof.
• Compound having formula (I) or (II), in which R 3 or R4 is (phenylmethyl) OC (0) NH-, may be converted to compounds having formula (I) or (II), in which R 3 or R4 is -NH 2 , by reacting the former, a hydride source and a palladium catalyst.
• hydride sources include cyclohexene, 1, 4-cyclohexadiene, formic acid, hydrogen, and ammonium formate .
• Examples of palladium catalysts include palladium black, palladium on carbon, and palladium hydroxide.
• the reaction is typically conducted at about 25°C to about 70°C, over about 2 hours to about 3 days, in solvents such as ethanol, isopropanol, ethyl acetate, and mixtures thereof.
• EXAMPLE 3 A solution of EXAMPLE 2 (820 mg) , CDI (405 mg) , DMAP (12.2 mg) , and DBU (224 ⁇ L) in THF (10 mL) and DMF (3 mL) at 25°C was stirred for 18 hours, treated with ethyl acetate, washed with water and saturated NaHC0 3 , and dried (Na 2 S0 4 ) , filtered, and concentrated.
• EXAMPLE 6 A solution of EXAMPLE 3 (286 mg) and 1- (2-methoxyphenyl) ethanone (65 ⁇ L) , in acetonitrile (2 mL) at 80°C was stirred for 18 hours and concentrated.
• EXAMPLE 7 A solution of the EXAMPLE 6 concentrate in methanol (2 mL) at 0°C was treated with sodium cyanoborohydride (30 mg) , stirred for 3 hours, acidified to pH 3 with 1M HCI, stirred for 15 minutes at 25°C, treated with 5% Na 2 C0 until basic, and extracted with dichloromethane; and the extract was dried (Na 2 S0 4 ) , filtered, and concentrated.
• EXAMPLE 8 (1-(S or R) ,2R,5R, 6S, 7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy-3, 15- dioxabicyclo(10.2.1) pentadec-6-yl 2, 6-dideoxy-4-0- ( ( (2- ( (1- (2-methoxyphenyl) ethyl) amino) ethyl) amino) carbonyl) -3-C- methyl-3-O-methyl- ⁇ -L-ribo-hexopyranoside
• a solution of the EXAMPLE 7 concentrate in methanol (5 mL) was refluxed for 4 hours and concentrated; and the concentrate was flash chromat
• EXAMPLE 9 This example was prepared by substituting quinoline-3-carboxaldehyde for 1- (2-methoxyphenyl) ethanone in EXAMPLE 6.
• EXAMPLE 11 (1-(S or R) ,2R,5R,6S,7S,8R,9S,llR,12S,13S)-2-ethyl-9- hydroxy-1, 5, 7, 9, 11, 13-hexamethyl-4 , 14-dioxo-8- ( (3, 4, 6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 2, 6-dideoxy-3-C-methyl-3- O-methyl-4-0- ( ( (2- ( (quinolin-3- ylmethyl) amino) ethyl) amino) carbonyl) - ⁇ -L-ribo- hexopyranoside
• EXAMPLE 10 (1-(S or R) ,2R,5R,6S,7S,8R,9S,llR,12S,13S)-2-ethyl
• EXAMPLE 14 (1-(S or R) , 2R,5R, 6S,7S, 8R, 9S,11R, 12S, 13S) -2-ethyl-9- hydroxy-1, 5,7,9,11, 13-hexamethyl-4, 14-dioxo-8- ((3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 2, 6-dideoxy-3-C-methyl-3- O-methyl-4-O- ( ( (2- ( (quinolin-4- ylmethyl) amino) ethyl) amino) carbonyl) - ⁇ -L-ribo-hexopyranoside
• EXAMPLE 15 This example was prepared by substituting pyridine-2-carboxaldehyde for 1- (2-methoxyphenyl) ethanone in EXAMPLE 6.
• EXAMPLE 16 This example was prepared by substituting EXAMPLE 15 for in EXAMPLE 6 in EXAMPLE 7.
• EXAMPLE 18 A solution of EXAMPLE 1 (6.4g), hydroxylamine hydrochloride (7.33g), and triethylamine (8.62 mL) in ethanol (80 mL) at 70°C was stirred for four days, cooled, and concentrated. The concentrate was dissolved in 5% NaHC0 , adjusted to pH 10 with concentrated ammonium hydroxide, and extracted with dichloromethane. The extract was washed with water and 10% NaHC0 and dried (Na 2 S0 4 ) , filtered, and concentrated; and the concentrate was purified on silica gel with 97:3:0.5 to 95:5:0.5 dichloromethane/methanol/ammonium hydroxide .
• EXAMPLE 20 A solution of EXAMPLE 19 (3.93g) and triethylamine (2.29 mL) in dichloromethane (50 mL) at 25°C was treated with di-tert-butyl dicarbonate (1.32g) in dichloromethane (10 mL) , stirred for 1 hour at room temperature, diluted with dichloromethane, washed with water and saturated NaHC0 3 , and dried (Na 2 S0 4 ) , filtered, and concentrated; and the concentrate was purified on silica gel with 97:3:0.5 dichloromethane/methanol/ammonium hydroxide .
• EXAMPLE 21 A solution of EXAMPLE 20 (1.9g) in dichloromethane (10 mL) at 0°C was treated with benzoic anhydride (789 mg) and triethylamine (485 ⁇ L) , stirred at 25°C for 17 hours, and concentrated; and the concentrate was flash chromatographed on silica gel with 97:3:0.5 dichloromethane/methanol/ ammonium hydroxide.
• EXAMPLE 22 A solution of EXAMPLE 21 (185 mg) , CDI (81 mg) , DMAP (2.4 mg) , and DBU (45 ⁇ L) in THF (2 mL) and DMF (0.6 mL) at 25°C was stirred for 18 hours, treated with ethyl acetate, washed with water and saturated NaHC0 3 , and dried (Na 2 S0 4 ), filtered, and concentrated.
• EXAMPLE 23 A solution of the EXAMPLE 22 concentrate and ethylenediamine (133 ⁇ L) in acetonitrile (10 mL) and water (1 mL) at 25°C was stirred for 2 days and concentrated; and the concentrate was flash chromatographed on silica gel with 95:5:0.5 dichloromethane/methanol/ammonium hydroxide.
• EXAMPLE 24 A solution of EXAMPLE 23 (182 mg) and pyridine-2-carboxaldehyde (29 ⁇ L) in acetonitrile (2 mL) at 80°C was stirred for 18 hours and concentrated.
• EXAMPLE 25 A solution of the EXAMPLE 24 concentrate in methanol (2 mL) at 0°C was treated with sodium cyanoborohydride (19 mg) , stirred for 3 hours, acidified to pH 3 with IM HCI, stirred for 15 minutes at 25°C, made basic with 5% Na 2 C0 3 , and extracted with dichloromethane. The extract was dried (Na 2 S0 4 ), filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 98:2:0.5 dichloromethane/methanol/ammonium hydroxide .
• EXAMPLE 26 (1-(S or R) ,2R,5R, 6S,7S, 8R,9S,11R, 12S,13R,14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9,11, 13-hexamethyl-4-oxo-8- ((3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 2, 6-dideoxy-3-C-methyl-3- O-methyl-4-O- ( ( (2- ( (pyridin-2- ylmethyl) amino) ethyl) amino) carbonyl) - ⁇ -L-ribo- hexopyranoside
• EXAMPLE 25 (1.98g) in methanol (5 mL) , was refluxed for 4 hours and concentrated; and the concentrate was flash
• EXAMPLE 28 benzyl (IS, 2R, 4S, 5R, 6S, 7S, 8R, 11R, 12- (S or R),13S,14R)- ll-ethyl-4, 7-dihydroxy-2 , 4, 6, 8, 12, 14-hexamethyl-9-oxo-5-
• EXAMPLE 32 This example was prepared by substituting cyclopentylisocyanate for isopropylisocyanate in EXAMPLE 30.
• EXAMPLE 33 (1-(S or R) ,2R, 5R, 6S, 7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9, 11, 13-hexamethyl-4-oxo-8- ((3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl cyclopentylcarbamate
• EXAMPLE 32 This example was prepared by substituting EXAMPLE 32 for EXAMPLE 30 in EXAMPLE 31.
• EXAMPLE 34 This example was prepared by substituting cyclohexylisocyanate for isopropylisocyanate in EXAMPLE 30.
• EXAMPLE 35 (1-(S or R) ,2R,5R, 6S,7S,8R, 9S,11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl cyclohexylcarbamate
• EXAMPLE 34 was prepared by substituting EXAMPLE 34 for EXAMPLE 30 in EXAMPLE 31.
• EXAMPLE 37 (1-(S or R) , 2R,5R, 6S, 7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9,11, 13-hexamethyl-4-oxo-8- ((3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 4-fluorobenzylcarbamate
• This example was prepared by substituting EXAMPLE 36 for EXAMPLE 30 in EXAMPLE 31.
• EXAMPLE 38 This example was prepared by substituting 3,5- dichlorophenylisocyanate for isopropylisocyanate in EXAMPLE 30.
• EXAMPLE 39 (1-(S or R) , 2R,5R, 6S,7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3, 4, 6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 3, 5- dichlorophenylcarbamate
• EXAMPLE 38 was prepared by substituting EXAMPLE 38 for EXAMPLE 30 in EXAMPLE 31.
• EXAMPLE 40 and EXAMPLE 41 These examples were prepared by substituting trans-phenylcyclopropylisocyanate for isopropylisocyanate in EXAMPLE 30.
• EXAMPLE 42 and EXAMPLE 43 (1-(S or R) ,2R,5R, 6S, 7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9,11, 13-hexamethyl-4-oxo-8- ((3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.l)pentadec-6-yl (1S,2R) -2- phenylcyclopropylcarbamate and (1-(S or R) ,2R,5R, 6S,7S,8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5, 7, 9, 11, 13-hexamethyl-4-oxo-8- (
• EXAMPLE 44 This example was prepared by substituting allylisocyanate for isopropylisocyanate in EXAMPLE 30.
• EXAMPLE 45 (1-(S or R) ,2R,5R, 6S,7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl propylcarbamate
• EXAMPLE 44 was prepared by substituting EXAMPLE 44 for EXAMPLE 30 in EXAMPLE 31.
• EXAMPLE 46 A suspension of tris (dibenzylideneacetone) dipalladium (0) (4 mg) and dppe (4 mg) in THF (15 mL) was treated with EXAMPLE 30 (500 mg) and tert-butyl allyl carbonate (70 mg) , refluxed for 5 hours, treated with more tris (dibenzylideneacetone) dipalladium (0) (4 mg) and tert-butyl allyl carbonate (35g) , refluxed for another 5 hours and cooled, treated with ethyl acetate, washed with saturated NaHC0 3 , water, and brine, and dried (MgS0 4 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 85:15:1.5 hexanes/ acetone/triethylamine .
• N-chlorosuccinamide (380 mg) and pyridine (catalytic) in dichloromethane (20 mL) was stirred for 5 hours, added to a solution of EXAMPLE 46 (230 mg) in dichloromethane (5 mL) , treated with triethylamine (300 mg) , stirred for 12 hours, treated with ethyl acetate, washed with saturated NaHC0 3 , water, and brine, and dried (MgS0 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 70:30:1.5 hexane/acetone/triethylamine .
• This example was prepared by substituting 2-pyridyl oxime for 4-fluorophenyl oxime in EXAMPLE 47.
• EXAMPLE 50 (1S,2R,4S,5R, 6S,7S,8R, 11R, 12- (S or R) , 13S, 14R) -13-amino-ll- ethyl-4-hydroxy-2, 4, 6, 8, 12, 14-hexamethyl-9-oxo-7- ( (3- pyridin-2-yl-4, 5-dihydroisoxazol-5-yl) methoxy) -10, 15- dioxabicyclo (10.2.1) pentadec-5-yl 3,4, 6-trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranoside
• EXAMPLE 49 for EXAMPLE 47 in EXAMPLE 48.
• EXAMPLE 51 A solution of EXAMPLE 29 (5g) and CDI (2.2g) in 1 : 1 dichloromethane/THF (100 mL) was heated at reflux for 12 hours, treated with ethyl acetate, washed with saturated NaHC0 3 , water, and brine, and dried (MgS0 4 ) , filtered, and concentrated; and the concentrate was purified by flash chromatography on silica gel with 70:30:1.5 hexane/acetone/triethylamine .
• EXAMPLE 52 A solution of EXAMPLE 51 (200g) and 2- (aminomethyl) pyridine (400g) in 5 : 1 acetonitrile/water (6 mL) was stirred for 12 hours, treated with ethyl acetate, washed with saturated NaHC0 3 , water, and brine, and dried
• EXAMPLE 54 This example was prepared by substituting 2- (2-aminoethyl) pyridine for 2- (aminomethyl) pyridine in EXAMPLE 52.
• EXAMPLE 56 (1S,2R,4S,5R,6S,7S,8R,11R,12-(S or R) , 13S, 14R) -13-amino-ll- ethyl-4-hydroxy-2, 4, 6, 8, 12, 14-hexamethyl-9-oxo-7-propoxy- 10, 15-dioxabicyclo (10.2.1) pentadec-5-yl 3, 4, 6-trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranoside
• EXAMPLE 46 200 mg
• EXAMPLE 57 This example was prepared by substituting phenyl oxime for 4-fluorophenyl oxime in EXAMPLE 47.
• EXAMPLE 61 This example was prepared by substituting 4- (aminomethyl) pyridine for 2- (aminomethyl) pyridine in EXAMPLE 52.
• EXAMPLE 62 (1-(S or R) ,2R,5R, 6S, 7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9, 11, 13-hexamethyl-4-oxo-8- ((3,4, 6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl pyridin-4- ylmethylcarbamate
• EXAMPLE 61 was prepared by substituting EXAMPLE 61 for EXAMPLE 52 in EXAMPLE 53.
• This example was prepared by substituting 3- (aminomethyl) pyridine for 2- (aminomethyl) pyridine in EXAMPLE 52.
• EXAMPLE 65 A solution of EXAMPLE 30 (0.5g), 2-py ⁇ dylacet ⁇ c acid (180 mg), DIEA (120 mg) , EDCI (200 mg) , and DMAP (catalytic) in dichloromethane (20 mL) was stirred for 12 hours, diluted with ethyl acetate, washed with saturated NaHC0 3 , water, and brine, and dried (MgS0 4 ), filtered, and concentrated.
• EXAMPLE 66 (1-(S or R) ,2R,5R,6S,7S,8R,9S,llR,12S,13R,14S)-14-am ⁇ no-2- ethyl-9-hydroxy-l,5,7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3, 4, 6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl pyr ⁇ d ⁇ n-2-ylacetate;
• EXAMPLE 68 (1-(S or R) , 2R, 5R, 6S, 7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-am ⁇ no-2- ethyl-9-hydroxy-l, 5,7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3, 4, 6- tr ⁇ deoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 2-pyridin-3- ylethylcarbamate
• EXAMPLE 67 for EXAMPLE 65 in EXAMPLE 66.
• EXAMPLE 69 This example was prepared by substituting 2- (2-aminoethyl) pyridine for 2- (aminomethyl) pyridine in EXAMPLE 52.
• EXAMPLE 72 (1-(S or R) ,2R,5R, 6S,7S,8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3, 4, 6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 3-fluorobenzylcarbamate
• EXAMPLE 71 for EXAMPLE 65 in EXAMPLE 66.
• EXAMPLE 73 This example was prepared by substituting 2-fluorobenzylisocyanate for isopropylisocyanate in EXAMPLE 30.
• EXAMPLE 74 (1-(S or R) ,2R,5R, 6S,7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9,11, 13-hexamethyl-4-oxo-8- ( (3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 2-fluorobenzylcarbamate
• EXAMPLE 73 was prepared by substituting EXAMPLE 73 for EXAMPLE 65 in EXAMPLE 66.
• EXAMPLE 75 This example was prepared by substituting 4-methylbenzylisocyanate for isopropylisocyanate in EXAMPLE 30.
• EXAMPLE 76 (1-(S or R) ,2R,5R, 6S,7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9,11, 13-hexamethyl-4-oxo-8- ((3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 4-methylbenzylcarbamate
• EXAMPLE 75 for EXAMPLE 65 in EXAMPLE 66.
• EXAMPLE 78 (1-(S or R) ,2R, 5R, 6S, 7S, 8R, 9S, 11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5, 7, 9, 11, 13-hexamethyl-4-oxo-8- ((3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 3-pyridin-3-ylpropanoate
• EXAMPLE 77 was prepared by substituting EXAMPLE 77 for EXAMPLE 65 in EXAMPLE 66.
• EXAMPLE 79 This example was prepared by substituting 4-methoxybenzylisocyanate for isopropylisocyanate in EXAMPLE 4
• EXAMPLE 80 (1-(S or R) ,2R,5R,6S,7S,8R,9S,11R, 12S, 13R, 14S) -14-amino-2- ethyl-9-hydroxy-l, 5,7,9,11, 13-hexamethyl-4-oxo-8- ( (3,4,6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl 4-methoxybenzylcarbamate
• EXAMPLE 79 for EXAMPLE 65 in EXAMPLE 66.
• This example was prepared by substituting benzylisocyanate for isopropylisocyanate in EXAMPLE 4.
• EXAMPLE 82 (1-(S or R) ,2R, 5R, 6S,7S, 8R, 9S, 11R, 12S, 13R, 14S)-14-amino-2- ethyl-9-hydroxy-l,5, 7, 9, 11, 13-hexamethyl-4-oxo-8- ( (3, , 6- trideoxy-3- (dimethylamino) - ⁇ -D-xylo-hexopyranosyl) oxy) -3, 15- dioxabicyclo (10.2.1) pentadec-6-yl benzylcarbamate
• EXAMPLE 45 13 X,, NMR (CDCI 3 ) ⁇ 174.2, 156.2, 104.2, 86.6, 85.6, 84.4, 78.6, 77.4, 74.0, 70.5, 69.4, 65.9, 54.5, 44.2, 42.7, 40.3, 37.3, 36.2, 34.4, 29.7, 28.8, 28.6, 25.4, 24.1, 23.3, 21.1, 20.6, 16.9,15.5, 14.6, 11.3, 10.9, 9.5.
• EXAMPLE 64 13 C NMR (CDCI3) ⁇ 174.2, 149.0, 148.9, 123.0, 104.2, 86.6, 85.7, 84.3, 74.0, 70.5, 69.4, 65.7, 54.5, 44.1, 42.6, 40.3, 37.3, 36.1, 28.6, 28.5, 25.3, 24.0, 21.1, 20.5, 16.9, 15.5,
• EXAMPLE 70 13 C NMR (CDCI 3 ) ⁇ 176.3, 165.1, 149.3, 144.0, 136.3, 116.5, 110.2, 107.2, 86.6, 85.5, 84.4, 78.8, 74.0, 70.6, 69.5,

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