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WO2001028981A1 - Acide 1-cyclohexene-1-carboxylique et 1-cyclohexene1-1carboxylates comme inhibiteurs de la neuraminidase - Google Patents

Acide 1-cyclohexene-1-carboxylique et 1-cyclohexene1-1carboxylates comme inhibiteurs de la neuraminidase Download PDF

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Publication number
WO2001028981A1
WO2001028981A1 PCT/US2000/026119 US0026119W WO0128981A1 WO 2001028981 A1 WO2001028981 A1 WO 2001028981A1 US 0026119 W US0026119 W US 0026119W WO 0128981 A1 WO0128981 A1 WO 0128981A1
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alkyl
alkenyl
hours
specific examples
group
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PCT/US2000/026119
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English (en)
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Clarence J. Maring
Vincent L. Giranda
Dale J. Kempf
Vincent S. Stoll
Minghua Sun
Chen Zhao
Yu Gui Gu
Stephen Hanessian
Kent D. Stewart
Gary T. Wang
Jianchio Wang
Darold L. Madigan
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Abbott Laboratories
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Priority to AU76081/00A priority Critical patent/AU7608100A/en
Priority to BR0010525-2A priority patent/BR0010525A/pt
Publication of WO2001028981A1 publication Critical patent/WO2001028981A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to novel compounds, compositions, and methods for inhibiting neuraminidase, especially influenza neuraminidase.
  • the invention also contemplates compositions and methods for preventing and treating an influenza infection, and processes for making such compounds, and synthetic intermediates employed in these processes .
  • neuraminidase also known as sialidase
  • viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase.
  • Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus- related diseases) , pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1) .
  • Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens. Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.
  • influenza virus Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness. The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year. There are two major strains of influenza virus (designated A and B) . Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.
  • Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked.
  • siastatin B analogs that are useful as neuraminidase inhibitors :
  • the present invention provides compounds of formula la and lb
  • R 1 is selected from the group consisting of (a) -C0 2 H, (b) -S0 3 H,
  • T is selected from the group consisting of
  • R 11 is selected from the group consisting of (i) C ⁇ -C 12 alkyl, (ii) C 2 -C 1 alkenyl, (iii) cycloalkyl,
  • R 12 and R 36 are independently selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R 2a is selected from the group consisting of
  • R 14 and R 15 are independently selected from the group consisting of
  • R 37a is selected from the group consisting of
  • R 37c at each occurrence is independently selected from the group consisting of
  • n 0, 1, or 2; and Q is O, S, NR , or CHR 26
  • R is selected from the group consisting of
  • R 25 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or
  • R is hydrogen, methyl or ethyl
  • R 28a is hydrogen, hydroxy, methyl, ethyl, amino, -NHCH 3 , -N(CH 3 ) 2 , methoxy, ethoxy, or -CN;
  • R 28b is hydrogen, methyl or ethyl; or R 28a , R 8b and the nitrogen to which they are bonded taken together represent azetidinyl;
  • R 29 is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
  • R 22 is selected from the group consisting of hydrogen, -CH 3 , -C 2 H 5 , -C 3 H 7 , -0CH 3 , -SCH 3 , -0-C 2 H 5 , and -S-C 2 H 5;
  • R 6 is independently selected from the group consisting of
  • R 8 and R 9 are independently selected from the group consisting of
  • R 10 is selected from the group consisting of
  • neuraminidase enzyme of disease-causing microorganisms particularly viral neuraminidase, and, especially influenza neuraminidase.
  • acid protecting group refers to groups used to protect acid groups (for example, -C0 2 H, -S0 3 H, -S0 2 H, -P0 3 H 2 , -P0 2 H groups and the like) against undesirable reactions during synthetic procedures.
  • acid protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991) which is incorporated herein by reference. Most frequently, such acid protecting groups are esters.
  • esters include:
  • alkyl esters especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
  • arylalkyl esters including, but not limited to, benzyl, phenethyl, 3 -phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein; silylesters, especially, (tri - loweralkyl ) silyl esters, (di-loweralkyl) (aryl) silyl esters and (loweralkyl) (di- aryl) silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t- butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t- butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl , but
  • Preferred acid protecting groups are loweralkyl esters.
  • activated carboxylic acid group refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'- carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N- hydroxybenzotriazole derived esters, N-hydroxy-5- norbornene-2, 3-dicarboximide derived esters, 2,4,5- trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
  • acylalkyl refers to an acyl group appended to an alkyl radical.
  • Representative examples of acylalkyl groups include acetylmethyl , acetylethyl, propionylmethyl, propionylethyl and the like.
  • acylamino refers to groups having the formula -NHR 89 wherein R 89 is an acyl group.
  • Representative examples of acylamino include acetylamino, propionylamino, and the like.
  • acyloxyalkyl refers to an acyloxy group (i.e., R 95 -C(0)-0- wherein R 95 is hydrogen or an alkyl group) which is appended to an alkyl radical.
  • Representative examples of acyloxyalkyl include acetyloxymethyl, acetyloxyethyl, propioyloxymethyl , propionyloxyethyl and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • lower alkenyl refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms.
  • Representative examples of alkenyl groups include groups such as, for example, vinyl, 2 -propenyl, 2 -methyl-1-propenyl , 3 -butenyl, 4-pentenyl, 5 -hexenyl and the like.
  • alkenylene refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • lower alkenylene refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms.
  • alkenyloxy refers to groups having the formula -OR 81 where R 81 is an alkenyl group.
  • alkoxy refers to groups having the formula -OR 99 wherein R 99 is an alkyl group. Preferred R 99 groups are loweralkyl groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tert-butoxy, and the like.
  • alkoxyalkoxy refers to groups having the formula -0-R 96 -0-R 97 wherein R 97 is loweralkyl, as defined herein, and R 96 is a lower alkylene group.
  • Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
  • alkoxyalkyl refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
  • alkoxycarbonyloxyalkyl refers to an alkoxycarbonyloxy group (i.e., R 80 -C(O)-O wherein R 80 is an alkoxy group) appended to an alkyl radical.
  • alkoxycarbonyloxyalkyl include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl and the like.
  • alkyl refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms.
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms.
  • Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2 , 2-dimethylbutyl, 2-methylpentyl, 2 , 2-dimethylpropyl, n-hexyl, and the like.
  • hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl- containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R 27 )- and sulfur wherein R 27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
  • alkylamino refers to groups having the formula -NHR 91 wherein R 91 is an alkyl group. Preferred R 91 groups are loweralkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
  • alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon.
  • lower alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms .
  • Representative examples of alkylene groups include groups such as, for example, methylene (-CH 2 -), 1,2-ethylene (-CH 2 CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1, 3-propylene
  • alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R 27 )- and sulfur wherein R 27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
  • alkylsulfonyl refers to the group having the formula, -S0 2 -R 78 , where R 78 is an alkyl group. Preferred groups R 78 are loweralkyl groups.
  • alkyFsulfonylamino refers to the group having the formula, -S0 2 -R 77 , appended to the parent molecular moiety through an amino linkage (-NH-), where R 77 is an alkyl group.
  • Preferred groups R 77 are loweralkyl groups .
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond.
  • lower alkynyl refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms.
  • Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
  • alkynylene refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond.
  • lower alkynylene refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms.
  • Representative examples of alkynylene groups include groups such as, for example, -C ⁇ C-, -CH 2 -C ⁇ C-, -C ⁇ C-CH 2 -, -CH(CH 3 ) -C ⁇ C-, and the like.
  • aminoalkyl refers to an alkyl radical to which is appended an amino (-NH 2 ) group.
  • aryl refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro.
  • substituted aryl include 3-chlorophenyl, 3 -fluorophenyl, 4-chlorophenyl, 4-fluorophenyl , 3 , 4 -dichlorophenyl,
  • (aryl) alkenyl refers to a lower alkenyl group having appended thereto an aryl group.
  • Representative examples of (aryl) alkenyl groups include groups such as, for example phenylethylenyl , phenylpropenyl , and the like.
  • (aryl) alkyl refers to a loweralkyl group having appended thereto an aryl group.
  • Representative examples of (aryl) alkyl groups include groups such as, for example benzyl and phenylethyl .
  • arylalkoxy refers to the group having the formula, -O-R 76 where R 76 is an arylalkyl group.
  • (aryl) alkynyl refers to an alkynylene group having appended thereto an aryl group.
  • Representative examples of (aryl) alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
  • aryloxy refers to the group having the formula, -O-R 72 , where R 72 is an aryl group.
  • Carboxyalkyl refers to the group having the formula, -R 6 -C00H, where R 64 is a lower alkylene group.
  • cyanoalkyl refers to an alkyl radical to which is appended a cyano group (-CN) .
  • cycloalkenyl refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure.
  • Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
  • Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl.
  • Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
  • (cycloalkenyl) alkenyl refers to a cycloalkenyl group appended to a lower alkenyl radical.
  • Representative examples of (cycloalkenyl) alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
  • (cycloalkenyl) alkyl refers to a cycloalkenyl group appended to a lower alkyl radical.
  • Representative examples of (cycloalkenyl) alkyl groups include groups such as, for example, cyclohexenylmethyl , cyclopentenylmethyl , cyclohexenylethyl, cyclopentenylethyl, and the like.
  • (cycloalkenyl) alkynyl refers to a cycloalkenyl group appended to a lower alkynyl radical.
  • Representative examples of (cycloalkenyl) alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
  • cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings.
  • Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo [2.2.2] octane and the like.
  • Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl.
  • Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
  • (cycloalkyl) alkyl refers to a cycloalkyl group appended to a loweralkyl radical .
  • Representative examples of (cycloalkyl) alkyl groups include groups such as, for example, cyclohexylmethyl , cyclopentylmethyl , cyclohexylethyl, cyclopentylethyl, and the like.
  • (cycloalkyl) alkenyl refers to a cycloalkyl group appended to a lower alkenyl radical.
  • Representative examples of (cycloalkyl) alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.
  • (cycloalkyl) alkynyl refers to a cycloalkyl group appended to a lower alkynyl radical.
  • Representative examples of (cycloalkyl) alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
  • dialkylamino refers to groups having the formula -N(R 90 ) 2 wherein each R 90 is independently a lower alkyl group.
  • Representative examples of dialkylamino include dimethylamino, diethylamino, N- methyl-N-isopropylamino and the like.
  • dialkylaminoalkyl refers to a dialkylamino group appended to an alkyl radical.
  • dialkylaminoalkyl examples include dimethylaminomethyl , dimethylaminoethyl, N-methyl-N- ethylaminoethyl and the like.
  • dialkylaminocarbonylalkyl refers to a -C (O) -N (R 90 ) 2 group (wherein each R 90 is independently a lower alkyl group) appended to an alkyl radical .
  • Representative examples of dialkylaminocarbonylalkyl include dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, N- methyl-N-ethylaminocarbonylethyl and the like.
  • dialkylaminocarbonyloxyalkyl refers to a -0-C (O) -N (R 90 ) 2 group (wherein each R 90 is independently a lower alkyl group) appended to an alkyl radical.
  • Representative examples of dialkylaminocarbonyloxyalkyl include dimethylaminocarbonyloxymethyl , diethylaminocarbonyloxymethyl , N-methyl -N- ethylaminocarbonyloxyethyl and the like.
  • enantiomerically enriched refers to a compound which comprises unequal amounts of the enantiomers of an enantiomeric pair.
  • an enantiomerically enr-ched compound comprises more than 50% of one enantiomer of an enantiomeric pair and less than 50% of the other enantiomer of the enantiomeric pair.
  • a compound that is enantiomerically enriched comprises predominantly one enantiomer of an enantiomeric pair.
  • an enantiomerically enriched compound comprises greater than 80% of one enantiomer of an enantiomeric pair and less than 20% of the other enantiomer of the enantiomeric pair.
  • an enantiomerically enriched compound comprises greater than 90% of one enantiomer of an enantiomeric pair and less than 10% of the other enantiomer of the enantiomeric pair. Even more preferably, an enantiomerically enriched compound comprises greater than 95% of one enantiomer of an enantiomeric pair and less than 5% of the other enantiomer of the enantiomeric pair. Even more highly preferably, an enantiomerically enriched compound comprises greater than
  • an enantiomerically enriched compound comprises greater than 98% of one enantiomer of an enantiomeric pair and less than 2% of the other enantiomer of the enantiomeric pair. Most preferably, an enantiomerically enriched compound comprises greater than 99% of one enantiomer of an enantiomeric pair and less than 1% of the other enantiomer of the enantiomeric pair.
  • halo or halide as used herein refers to F, Cl, Br or I.
  • haloalkenyl refers to a loweralkenyl group in which one or more hydrogen atoms is replaced with a halogen.
  • haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2- difluoroethylene, trifluoroethylene, 1, 1 , 1-trifluoro-2- propylene and the like.
  • haloalkoxy refers to the group having the formula, -OR 69 , where R 69 is a haloalkyl group as defined herein.
  • examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
  • haloalkyl refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl , 2 , 2-dichloroethyl, 2 , 2 , 2-trichloroethyl , pentafluoroethyl and the like.
  • heterocyclic ring refers to any 3- or 4 -membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl , decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
  • Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl , pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl , thiazolyl, thiazolinyl,
  • X* is -CH or -O- and Y* is -C(O)- or [-C(R 92 ) 2 -]v where R 92 is hydrogen or C ⁇ -C 4 alkyl where v is 1, 2, or 3 such as 1, 3-benzodioxolyl, 1, 4-benzodioxanyl and the like.
  • Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
  • Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen.
  • nitrogen containing heterocyclic rings can be N-protected.
  • heterocyclic alkenyl refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
  • (heterocyclic) alkoxy refers to the group having the formula, -OR 68 , where R 68 is a (heterocyclic) alkyl group.
  • R 68 is a (heterocyclic) alkyl group.
  • (heterocyclic) alkyl refers to a heterocyclic group appended to a loweralkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
  • heterocyclic alkynyl refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl , morpholinylpropynyl and the like.
  • (heterocyclic) carbonylalkyl refers to a heterocyclic group appended to an alkyl radical via a carbonyl group.
  • Representative examples of (heterocyclic) carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
  • heterocyclic carbonyloxyalkyl refers to a heterocyclic group appended to an alkyl radical via a carbonyloxy group (i.e.,
  • heterocyclic carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
  • heterocyclic oxy refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (-0-) .
  • hydroxy protecting group refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991) which is incorporated by reference herein. Such hydroxy protecting groups include:
  • substituted methyl ethers including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p- methoxybenzyloxymethyl, (4 -methoxyphenoxy) methyl, t- butoxymethyl, 2-methoxyethoxymethyl, 2,2,2- trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl , tetrahydropyranyl, tetrahydrothiopyranyl , tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
  • substituted ethyl ethers including, but not limited to, 1-ethoxyethyl, 1 -methyl-1-methoxyethyl , 1-methyl-l- benzyloxyethyl, 2 , 2 , 2-trichloroethyl , trimethylsilylethyl, t-butyl ether and the like;
  • substituted benzyl ethers including, but not limited to, p-methoxybenzyl, 3 , 4-dimethoxybenzyl , o-nitorbenzyl, p- halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
  • silyl ethers including, but not limited to, trimethylsilyl, triethylsilyl , triisopropylsilyl, dimethylisopropylsilyl , diethylisopropylsilyl , dimethylthexylsilyl, ⁇ t-butyldimethylsilyl, t- butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
  • esters including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
  • Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
  • hydroxyalkyl refers to the group having the formula, -R 65 -OH, where R 65 is an alkylene group
  • leaving group refers to a group which is easily displaced from the compound by a nucleophile.
  • leaving groups include a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991) .
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, alpha-chlorobutyryl, benzoyl, 4-chlorobenzoyl , 4-bromo- benzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl (phenyl-S-), triphenylmethylsulfenyl (trityl-S-) and the like; sulfinyl groups such as p-methylphenylsulfin
  • N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) .
  • thioalkoxy refers to groups having the formula -SR 98 wherein R 98 is an alkyl group. Preferred groups R 98 are loweralkyl groups.
  • thio-substituted alkyl refers to an alkyl radical to which is appended a thiol group (-SH) .
  • the compounds of the invention can comprise asymmetrically substituted carbon atoms.
  • all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the' invention substantially free from their enantiomers or other diastereomers.
  • substantially free is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
  • Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
  • 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 often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
  • Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with 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.
  • Enzymes such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture.
  • an ester derivative of a carboxyl group in 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.
  • solvates and hydrates of the compounds of Formula la or lb are meant to be included in this invention.
  • any variable for example R 1 , R 2 , R 3 , m, n, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents are permissible only if such combinations result in stable compounds.
  • Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
  • This invention is intended to encompass compounds having Formula la or lb when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body ( in vivo) or processes occurring in vi tro .
  • the reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wl, USA); Sigma Chemical Co. (St. Louis, MO, USA) ; and Fluka Chemical Corp. (Ronkonkoma, NY, USA) ; Alfa Aesar (Ward Hill, MA 01835-9953) ; Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc.
  • hydroxy-protecting group refers to selectively removable groups which protect hydroxyl groups against undesirable reactions during synthetic procedures.
  • the use of hydroxy-protecting groups is well-known in the art and is discussed in T.H. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd edition, John Wiley & Sons, New York (1991), pp 10-86.
  • Examples of hydroxy-protecting groups include methylthiomethyl, tertiary-butyldimethylsilyl, tertiary- butyldiphenylsilyl, acetyl, benzoyl, and the like.
  • the invention contemplates the various stereoisomers and mixtures thereof.
  • Individual stereoisomers of compounds of the invention can be made by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation as, for example, by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques, or by direct separation of the optical enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the art.
  • THF for tetrahydrofuran
  • AcOH for acetic acid
  • Ac for acetate
  • MeCN for acetonitrile
  • MeOH for methanol
  • TMS for trimethylsilyl
  • TES for triethylsilyl
  • TFA for trifluoroacetic acid
  • TBDMS for tertiary-butyldimethylsilyl
  • TMSCl for trimethylsilyl chloride
  • TMSBr for trimethylsilyl bromide
  • TMSN 3 for trimethylsilyl azide
  • BF 3 »OEt 2 for boron trifluoride diethyl etherate
  • DBU for 1, 8-diazabicyclo [5.4.0] undec-7-ene
  • TEA for triethylamine
  • TMSOTf for trimethylsilyl triflate
  • DMF for N,N-dimethylformamide
  • Ph for phenyl
  • DCM dichloromethane
  • the conversion of (i) to (1A) can be accomplished by treating the former with a protecting group precursor, and an additive in a solvent.
  • protecting group precursors include acetaldehyde, acetone, benzaldehyde, para- methoxybenzaldehyde, 3-pentanone, cyclohexanone, and 2,2- dimethoxypropane .
  • additives include acids and bases. More preferred are the following acids: triflie acid, TFA, TsOH and hydrogen chloride. Since water is generated during the course of the reaction, the reaction can be dried by azeotropic removal of the water. An appropriate solvent for this conversion, therefore, is one which azeotropes with water.
  • solvents which azeotrope with water include benzene, toluene, and xylene.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
  • a solution of (i) , benzaldehyde, and TsOH in toluene is refluxed for about 10 hours.
  • the water is removed azeotropically .
  • Conversion of (1A) to (IB) can be accomplished by treating the former with a free radical precursor and a free radical initiator in a solvent.
  • free radical precursors include N-bromosuccinimide, N- chlorosuccinimide, Br 2 , and Cl 2 .
  • free radical initiators include AIBN and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat .
  • solvents include benzene, toluene, and xylene.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
  • (1A) is treated with AIBN and N- bromosuccinimide in refluxing benzene for about four hours.
  • the conversion of (IB) to (IC) can be accomplished by treating the former with an organostannane and a free radical initiator in a solvent.
  • organostannanes include 2- (tributylstannyl) furan, tributyltin hydride, allyltributyltin, vinyltributyltin, and
  • 2- (tributylstannyl) thiophene 2- (tributylstannyl) thiophene.
  • free radical initiators include AIBN and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat .
  • solvents include benzene, toluene, and xylene.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
  • (IB) , allyltributyltin and AIBN in benzene are refluxed for about 10 hours.
  • the conversion of (IC) to (ID) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (IC) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about two hours .
  • the conversion of (ID) to (IE) can be accomplished by treating the former with a base and an alcohol.
  • bases include K 2 C0 3 , NaOMe, NaOEt, NaOH, and KOH.
  • Specific examples of alcohols include methanol, ethanol, and isopropanol.
  • the conversion of (IE) to (IF) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the conversion of (IF) to (1G) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME and diethyl ether. Although the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (IF) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about 10 hours.
  • the conversion of (1G) to (IH) can be accomplished by treating the former with a base, and an alcohol.
  • bases include K 2 C0 3 , NaOMe, NaOEt, NaOH, and KOH.
  • Specific examples of alcohols include methanol, ethanol, and isopropanol.
  • reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (1G) in methanol at room temperature is treated with potassium carbonate for about 30 minutes.
  • the conversion of (IH) to (II) can be accomplished by treating the former with a base in a solvent.
  • bases include potassium tertiary-butoxide, diisopropylethylamine, and DBU.
  • Specific examples of solvents include THF, chloroform, TBME, and benzene.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (IH) in THF is treated with DBU and refluxed for about 6 hours.
  • the conversion of (II) to (1J) can be accomplished by treating the former with a nucleophile and an additive.
  • nucleophiles include NaN 3 , TMSN 3 , TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN 3 and TMSN 3 .
  • additives include acids and bases. More preferred are the following acids: NH 4 C1, (NH 4 ) 2 S0 4 , and AcOH.
  • Specific examples of solvents include MeOH, EtOH, i- PrOH, NMP, water, and mixtures thereof.
  • reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed.
  • the reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature.
  • (II) NaN 3 and NH 4 C1 in methanol-water is refluxed for about 5 hours.
  • (1J) (IK) ( ID As shown in Scheme 6, the conversion of (1J) to (IK) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases.
  • solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (1J) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about two hours.
  • the conversion of (IK) to (IL) can be accomplished by treating the former with a reducing agent in a solvent.
  • reducing agents include phosphines followed by water and base, and H 2 S and pyridine. More preferred are the following phosphines: PPh 3 and PEt 3 .
  • bases include TEA, NH 4 0H, and NaOH.
  • Specific examples of solvents include THF, MeOH, TBME and DCM.
  • the conversion of (IL) to (IM) can be accomplished by treating the former with a protecting group and a base in a solvent.
  • protecting groups include trityl, nosyl and brosyl .
  • Specific examples of base include pyridine, TEA and 2 , 6-lutidine .
  • Specific examples of solvents include DCM, THF, chloroform and diethyl ether.
  • the conversion of (IM) to (IN) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base.
  • Lewis acids include ZnCl 2 , TiCl 4 , BF 3 .OEt 2 , and SnCl 4 .
  • Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol.
  • Specific examples of solvents include an aforementioned alcohol, THF, 1, 1, 1-trichloroethane, DCM and chloroform.
  • the conversion of the intermediate compound to (IN) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the conversion of (IN) to (10) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (IM) to (2A) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base.
  • Lewis acids include ZnCl 2 ,
  • the conversion of the intermediate compound to (2A) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the conversion of (2A) to (2B) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (IN) to (3A) can be accomplished by treating the former with an epoxidizing reagent in a solvent.
  • epoxidizing reagents include peracids, dioxirane, hydrogen peroxide and bases such as NaOH, KOH, and LiOH, and VO(acac) 2 and tertiary-butylperoxide . More preferred are the following peracids: MCPBA, peracetic acid, and trifluoroperacetic acid.
  • solvents include DCM, chloroform, cyclohexane, and hexanes.
  • reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature.
  • (IN) in room temperature DCM is treated with MCPBA for about 16 hours.
  • the conversion of (3A) to (3B) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (2A) to (4A) can be accomplished by treating the former with an epoxidizing reagent in a solvent.
  • epoxidizing reagents include peracids, dioxirane, hydrogen peroxide and bases such as NaOH, KOH, and LiOH, and VO(acac) 2 and tertiary-butylperoxide. More preferred are the following peracids: MCPBA, peracetic acid, and trifluoroperacetic acid.
  • solvents include DCM, chloroform, cyclohexane, and hexanes.
  • the reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature.
  • (2A) in room temperature DCM is treated with MCPBA for about 16 hours.
  • the conversion of (4A) to (4B) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the reaction is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (4A) in THF at room temperature is treated with aqueous LiOH for about 10 hours .
  • the conversion of (2A) to (5A) can be accomplished by treating the former with an oxidant and bulk oxidant in a solvent.
  • oxidant and bulk oxidants include the following: Os0 4 and NMO, and KMn0 4 with a base such as LiOH, NaOH, and KOH.
  • solvents include toluene, benzene, xylene, acetone, tertiary-butyl alcohol, water, and mixtures thereof.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (2A) in room temperature acetone is treated with water, NMO and Os0 4 in toluene for about 3 hours.
  • the conversion of (4A) to (6A) can be accomplished by treating the former with a nucleophile and an additive in a solvent.
  • nucleophiles include NaN 3 , TMSN 3 , TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN 3 , and TMSN 3 .
  • additives include acids and bases. More preferred are the following acids: NH 4 C1, (NH 4 ) 2 S ⁇ 4 , and AcOH.
  • Specific examples of solvents include MeOH, EtOH, i- PrOH, NMP, water, and mixtures thereof.
  • the conversion of (6A) to (6B) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include' acids and bases. More preferred are the following bases: LiOH, KOH and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (5A) to (7A) can be accomplished by treating the former with an oxidizing agent in a solvent.
  • oxidizing agents include NaI0 4 , HI0 4 , and Pb(OAc) 4 .
  • solvents include THF, methanol, ethanol, isopropanol, water, and mixtures thereof.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (5A) in methanol at room temperature is treated with NaI0 in water for about three hours .
  • the conversion of (7A) to (7B) can be accomplished by treating the former with an oxidizing agent and an additive in a solvent.
  • oxidizing agents include sodium chlorite in acidic buffer, KMn0 4 , H 2 Cr0 4 , AgO and Na 2 Cr 2 0 7 .
  • a specific example of an additive is 2- methyl-2-butene .
  • solvents include THF, DCM, tertiary-butyl alcohol, methanol, ethanol, and isopropanol.
  • the conversion of (7A) to (8A) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (6A) in THF at room temperature is treated with aqueous LiOH for about 12 hours.
  • the conversion of (IN) to (9A) can be accomplished by treating the former with an oxidant in a solvent.
  • oxidants include: Os0 4 and NMO and KMn0 4 and a base such as KOH, LiOH, and NaOH.
  • solvents include toluene, benzene, xylene, acetone, and water, and mixtures thereof.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (IN) in room temperature acetone is treated with water, NMO and Os0 4 in toluene for about 3 hours.
  • the conversion of (9A) to (9B) can be accomplished by treating the former with an oxidizing agent in a solvent.
  • oxidizing agents include NaI0 4 , HI0 4 , and Pb(OAc) 4 .
  • solvents include THF, methanol, ethanol, isopropanol, water, and mixtures thereof.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated tem- peratures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (5A) in methanol at room temperature is treated with NaI0 4 in water for about three hours .
  • (9B) can be directly prepared from (IN) by treating the latter with a combination of oxidants in a solvent.
  • oxidants include Os0 4 , and KMn0 and a base such as KOH, LiOH, and NaOH, NaI0 4 , HI0 4 , and Pb(OAc) 4 .
  • solvents include toluene, benzene,- xylene, acetone, water, and mixture thereof.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (IN) in room temperature acetone is treated with water, Os0 4 , and NaI0 4 for about three hours.
  • the conversion of (9B) to (9C) can be accomplished by treating the former with a reducing agent in a solvent.
  • reducing agents include NaBH 4 , NaBH 3 CN, and BH 3 *NH 2 (C (CH 3 ) 3 ) .
  • solvents include methanol, ethanol, and isopropanol.
  • the conversion of (9C) to (9D) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (10) to (10A) can be accomplished by treating the former with a protecting group precursor, a base, and an additive in a solvent.
  • a specific example of a protecting group precursor is 2- (trimethylsilyl) ethanol .
  • a specific example of an additive is 2-chloro-l-methylpyridinium iodide.
  • bases include TEA, diisopropylamine, and lutidine.
  • Specific examples of solvents include DCM, THF, chloroform, and diethyl ether.
  • the conversion of (10A) to (10B) can be accomplished by treating the former with an oxidant and bulk oxidant in a solvent.
  • oxidant and bulk oxidants include: Os0 4 and NMO, and KMn0 4 and a base such as KOH, LiOH, and NaOH.
  • solvents include toluene, benzene, xylene, acetone, and water, and mixtures thereof.
  • IOC can be accomplished by treating the former with an oxidizing agent in a solvent.
  • oxidizing agents include NaI0 4 , HI0 4 , and Pb(OAc) 4 .
  • solvents include THF, methanol, ethanol, isopropanol, water, and mixtures thereof.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (10B) in methanol at room temperature is treated with NaI0 in water for about three hours .
  • the conversion of (IOC) to (10D) can be accomplished by treating the former with an oxidizing agent and an additive in a solvent to generate the acid which can then be esterified.
  • oxidizing agents include sodium chlorite in acidic buffer, KMn0 4 , H 2 Cr0 , AgO and Na 2 Cr 2 0 7 -
  • an additive is 2-methyl-2-butene .
  • solvents include THF, DCM, tertiary-butyl alcohol, methanol, ethanol, and isopropanol.
  • the acid can then be converted to (10D) by treating it with an esterifying reagent in a solvent.
  • esterifying reagents include diazomethane, an alcohol and a mineral acid, and SOCl 2 followed by an alcohol.
  • solvents include methanol, THF, DCM, TBME, and chloroform.
  • the conversion of (10D) to (10E) can be accomplished by treating the former with a deprotecting agent in a solvent.
  • deprotecting agents include TBAF, and HF.
  • solvents include THF, DCM, chloroform, and diethyl ether.
  • the conversion of (IB) to (11A) can be accomplished by treating the former with an organostannane and a free radical initiator in a solvent.
  • organostannanes include 2- (tributylstannyl) furan, tributyltin hydride, allyltributyltin, vinyltributyltin, and 2- (tributylstannyl) thiophene.
  • free radical initiators include AIBN, and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat.
  • solvents include benzene, toluene, and xylene.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
  • (IB) , 2-methylallyl tributyltin and AIBN in benzene are refluxed for about 10 hours.
  • the conversion of (11A) to (11B) can be accomplished by treating the former with a catalyst and hydrogen, in a solvent.
  • catalysts include palladium hydroxide, palladium on carbon, PdCl 2 , and platinum on carbon.
  • Specific sources of hydrogen include ammonium formate and hydrogen gas.
  • Specific examples of solvents include EtOAc, isopropyl acetate, and THF.
  • the conversion of (11B) to (11C) can be accomplished by treating the former with sulfonyl chloride and a base in a solvent to generate an intermediate compound which can then be transesterified.
  • sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride.
  • bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine.
  • Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (11B) in DCM at 0 °C is treated with methanesulfonyl chloride and TEA for about 5 hours .
  • the intermediate compound is then converted to (11C) by treating the former with a base and an alcohol.
  • bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH.
  • alcohols include methanol, ethanol, propanol and isopropanol.
  • Co- solvents such as THF, TBME, DCM and chloroform can be added to the reaction mixture to enhance solubility of the starting materials and products.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • the intermediate compound in methanol at room temperature is treated with potassium carbonate for about one hour.
  • the conversion of (11C) to (11D) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine and diethyl ether.
  • the conversion of (11D) to (HE) can be accomplished by treating the former with sulfonyl chloride and a base in a solvent to generate an intermediate compound which can then be transesterified.
  • sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride.
  • bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME and diethyl ether.
  • reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (11D) in DCM at 0 °C is treated with methanesulfonyl chloride and TEA for about 10 hours.
  • the intermediate compound is then converted to (HE) by treating the former with a base and an alcohol.
  • bases include potassium carbonate,
  • reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • the intermediate compound in methanol is treated with potassium carbonate for about 10 hours.
  • the conversion of (HE) to (11F) can be accomplished by treating the former with a base to generate an intermediate which is then treated with a nucleophile.
  • bases include DBU, potassium tertiary- butoxide, and diisopropylethylamine.
  • Specific examples of solvents include THF, chloroform, TBME, and benzene.
  • the conversion of the intermediate compound to (HF) can be accomplished by treating the former with a nucleophile and an additive.
  • nucleophiles include NaN 3 , TMSN 3 , TMSCl , TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN 3 and TMSN 3 .
  • additives include acids and bases. More preferred are the following acids: NH 4 C1, (NH 4 ) 2 S0 4 , and AcOH.
  • Specific examples of solvents include MeOH, EtOH, i-PrOH, NMP, water, and mixtures thereof.
  • reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed.
  • the reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature.
  • the intermediate compound in a methanol -water mixture is treated with NaN 3 and NH 4 C1 and refluxed for about 5 hours .
  • the conversion of (HF) to (HG) can be accomplished by treating the former with sulfonyl chloride and a base to generate an intermediate compound which can then be reduced to generate a second intermediate, protected to generate a third intermediate, treated with a Lewis acid and an alcohol to generate a fourth intermediate and acylated to generate HH.
  • sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride.
  • bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (HF) in DCM at 0 °C is treated with methanesulfonyl chloride and TEA for about two hours to generate the first intermediate.
  • the conversion of the first intermediate to a second intermediate can be accomplished by treating the former with a reducing agent in a solvent.
  • reducing agents include phosphines followed by water and a base, and H 2 S and pyridine. More preferred are the following phosphines: PPh 3 , and PEt 3 .
  • bases include TEA, NH 4 0H, and NaOH.
  • solvents include THF, MeOH, TBME and DCM.
  • (IK) in THF at room temperature is treated with PPh 3 for about two hours, followed by water and TEA for about 10 hours.
  • the conversion of the second intermediate to the third intermediate can be accomplished by treating the former with a protecting group and a base in a solvent.
  • protecting groups include trityl, nosyl and brosyl .
  • base include pyridine, TEA and 2 , 6-lutidine .
  • solvents include DCM, THF, chloroform and diethyl ether.
  • the conversion of the third intermediate to the fourth intermediate can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base.
  • Lewis acids include ZnCl 2 , TiCl 4 , BF 3 .OEt 2 , and SnCl 4 .
  • alcohols include methanol, ethanol, isopropanol, 3- pentanol, benzhydrol, and benzyl alcohol.
  • Specific examples of solvents include an aforementioned alcohol, THF, 1, 1, 1-trichloroethane, DCM and chloroform.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • the third intermediate in about 75 °C isopropanol is treated with BF 3 .OEt 2 for about two hours .
  • the conversion of the fourth intermediate to (HG) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the conversion of (HG) to (HH) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases:
  • LiOH, KOH, and NaOH LiOH, KOH, and NaOH.
  • solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (HG) in THF at room temperature is treated with aqueous LiOH for about 12 hours.
  • the conversion of (9C) to (12A) can be accomplished by treating the former with a phosphine, and a selenium compound in a solvent.
  • phosphines include triphenylphosphine and tributylphosphine .
  • a specific example of a selenium compound is ortho-nitrophenyl selenocyanate.
  • solvents include THF, DCM, chloroform, and diethyl ether.
  • (9C) in THF at room temperature is treated with tributylphosphine and ortho-nitrophenyl selenocyanate for about two hours .
  • the conversion of (12A) to (12B) can be accomplished by treating the former with a peroxide in a solvent.
  • peroxides include hydrogen peroxide, di-tertiary-butyl peroxide, and ozone.
  • Specific examples of solvents includes THF, DCM, chloroform, and diethyl ether.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature.
  • (12A) in THF at room temperature is treated with hydrogen peroxide for about 12 hours.
  • the conversion of (12B) to (12C) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • conversion of (i) to (13A) can be accomplished by treating the former with an aldehyde, ketone or acetal in the presence of an acid.
  • aldehydes, ketones, and acetals include benzaldehyde, 4-methoxybenzaldehyde, acetaldehyde, 3-pentanone, and 2 , 2-dimethoxy propane.
  • acids include para-toluenesulfonic acid, trifluoroacetic acid, and concentrated hydrochloric acid.
  • solvents include benzene, toluene, xylene, dichloromethane, acetone, and mixtures thereof.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
  • a solution of (i) in acetone is treated with 2 , 2-dimethoxy propane and para-toluenesulfonic acid and refluxed for about four hours.
  • the conversion of (13A) to (13B) can be achieved by treating the former with a base and an alcohol.
  • bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH.
  • alcohols include methanol, ethanol, propanol, and isopropanol.
  • Co- solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials and products.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (13A) in methanol at room temperature is treated with potassium carbonate for about one hour .
  • the conversion of (13B) to (13C) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the conversion of (13C) to (13D) can be accomplished by treating the former with a chloride source and a base in a solvent.
  • chloride sources include thionyl chloride and sulfuryl chloride.
  • bases include pyridine, DBU, diisopropylethylamine, and TEA.
  • solvents include DCM, THF, TBME, and diethyl ether.
  • the conversion of (13D) to (13E) can be accomplished by treating the former with an acid in an alcohol.
  • acids include para-toluenesulfonic acid, trifluoroacetic acid, and concentrated hydrochloric acid.
  • alcohols include methanol, ethanol, and isopropanol.
  • the conversion of (13E) to (13F) can be accomplished by treating the former with an activating group and a base in a solvent.
  • An activating group is thionyl chloride.
  • bases include TEA, diisopropylethylamine pyrrolidine, and pyridine.
  • Specific examples of solvents include THF, DCM, TBME, and diethyl ether.
  • the conversion of (13F) to (13G) can be accomplished by treating the former with a nucleophile in a solvent.
  • nucleophiles include NaN 3 , TMSN 3 ,
  • TMSCl, TMSBr, carbanions, thioacetate, and cyanide More preferred are the following nucleophiles: NaN 3 and TMSN 3 .
  • solvents include MeOH, EtOH, i-PrOH, DMF, NMP, water, and mixtures thereof.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed.
  • the reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature.
  • (13F) in room temperature DMF is treated with NaN 3 for about 16 hours.
  • the conversion of (13G) to (13H) can be accomplished by treating the former with sulfonyl chloride and a base in a solvent.
  • sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride.
  • bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine.
  • Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (13G) in DCM at 0 °C is treated with methanesulfonyl chloride and TEA for about two hours .
  • the conversion of (13H) to (131) can be accomplished by treating the former with a reducing agent in a solvent.
  • reducing agents include phosphines followed by water and a base, and H 2 S and pyridine. More preferred are the following phosphines: PPh 3/ and PEt 3 .
  • Specific examples of bases include TEA, NH 4 OH, and NaOH.
  • solvents include THF, MeOH, TBME, and DCM.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (13H) in THF at room temperature is treated with PPh 3 for about two hours, followed by water and TEA for about 10 hours.
  • the conversion (131) to (13J) can be accomplished by treating the former with a protecting group and a base in a solvent.
  • protecting groups include trityl, nosyl, and brosyl .
  • Specific examples of base include pyridine, TEA, and 2 , 6-lutidine .
  • solvents include DCM, THF, chloroform, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (131) in DCM at about 0 °C is treated with trityl chloride and TEA for about two hours .
  • the conversion of (13J) to (13K) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base.
  • Lewis acids include ZnCl 2 , TiCl 4 , BF 3 »OEt 2 , and SnCl 4 .
  • alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol .
  • Specific examples of solvents include an aforementioned alcohol, THF, 1, 1, 1-trichloroethane, DCM, and chloroform.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (13J) in isopropanol is treated with BF 3 »OEt 2 and heated to about 75 °C for about two hours.
  • the conversion of (13K) to (13L) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, diethyl ether. Although the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13K)in pyridine is treated with acetic anhydride for about 12 hours. The conversion of (13L) to (13M) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (13L) in THF at room temperature is treated with aqueous LiOH for about 12 hours .
  • the conversion of (13L) to (14A) can be accomplished by treating the former with a base and an alkylating agent in a solvent.
  • alkylating agents include Mel, EtBr, allyl bromide, benzyl bromide, and isopropyl bromide.
  • bases include NaH, KH, K 2 C0 3 , pyridine, and DBU.
  • solvents include THF, DMF, DCM, TBME, and diethyl ether.
  • the conversion of (14A) to (14B) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (13L) to (15A) is accomplished by treating the former with a protecting group precursor and an additive in a solvent.
  • protecting groups include vinyl ether, benzyl, TBS, and acetyl.
  • additives include acids and bases. More preferred are the following acids: para-toluenesulfonic acid, triflie acid, TFA, and concentrated hydrochloric acid.
  • solvents include vinyl ether, DCM, THF, and TBME.
  • (13L) in room temperature vinyl ether is treated with TFA for about 16 hours .
  • the conversion of (15A) to (15B) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (15A) in THF at room temperature is treated with aqueous LiOH for about 10 hours.
  • the conversion of (13L) to (16A) can be accomplished by treating the former with an oxidizing agent in a solvent.
  • oxidizing agents include PCC coated on Al 2 0 3 , oxalyl chloride and DMSO, KMN0 4 , and Cr 2 0 7 2" .
  • solvents include DCM, THF, TBME, and diethyl ether.
  • reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • a solution of (13L) in DCM can be treated with PCC on Al 2 0 3 for about 8 hours .
  • the conversion of (16A) to (16B) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF, and TBME.
  • nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates, and nitriles.
  • nucleophiles More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane, vinyl magnesium bromide, and methyl magnesium bromide.
  • the reaction generally proceeds at -78 °C, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 15 minutes to about 4 hours and can be selected depending on the reaction temperature.
  • a room temperature solution of vinyl magnesium bromide in THF can be treated with (16A) in THF for about two hours.
  • the conversion of (16B) to (16C) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (13B) to (17A) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases.
  • Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (13B) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about 10 hours.
  • the conversion of (17A) to (17B) is accomplished by treating the former with an acid in an alcohol.
  • acids include para-toluenesulfonic acid, triflic acid, trifluoroacetic acid, and concentrated hydrochloric acid.
  • alcohols include methanol, ethanol, and isopropanol.
  • the conversion of (17B) to (17C) is accomplished by treating the former with a base and an alcohol.
  • bases include K 2 C0 3 , NaOMe, NaOEt, NaOH, and KOH.
  • alcohols include methanol, ethanol, propanol, and isopropanol.
  • THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (17B) in methanol at room temperature is treated with potassium carbonate for about 5 hours .
  • the conversion of (17C) to (17D) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • (17C) in DCM at about 0 °C is treated with benzoyl chloride and TEA for about 5 hours .
  • the conversion of (17D) to (17E) can be accomplished by treating the former with a Lewis acid, a nucleophile, and a transition metal halide.
  • Lewis acids include ZnCl 2 , TiCl 4 , BF 3 .OEt 2 , and SnCl 4 .
  • nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates, and nitriles.
  • Grignard reagents vinyl magnesium bromide, methylmagnesium bromide, and ethylmagnesium bromide.
  • transition metal halides include Cul, and CuBr.
  • solvents include THF, diethyl ether, and TBME.
  • the conversion of (17E) to (17F) is accomplished by treating the former with a base and an alcohol.
  • bases include K 2 C0 3 ,
  • reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (17E) in methanol at room temperature can be treated with potassium carbonate for about one hour.
  • the conversion of (17F) to (17G) can be accomplished by treating the former with an activating group and a base in a solvent.
  • an activating group is thionyl chloride.
  • bases include TEA, diisopropylethylamine pyrrolidine, and pyridine.
  • Specific examples of solvents include THF, DCM, TBME, and diethyl ether.
  • the reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (17F) in DCM at 0 °C can be treated with thionyl chloride and TEA for about 30 minutes.
  • the conversion of (17G) to (17H) can be accomplished by treating the former with a nucleophile in a solvent.
  • nucleophiles include NaN 3 , TMSN 3 , TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN 3 and TMSN 3 .
  • solvents include MeOH, EtOH, i-PrOH, NMP, DMF, water, and mixtures thereof.
  • the conversion of (17H) to (171) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (17H) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about two hours.
  • the conversion of (171) to (17J) can be accomplished by treating the former with a reducing agent in a solvent.
  • reducing agents include phosphines followed by water and a base, and H 2 S and pyridine.
  • phosphines More preferred are the following phosphines: PPh 3 , and PEt 3 .
  • bases include TEA, NH 4 OH, and NaOH.
  • solvents include THF, MeOH, TBME, and DCM.
  • the conversion of (17J) to (17K) can be accomplished by treating the former with a protecting group and a base in a solvent.
  • protecting groups include trityl, nosyl, and brosyl .
  • Specific examples of base include pyridine, TEA, and 2 , 6-lutidine.
  • Specific examples of solvents include DCM, THF, chloroform, and diethyl ether.
  • the conversion of (17K) to (17L) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base.
  • Lewis acids include ZnCl 2 , TiCl 4 , BF 3 «OEt 2 , and SnCl 4 .
  • alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol.
  • Specific examples of solvents include an aforementioned alcohol, THF, 1, 1 , 1-trichloroethane, DCM, and chloroform.
  • the reaction generally proceeds at about 75 °C, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (17K) in isopropanol can be treated with BF 3 .OEt 2 and heated to about 75 °C for about two hours.
  • the conversion of the intermediate to (17L) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the conversion of (17L) to (17M) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (1A) to (18A) can be accomplished by treating the former with a base and an alcohol.
  • bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH.
  • alcohols include methanol, ethanol, propanol, and isopropanol.
  • Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (1A) in methanol at room temperature can be treated with potassium carbonate for about one hour.
  • the conversion of (18A) to (18B) can be accomplished by treating the former with a protecting group precursor and an additive in a solvent.
  • protecting groups include benzyl, TMS, TES, and TBDMS .
  • additives include acids and bases. More preferred are the following bases: pyridine, TEA, DMAP, imidazole, and 2 , 6-lutidine .
  • Specific examples of solvents include DCM, THF, chloroform, DMF, and diethyl ether.
  • the conversion of (18B) to (18C) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (18B) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about 16 hours.
  • Conversion of (18C) to (18D) can be accomplished by treating the former with a free radical precursor and a free radical initiator in a solvent.
  • free radical precursors include N-bromosuccinimide, N- chlorosuccinimide, Br 2 , and Cl 2 .
  • free radical initiators include AIBN, and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat.
  • solvents include benzene, toluene, and xylene.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
  • (18C) can be treated with AIBN and N-bromosuccinimide in refluxing benzene for about four hours .
  • the conversion of (18D) to (18E) can be accomplished by treating the former with an organostannane and a free radical initiator in a solvent.
  • organostannanes include 2- (tributylstannyl) furan, tributyltin hydride, allyltributyltin, vinyltributyltin, and 2- (tributylstannyl) thiophene.
  • free radical initiators include AIBN, and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat.
  • solvents include benzene, toluene, and xylene.
  • the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure.
  • the reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
  • (18D) allyltributyltin and AIBN in benzene can be refluxed for about 10 hours.
  • the conversion of (18E) to (18F) can be accomplished by first, treating the former with a base and an alcohol to form the first intermediate, which can then be treated with a sulfonyl chloride and base to yield the second intermediate, which can be treated with a deprotecting agent to yield (18F) .
  • bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH.
  • alcohols include methanol, ethanol, propanol, and isopropanol.
  • Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature.
  • (18E) in methanol at room temperature can be treated with potassium carbonate for about 16 hours.
  • the conversion of the first intermediate to the second intermediate can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • the first intermediate in DCM at about 0 °C is treated with methanesulfonyl chloride, and TEA for about 12 hours.
  • the conversion of the third intermediate to (18F) can be accomplished by treating the former with a deprotecting agent in a solvent.
  • deprotecting agents include HF and TBAF.
  • solvents include THF, DCM, TBME, and diethylether .
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature.
  • the third intermediate in THF at room temperature can be treated with TBAF for about 12 hours.
  • the conversion of (18F) to (18G) can be accomplished by treating the former with a nucleophile in a solvent.
  • nucleophiles include NaN 3 , TMSN 3 , TMSC1, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN 3 and TMSN 3 .
  • solvents include MeOH, EtOH, i-PrOH, NMP, DMF, water, and mixtures thereof.
  • (18F) in room temperature DMF can be treated with NaN 3 for about 16 hours.
  • the conversion of (18G) to (18H) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases.
  • Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (18G) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about two hours.
  • the conversion of (18H) to (181) can be accomplished by treating the former with a reducing agent in a solvent.
  • reducing agents include phosphines followed by water and a base, and H 2 S and pyridine. More preferred are the following phosphines: PPh 3 , and PEt 3 .
  • bases include TEA, NH 4 OH, and NaOH.
  • Specific examples of solvents include THF, MeOH, TBME, and DCM.
  • the conversion of (181) to (18J) can be accomplished by treating the former with a protecting group and a base in a solvent.
  • protecting groups include trityl, nosyl, and brosyl .
  • Specific examples of base include pyridine, TEA, and 2 , 6-lutidine .
  • Specific examples of solvents include DCM, THF, chloroform, and diethyl ether.
  • the conversion of (18J) to (18K) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base.
  • Lewis acids include ZnCl 2 , TiCl , BF 3 «OEt 2 , and SnCl 4 .
  • alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol .
  • Specific examples of solvents include an aforementioned alcohol, THF, 1 , 1, 1-trichloroethane, DCM, and chloroform.
  • the conversion of the intermediate to (18K) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the intermediate in pyridine at room temperature can be treated with acetic anhydride and pyridine for about 12 hours.
  • the conversion of (18K) to (18L) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the conversion of (18D) to (19A) can be accomplished by treating the former with a transition metal catalyst and an organostannane in a solvent.
  • a transition metal catalysts include palladium on carbon, platinum on carbon, PdCl 2 ,
  • Pd(PPh 3 ) 4 and bis (dibenzylidenacetone) palladium (0) . It can be necessary to add a ligand for the transition metal catalyst. Specific examples include triphenylphosphine, dba, and dppf . Specific examples of organostannanes include vinyltributyltin,
  • reaction generally proceeds at about 55 °C, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 24 hours to about 48 hours and can be selected depending on the types of starting materials and the reaction temperature.
  • (18D) in THF can be treated with triphenylphosphine, vinyltributyltin, and bis (dibenzylideneacetone) palladium (0) and heated to about 55°C for about 24 hours.
  • the conversion of (19A) to (19B) can be accomplished by first, treating the former with a base and an alcohol to form the first intermediate, which can then be treated with a sulfonyl chloride and base to yield the second intermediate, which can be treated with a deprotecting agent to yield (19B) .
  • bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH.
  • alcohols include methanol, ethanol, propanol, and isopropanol.
  • Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature.
  • (19A) in methanol at room temperature can be treated with potassium carbonate for about 16 hours.
  • the conversion of the first intermediate to the second intermediate can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine.
  • solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • the first intermediate in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about 12 hours.
  • the conversion of the third intermediate to (19B) can be accomplished by treating the former with a deprotecting agent in a solvent.
  • deprotecting agents include HF and TBAF.
  • solvents include THF, DCM, TBME, and diethylether .
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature.
  • the third intermediate in THF ⁇ at room temperature can be treated with TBAF for about 12 hours.
  • the conversion of (19B) to (19C) can be accomplished by treating the former with a nucleophile in a solvent.
  • nucleophiles include NaN 3 , TMSN 3 , TMSC1, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN 3 and TMSN 3 .
  • solvents include MeOH, EtOH, i-PrOH, NMP, DMF, water, and mixtures thereof.
  • (19B) in room temperature DMF can be treated with NaN 3 for about 16 hours.
  • the conversion of (19C) to (19D) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent.
  • hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh 3 , and PBu 3 , trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride.
  • additives include acids and bases.
  • Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether.
  • the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (19C) in DCM at about 0 °C is treated with methanesulfonyl chloride and TEA for about two hours.
  • the conversion of (19D) to (19E) can be accomplished by treating the former with a reducing agent in a solvent.
  • reducing agents include phosphines followed by water and a base, and H 2 S and pyridine. More preferred are the following phosphines: PPh 3 , and PEt 3 .
  • bases include TEA, NH 4 OH, and NaOH.
  • Specific examples of solvents include THF, MeOH, TBME, and DCM.
  • the conversion of (19E) to (19F) can be accomplished by treating the former with a protecting group and a base in a solvent.
  • protecting groups include trityl, nosyl, and brosyl .
  • Specific examples of base include pyridine, TEA, and 2 , 6-lutidine .
  • Specific examples of solvents include DCM, THF, chloroform, and diethyl ether.
  • the conversion of (19F) to (19G) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base.
  • Lewis acids include ZnCl 2 , TiCl 4 , BF 3 «OEt 2 , and SnCl 4 .
  • alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol.
  • Specific examples of solvents include an aforementioned alcohol, THF, 1 , 1, 1-trichloroethane, DCM, and chloroform.
  • the conversion of the intermediate to (19G) can be accomplished by treating the former with an acylating agent and a base in a solvent.
  • acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride.
  • bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine.
  • solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether.
  • the intermediate in pyridine at room temperature can be treated with acetic anhydride and pyridine for about 12 hours.
  • the conversion of (19G) to (19H) can be accomplished by treating the former with a hydrolyzing agent in a solvent.
  • hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH.
  • Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform.
  • the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed.
  • the reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature.
  • (19G) in THF at room temperature can be treated with aqueous LiOH for about 10 hours.
  • Compounds of formula la and lb include compounds of formula la' and la" .
  • Compounds of formula lb include compounds of formula lb' and lb" .
  • Representative compounds of formulas la and lb include: ( 3R, AR, 5S) -4- (acetylamino) -5-allyl-3-isopropoxy-l- cyclohexene-1-carboxylic acid;
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, trifluoroacetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate) , lactate, maleate, methanesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate,
  • basic nitrogen- containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, lithium, calcium or magnesium or with ammonium or N(R**) 4 + salts (where R** is loweralkyl) .
  • salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.
  • Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate.
  • the compounds of the formula la or lb of this invention can have a substituent which is an acid group (for example, -C0 2 H, -S0 3 H, -S0 2 H, -P0 3 H 2 , -P0 2 H) .
  • Compounds of the formula la or lb of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention.
  • Such esters may serve as prodrugs.
  • the prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of formula la or lb. Prodrugs may also serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract .
  • prodrugs may also serve to increase solubility for intravenous administration of the compounds.
  • Prodrugs may also serve to increase the hydrophobicity of the compounds.
  • Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism.
  • Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues and/or reduced rate of clearance.
  • esters contemplated by this invention include:
  • alkyl esters especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
  • alkoxyalkyl esters especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1- ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t- butoxymethyl esters and the like;
  • alkoxyalkoxyalkyl esters especially, alkoxyalkoxy- substituted loweralkyl esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;
  • aryloxyalkyl esters especially, aryloxy-substituted loweralkyl esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;
  • haloalkoxyalkyl esters especially, haloalkoxy- substituted loweralkyl esters, including, but not limited to, 2, 2 , 2-trichloroethoxymethyl esters and the like;
  • alkoxycarbonylalkyl esters especially, loweralkoxycarbonyl-substituted loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters and the like;
  • cyanoalkyl esters especially, cyano-substituted loweralkyl esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;
  • thioalkoxymethyl esters especially, lowerthioalkoxy- substituted methyl esters, including, but not limited to, methylthiomethyl , ethylthiomethyl esters and the like;
  • alkylsulfonylalkyl esters especially, loweralkylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;
  • arylsulfonylalkyl esters especially, arylsulfonyl- substituted loweralkyl esters, including, but not limited to, 2-benzenesulfonylethyl and 2 -toluenesulfonylethyl esters and the like;
  • acyloxyalkyl esters especially, loweralkylacyloxy- substituted loweralkyl esters, including, but not limited to, formyloxymethyl , acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl esters and the like;
  • cycloalkylcarbonyloxyalkyl esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl , cyclopentanecarbonyloxyethyl , cyclohexanecarbonyloxyethyl esters and the like;
  • arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyl esters and the like;
  • alkoxycarbonyloxy alkyl esters
  • loweralkoxycarbonyloxy (loweralkoxycarbonyloxy) -substituted loweralkyl esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl , 1- (methoxycarbonyloxy) ethyl, 2- (ethoxycarbonyloxy) ethyl esters and the like;
  • (cycloalkyloxycarbonyloxy) alkyl esters especially, (cycloalkyloxycarbonyloxy) -substituted loweralkyl esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl , cyclopentyloxycarbonyloxyethyl , cyclohexyloxycarbonyloxypropyl esters and the like;
  • oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo-l, 3-dioxolen-4-yl) methyl, [5- (4- methylphenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- (4- methoxyphenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- (4- fluorophenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- (4- chlorophenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, (2-oxo-l, 3- dioxolen-4-yl) methyl , (5 -methyl-2-oxo-l, 3-dioxolen-4- yl) methyl, (5-e
  • phthalidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl esters and the like;
  • aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like; arylalkyl esters, especially, aryl-substitued loweralkyl esters, including, but not limited to, benzyl, phenethyl, 3 -phenylpropyl , naphthyl ethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
  • dialkylaminoalkyl esters especially dialkylamino- substituted loweralkyl esters, including, but not limited to, 2- (N,N-dimethylamino) ethyl, 2- (N,N-diethylamino) ethyl ester and the like
  • heterocyclic alkyl esters especially, heterocyclic- substituted loweralkyl esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic) methyl esters and the like, wherein the heterocyclic part of the (heterocyclic) alkyl group is unsubstituted or substituted as previously defined herein; and
  • carboxyalkyl esters especially, carboxy-substituted loweralkyl esters, including, but not limited to carboxymethyl esters and the like;
  • Preferred prodrug esters of acid-containing compounds of the Formula la or lb are loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters, 3-pentyl esters, cycloalkyl esters, cycloalkylalkyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.
  • Methods for the preparation of prodrug esters of compounds of the Formula la or lb are well-known in the art and include:
  • halide for example, chloride or acyl chloride
  • a base for example, triethylamine, DBU, N,N-dimethylaminopyridine and the like
  • an inert solvent for example, DMF, acetonitrile, N-methylpyrrolidone and the like
  • an activated derivative of the acid for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like
  • an activated derivative of the acid for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like
  • prodrugs of the present invention include amides derived from the substituent which is an acid group.
  • Such amides contemplated by this invention include:
  • alkylamino amides especially, loweralkylamino amides, including, but not limited to, methylamino, ethylamino, n-propylamino, isopropylamino amides and the like;
  • cylcoalkylamino amides including, but not limited to, cylopropylamino, cylcobutylamino, cyclopentylamino, cyclohexylamino amides and the like; acylamino amides, including, but not limited to acetylamino, propionylamino, butanoylamino amides and the like;
  • cylcoalkylcarbonylamino amides including, but not limited to, cyclopropylcarbonylamino, cyclobutylcarbonylamino amides and the like;
  • alkoxycarbonylalkylamino amides including, but not limited to, ethoxycarbonylmethylamino, t- butyloxycarbonylmethylamino and the like;
  • aminoacylamino amides including, but not limited to, aminoacetylamino amides and the like;
  • dialkylaminoacylamino amides including, but not limited to, dimethylaminoacetylamino, diethylaminoacetylamino amides and the like;
  • (heterocyclic) acylamino amides including, but not limited to, piperidin-1-ylacetylamino amides and the like;
  • amides derived from single naturally occuring L-amino acids or from acid-protected L-amino acids, for example, esters of such amino acids and the like) or from dipeptides comprising two naturally occuring L-amino acids wherein each of the two amino acids is the same or is different (or from acid-protected dipeptides, for example, esters of such dipeptides and the like) ;
  • Methods for preparation of prodrug amides of compounds of the invention include reacting the acid with the appropriate amine in the presence of an amide bond or peptide bond-forming coupling reagent or reacting an activated derivative of the acid with the appropriate amine and the like.
  • prodrugs of the present invention include esters of hydroxyl-substituted compounds of formula la and lb which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R 100 C(O)- or R 100 C(S)- wherein R 100 is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula
  • amino acid esters of particular interest are of glycine and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyl group is -C(O)CH 2 NR 102 R 103 wherein R 102 and R 103 are independently selected from hydrogen and lower alkyl, or the group -NR 102 R 103 , where R 102 and R 103 , taken together, forms a nitrogen containing heterocyclic ring.
  • prodrugs include a hydroxyl -substituted compound of formula la and lb wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R 10 )OC(O)R 105 or -CH (R 104 ) OC (S) R 105 wherein R 105 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R 104 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl , alkylaminocarbonyl or dialkylaminocarbonyl .
  • Such prodrugs can be prepared according to the procedure of Schreiber ( Tetrahedron Lett . 1983, 24 , 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.
  • esters of hydroxyl-substituted compounds of formula la and lb is carried out by reacting a hydroxyl-substituted compound of formula formula la or lb with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.
  • Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation of the hydroxyl substituted compound of formula formula la or lb with (halo) alkyl esters, transacetalization with bis- (alkanoyl) acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
  • This invention also encompasses compounds of the Formula la or lb which are esters or prodrugs and which are also salts.
  • a compound of the invention can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent in the same compound .
  • the compounds of the present invention are useful for inhibiting neuraminidase from disease-causing microorganisms which comprise a neuraminidase.
  • the compounds of the invention are useful (in humans, other mammals and fowl) for treating or preventing diseases caused by microorganisms which comprise a neuraminidase
  • the compounds of the present invention are useful for inhibiting influenza A virus neuraminidase and influenza B virus neuraminidase, in vi tro or in vivo (especially in mammals and, in particular, in humans) .
  • the compounds of the present invention are also useful for the inhibition of influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the inhibition of influenza A viruses and influenza B viruses in humans and other mammals.
  • the compounds of the present invention are also useful for the treatment of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the human diseases caused by influenza A and influenza B viruses .
  • the compounds of the present invention are also useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of influenza A and influenza B viral infections; and, in particular, the prophylaxis of influenza A and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.
  • Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily.
  • Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms and/or the confirmation of infection.
  • the compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder (for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques .
  • sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-propanediol .
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables .
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents. emulsifying and suspending agents, .and sweetening, flavoring, and perfuming agents.
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins) , both natural and synthetic.
  • agents to be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, clarithromycin, azithromycin and the like; and agents used to treat asthma, such as, for example, zileuton, albuterol (salbutamol) , salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone
  • the ability of the compounds of the invention to inhibit neuraminidase in vitro can be determined according to the method described below.
  • Influenza virus A/Nl/PR/8/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Laver, W. G. (1969) in "Fundamental Techniques in Virology” (K. Habel and N. P. Salzman, eds.) pp. 92-86, Academic Press, New York). Influenza virus A/N2/Tokyo/3/67 was obtained from the tissue culture supernatents of virus grown on MDCK cells.
  • Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Laver, W. G., Luo, M., Stray, S. J. , Legrone, G., and Webster, R. G. (1990) Virology 177, 578-587).
  • the neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/Nl/PR/8/34 or A/N2/Tokyo/3/67 whole virus, or the B/Memphis/3/89 catalytic head fragment.
  • the whole virus or catalytic fragment was diluted appropriately with 20 mM N- ethylmorpholme, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment.
  • Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholme, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO.
  • Reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30 ⁇ M 4-methylumbelliferyl sialic acid substrate in a total volume of 200 ⁇ L and were contained in white 96-well U- shaped plates. Typically, five to eight concentrations of inhibitor were used for each Ki value measurement .
  • the reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan II plate reader (ICN Biomedical) equipped with excitation and emission filters of 355 +/- 35 nm and 460 +/- 25 nm, respectively.
  • the plate reader was under the control of DeltaSoft II software (Biometallics) and a Macintosh computer. If the compound exhibited linear reaction velocities during the reaction period, then the reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley- Interscience, New York) .
  • Km 16 - 40 ⁇ M depending on the neuraminidase strain tested.
  • neuraminidase and inhibitor were preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate.
  • Data analysis for the resulting linear velocities was conducted as described above. Equation 2 was used to measure Ki values in the sub- nanomolar range (Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophvs . 2, 347-368) .
  • V A ⁇ sqrt ⁇ (Ki' + It -Et) ⁇ 2 + 4Ki'Et ⁇ - (Ki' + It - Et)] eqn. 2
  • V velocity
  • A ⁇ kcat [S] /2 (Km + [S] )
  • a is a factor to convert fluorescence units to molar concentrations
  • Ki' Ki(l + [S] /Km)
  • It total inhibitor concentration
  • Et total active concentration of neuraminidase.
  • the compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 0.1 nanomolar and about 500 micromolar.
  • Preferred compounds of the invention invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 0.1 nanomolar and about 3.5 micromolar.
  • the ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.
  • Cell Culture Plague Formation Inhibition Assay Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences) , 40 mM HEPES buffer (GibcoBRL) and antibiotics (GibcoBRL) . Cells were routinely cultured in flasks or roller bottles at 37°C and 5% C0 2 .
  • DMEM Dulbecco's Modified Eagle Medium
  • GabcoBRL high glucose
  • IbcoBRL 40 mM HEPES buffer
  • antibiotics GabcoBRL
  • Plaque Assay Protocol On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1% fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza A/Tokyo/3/67 [H2N2] ) (40 -100 plaque forming units) and 2x concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared.
  • assay media DMEM with 1% fetal calf serum, 40 mM HEPES buffer and antibiotics
  • pre-mixed virus influenza A/Tokyo/3/67 [H2N2]
  • Viral Stocks Stocks were prepared in MDCK confluent roller bottles incubated at 37 °C in DMEM supplemented with 1% FCS, 40mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell lysate. Stocks were titered and stored at -80°C. Compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 100 micromolar and about 1 nanomolar. Preferred compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 1 micromolar and about 1 nanomolar.
  • the compounds of the invention can be tested for in vivo antiviral activity using the method described below. In Vivo Antiviral Efficacy Method
  • mice Female BALB/c mice were placed under anesthesia (sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8-34) at IO "2 (diluted from frozen stock) . This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4h. pre-infection and 4h. post- infection, andperiodically thereafter, with one of the following therapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kg/day BID, PO) ; or vehicle (sterile water BID, PO) . A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined.
  • lungs were harvested, weighed and assigned scores of 0 , 1, 2, 3 or 4 based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively) .
  • each lung pair was image analyzed to determine objective lung consolidation percentages .
  • the reaction mixture was cooled to room temperature, washed with 20% aqueous NaHS0 3 , saturated Na 2 C0 3 , and brine, dried (MgS0 4 ) , filtered and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (3/2) to afford 10.1 g (80%) of the desired product as a white solid, m.p. 142-143 °C.
  • Example IB (IS, 3S.AR.5R) -3-allyl-l-hvdroxy-7-oxo-6- oxabicvclo [3.2.1] oct-4-yl benzoate
  • benzene 100 mL
  • AIBN 1.0 g, 6.1 mmol
  • the solution was concentrated and diluted with dichloromethane (100 mL) .
  • a 10% aqueous solution of KF»2H 2 0 (50 mL) was added, and the mixture was stirred for 2 hours. A white precipitate formed and was filtered off.
  • Methanesulfonyl chloride (4.6 mL, 59.4 mmol) was slowly added to a 0 °C solution of compound Example IC (10.0 g, 33.1 mmol) and triethylamine (9.2 mL, 66.1 mmol) in dichloromethane (200 mL) .
  • the reaction mixture was stirred for 2 hours, and filtered. The resulting solid was washed with dichloromethane and discarded.
  • Potassium carbonate 100 mg, 0.72 mmol
  • the reaction mixture was stirred for 30 minutes at room temperature, filtered and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel using ethyl acetate to afford 1.6 g (99%) of the desired product as a colorless oil.
  • Benzoyl chloride (2.3 mL, 19.8 mmol) was added dropwise to a 0 °C solution of Example IE (6.1 g, 19.8 mmol) and pyridine (3.2 mL, 39.6 mmol) in dichloromethane (100 mL) .
  • the reaction mixture was stirred for 5 hours, washed with aqueous HCl (2N) , saturated NaHC0 3 solution, and brine, dried (MgS0 4 ) , filtered and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (3/2) to afford 6.9 g (85%) of the desired product as a white solid, m.p. 46-47 °C.
  • Example IH methyl (IS. S.AR.5R) -3-allyl-5-hvdroxy-l , 4- bis T (methylsulfonyl) oxyl cyclohexanecarboxylate Potassium carbonate (80 mg, 0.58 mmol) was added to a solution of Example IG (2.0 g, 4.1 mmol) in methanol (40 mL) . The reaction mixture was stirred for 30 minutes at room temperature, acidified to pH 5-6 with DOWEX ® 50WX2-200 ion-exchange resin, filtered and concentrated.
  • Example 11 methyl (IR. SS.6S) -5-allyl-7-oxabicyclo ⁇ A .1.01hept-2- ene-3 -carboxylate
  • a solution of Example IH (3.4 mg, 8.8 mmol) and DBU (2.9 mL, 19.4 mmol) in THF (60 mL) was refluxed for 6 hours, washed with brine, dried (MgS0 4 ) , filtered and concentrated. The concentrate was passed through a short silica gel column using hexanes/ethyl acetate (4/1) to afford the desired product.
  • Example 1J methyl (3S, 4S.5S) -5-allyl-3-azido-4-hvdroxy-l- cyclohexene- 1-carboxylate
  • sodium azide 2.8 g, 43.1 mmol
  • NH 4 C1 1.0 g, 18.8 mL
  • Methanesulfonyl chloride 0.7 mL, 9.0 mmol
  • Example IJ methylsulfonyl
  • triethylamine 2.5 mL, 18.0 mmol
  • dichloromethane 40 mL
  • the reaction mixture was stirred for 2 hours, washed with saturated NaHC0 3 solution, brine, dried (MgS0 4 ) , filtered and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (3/1) to afford 1.48 g (78%) of the desired product as a white solid, m.p. 70-72 °C.
  • Triphenylphosphine (1.14 g, 4.35 mmol) was slowly added to a room temperature solution of Example IK (0.80 g, 2.54 mmol) in THF (30 mL) . After stirring for 2 hours, water (3.0 mL) and triethylamine (1.0 mL, 7.19 mmol) were added. The mixture was stirred for 10 hours, and concentrated. The concentrate was chromatographed on silica gel using ethyl acetate to afford the desired product with Ph 3 P as a contaminant.
  • Trityl chloride (0.85 g, 3.05 mmol) was added to a 0 °C solution of Example IL and triethylamine (0.5 mL, 3.59 mmol) in dichloromethane (30 mL) . After stirring for 2 hours at 0 °C, the reaction mixture was concentrated. The concentrate was purified by flash chromatography on silica gel using hexanes/ethyl acetate (10/1) to afford 1.02 g (92%, over steps L and M) of the desired product as a white solid, m.p. 58-60 °C. [ ⁇ ] D 295 -88.55° (c 0.585, chloroform).
  • X H NMR 400 MHz, CDCl 3 ) : ⁇ 7.47-7.21 (m, 16H) , 5.72 (m, IH) ,
  • the concentrate was dissolved in dry pyridine (1.5 mL) and treated with acetic anhydride (15 mL, 159 mmol) .
  • the reaction mixture was stirred at room temperature for 12 hours and concentrated.
  • the concentrate was dissolved in ethyl acetate (30 mL) , washed with aqueous HCl (2N) , saturated NaHC0 3 solution, and brine, dried (MgS0 4 ) , filtered and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (1/5) to afford 110 mg (81%) of the desired product as a white solid, m.p. 105-106 °C.
  • Aqueous lithium hydroxide solution (0.1N, 15 mL) was added to a room temperature solution of Example IN (40 mg,
  • the concentrate was purified by flash chromatography using acetic acid/ethyl acetate (1/5) to afford 34 mg (90%) of the desired product as a white solid, m.p. 202-203 °C.
  • Example 2A methyl (3J?,4J?,5S) -4- (acetylamino) -5-allyl-3- (1- ethylpropoxy) -1-cyclohexene-1-carboxylate Boron trifluoride eatherate (218 ⁇ L, 1.72 mmol) was added to a solution of Example IM (0.50 g, 1.15 mmol) in 3- pentanol (15 mL) . After stirring for 2 hours at 70-80 °C, the reaction mixture was concentrated.
  • the concentrate was dissolved in dry pyridine (1.5 mL) and treated with acetic anhydride (15 mL, 159 mmol) . After stirring for 10 hours, the reaction mixture was concentrated.
  • the concentrate was dissolved in ethyl acetate (30 mL) , washed with aqueous HCl (2N) , saturated NaHC0 3 solution, and brine, dried (MgS0 4 ) , filtered and concentrated.
  • the concentrate was purified by flash chromatography on silica gel using hexanes/ethyl acetate (1/5) to afford 315 mg (85%) of the desired product as a white solid, m.p. 102-103 °C .
  • Aqueous lithium hydroxide solution (0.1N, 15 mL) was added to a room temperature solution of Example 2A (150 mg, 0.464 mmol) in THF (5 mL) .
  • the solution was stirred for 10 hours, acidified to pH 5-6 with DOWEX ® 50WX2-200 ion- exchange resin, filtered and concentrated.
  • the concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 143 mg (100%) of the desired product as a white solid, m.p. 229-230 °C. [ ⁇ ] D 295 -63.68° (c 0.190, methanol).
  • Example 3B (3R.4R, 5J?) -4- (acetylamino) -3 -isopropoxy-5- (2- oxiranylmethyl) -1-cyclohexene-l-carboxylic acid
  • Aqueous lithium hydroxide solution (0.1N, 15 mL) was added to a room temperature solution of Example 3A (30 mg, 0.096 mmol) in THF (5 mL) .
  • the solution was stirred for 10 hours, acidified to pH 5-6 with DOWEX ® 50WX2-200 ion- exchange resin, filtered and concentrated.
  • the concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 25 mg (88%) of the desired product as a white solid, m.p. 156-157 °C. [ ⁇ ] D 295 -12.57° (c 0.350, methanol).
  • Example 4A methyl (3R . AR, SR) -A - (acetylamino) -3- (1-ethylpropoxy) -5- (2- oxiranylmethyl) -1 -cyclohexene- 1-carboxylate
  • Meta-chloro perbenzoic acid 200 mg, 0.811 mmol
  • Example 2A 150 mg, 0.464 mmol
  • dichloromethane 30 mL
  • the concentrate was purified by flash chromatography on silica gel using ethyl acetate to afford 134 mg (85%) of the desired product as a mixture of two diastereomers.
  • Example 5A methyl ( 3R. AR. SR) -4- (acetylamino) -5- (2 , 3-dihydroxypropyl) - 3- (1-ethylpropoxy) -1-cyclohexene- 1-carboxylate
  • Water (1.6 mL) , NMO (28 mg, 0.239 mmol), and Os0 4 (25 mg/ml in toluene, 16 ⁇ L, 1.57 ⁇ mol) were added to a room temperature solution of Example 2A (51 mg, 0.158 mmol) in acetone (15 mL) . After stirring for 3 hours, the reaction mixture was concentrated. The concentrate was purified by flash chromatography on silica gel using acetone to afford 23 mg (40%) of the desired product as a white solid, m.p. 125-126 °C.
  • the concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 19 mg (100%) of the desired product as a white solid, m.p. 189-190 °C . [ ⁇ ] 295 +35.59° (c 0.340, methanol).
  • Example 6A methyl ( 3R. AR. SR) -A - (acetylamino) -5- (3-azido-2- hydroxypropyl) -3- (1-ethylpropoxy) -1-cyclohexene-l- carboxylate
  • Water 5 mL
  • sodium azide 100 mg, 1.53 mmol
  • ammonium chloride 40 mg, 0.747 mmol
  • Example 4A 120 mg, 0.354 mmol
  • Example 7 A methyl ( 3R. AR. SR) -A - (acetylamino) -3- (1-ethylpropoxy) -5- (2- oxoethyl ) -1 -cyclohexene- 1-carboxylate
  • Example 5A Sodium periodate (46 mg, 0.215 mmol) and water (1.0 mL) were added to a room temperature solution of Example 5A
  • Example 7B ⁇ ( 1R . SR. 6R) - 6 - (acetylamino) -5- (1-ethylpropoxy) -3- (methoxycarbonyl) -3-cvclohexen-l-yll acetic acid
  • Sodium chlorite commercial 80%, 16 mg, 0.142 mmol
  • KH 2 P0 4 buffer pH 3-4
  • 2-methyl-2-butene 118 ⁇ L, 1.10 mmol
  • tert-butyl alcohol 15 mL
  • Example 8A (3R, AR. SR) -A- (acetylamino) -3- (1-ethylpropoxy) -5- (2- oxoethyl) -1-cyclohexene-l-carboxylic acid
  • Aqueous lithium hydroxide solution (0.1N, 15 mL) was added to a room temperature solution of Example 7A (30 mg, 0.092 mmol) in THF (3 mL) .
  • the solution was stirred for 12 hours, acidified to pH 5-6 with DOWEX ® 50WX2-200 ion- exchange resin, filtered and concentrated.
  • the concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 23 mg (100%) of the desired product as a white solid. m.p. 70-71 °C.
  • Example 9B methyl (3J?, AR . SR) -A - (acetylamino) -3-isopropoxy-5- (2- oxoethyl ) -1-cyclohexene-1-carboxylate
  • Procedure A Sodium periodate (70 mg, 0.327 mmol) and water (1.5 mL) were added to a room temperature solution of Example 9A (71 mg, 0.216 mmol) in methanol (15 mL) . After stirring for 3 hours, the reaction mixture was filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using ethyl acetate to afford 45 mg (71%) of the desired product as a white solid.
  • Procedure B Sodium periodate (0.174 g, 0.814 mmol), water (1.0 mL) and Os0 4 (25 mg/ml in toluene, 70 ⁇ L, 6.89 ⁇ mol) were added to a room temperature solution of Example IN (0.200 g, 0.678 mmol) in acetone (15 mL) . After stirring for 3 hours, the reaction mixture was concentrated. The concentrate was purified by flash chromatography on silica gel using hexanes/ethyl acetate (1/6) to afford 0.120 g (60%) of the desired product as a white solid, m.p. 116-117 °C.
  • Example 9C methyl (3R.AR. SR) -A- (acetylamino) -5- (2 -hydroxyethyl) -3- isopropoxy-1-cyclohexene-1-carboxylate
  • Sodium borohydride (20 mg, 0.529 mmol) was added to a 0 °C solution of Example 9B (45 mg, 0.152 mmol) in methanol (10 mL) . After stirring for 30 minutes, the reaction mixture was quenched with aqueous NH 4 C1, and concentrated. The concentrate was purified by flash chromatography on silica gel using acetone/ethyl acetate (1/4) to afford 41.7 mg (92%) of the desired product as a white solid. m.p. 118-119 °C.
  • Aqueous lithium hydroxide solution (0.1N, 15 mL) was added to a room temperature solution of Example 9C (30 mg, 0.10 mmol) in THF (3 mL) .
  • the solution was stirred for 12 hours, acidified to pH 5-6 with DOWEX ® 50WX2-200 ion- exchange resin, filtered and concentrated.
  • the concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 27 mg (96%) of the desired product as a white solid, m.p. 114-115 °C . [ ⁇ ] D 295 -26.66° (c 0.210, methanol).
  • Triethylamine (0.4 mL, 2.88 mmol) and 2-chloro-l- methylpyridinium iodide (350 mg, 1.37 mmol) were added to a room temperature solution of Example 10 (188 mg, 0.670 mmol) and 2- (trimethylsilyl) ethanol (165 mg, 1.40 mmol) in dichloromethane (30 mL) . After stirring for 16 hours, the reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate layers were dried
  • Example 10D (IJ?, SR , ⁇ R) -6- (acetylamino) -5-isopropoxy-3- ⁇ [2- (trimethylsilyl) ethoxy] carbonyl ⁇ -3-cvclohexen-l- yl) ethaneperoxoic acid
  • Example IOC Sodium chlorite (commercial 80%, 80 mg, 0.708 mmol) in 10 mL of KH 2 P0 4 buffer (pH 3-4) was added dropwise to a room temperature solution of Example IOC (194 mg, 0.528 mmol) and 2-methyl-2-butene (560 ⁇ L, 5.28 mmol) in tert-butyl alcohol (30 mL) . After stirring for 16 hours, the reaction mixture was concentrated. The concentrate was passed through a short pad of silica gel using acetic acid/ethyl acetate (1/5) affording the crude acid.
  • Diazomethane in ether was added to the crude acid in 0 °C THF. After stirring for 30 minutes, the concentrate was purified by flash chromatography on silica gel using ethyl acetate to afford 84 mg (40%) of the desired product. [ ⁇ ] D 295 -35.00° (c 0.200, ethyl acetate).
  • the concentrate was dissolved in methanol (30 mL) and K 2 C0 3 (100 mg) was added. After stirring for 1 hour the reaction mixture was filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel using ethyl acetate to afford 3.7 g (92%) of the desired product as a white solid, m.p. 122-123 °C. [ ⁇ ] D 295 +42.22° (c 0.180, ethyl acetate) .
  • Example HP (IR.2R, 35, 55) -2-hydroxy-3 -isobutyl-5- (methoxycarbonyl) -5- [ (methylsulfonyl) oxy] cyclohexyl benzoate
  • Benzoyl chloride (0.68 mL, 5.86 mmol) was added dropwise to a 0 °C solution of Example HC (1.9 g, 5.86 mmol) and pyridine (1.0 mL, 12.4 mmol) in dichloromethane (30 mL) . After stirring for 5 hours, the reaction mixture was washed with aqueous HCl (2N) , saturated NaHC0 3 solution, brine, dried (MgS0 4 ) , filtered and concentrated.
  • the concentrate was purified by flash chromatography on silica gel using hexanes/ethyl acetate (3/2) to afford 2.1 g (86%) of the desired product as a white solid, m.p. 161-162 °C . [ ⁇ ] D 295 +18.75° (c 0.160, ethyl acetate) .
  • the concentrate was dissolved in dichloromethane (30 mL) , and K 2 C0 3 (100 mg) and methanol (15 mL) were added.
  • Example HE (0.78 g, 2.5 mmol) and DBU (0.8 mL, 5.4 mmol) in THF (30 mL) was refluxed for 6 hours.
  • Trityl chloride (0.85 g, 3.05 mmol) was added to a 0 °C solution of the crude aziridine and triethylamine (0.6 mL, 4.3 mmol) in dichloromethane (20 mL) . After stirring for 2 hours, the reaction mixture was concentrated. The concentrate was chromatographed on silica gel using hexanes/ethyl acetate (10/1) to afford the crude tritylated aziridine with trityl chloride as a contaminant.
  • Example 12A methyl (3R. R.5R) -A- (acetylamino) -3-isopropoxy-5- ⁇ 2- f (2- nitrophenyl) selanyl] ethyl ⁇ -1-cyclohexene-l-carboxylate
  • Tributylphosphine (73 ⁇ L, 0.29 mmol) was added dropwise to a solution of Example 9C (72 mg, 0.24 mmol) and ortho- nitrophenyl selenocyanate (66 mg, 0.29 mmol) in THF (8 mL) .
  • reaction mixture was stirred for 2 hours, concentrated and the concentrate was purified by flash chromatography on silica gel using hexanes/ethyl acetate (1/3) to afford 110 mg (95%) of the desired product as a light yellow solid, m.p. 170-171 °C.
  • Example 12B methyl (3R, AR. SR) -A- (acetylamino) -3 -isopropoxy-5 -vinyl-1- cyclohexene-1-carboxylate Hydrogen peroxide (30%, 1.0 mL, 8.8 mmol) was added dropwise to a solution of Example 12A (58 mg, 0.12 mmol) in THF (10 mL) . The reaction mixture was stirred for 12 hours, diluted with water, and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgS0 4 ) , filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel (hexanes/ethyl acetate 1:4) to afford 30 mg (89%) of the desired product as a white solid, m.p. 132-133 °C . [ ] 295 -71.78° (c 0.350, ethyl acetate).

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Abstract

L'invention concerne des composés de formule Ia et Ib ou un sel, un promédicament ou un ester de ceux-ci pharmaceutiquement acceptables, servant à inhiber des enzymes neuraminidases de micro-organismes pathogènes, notamment la neuraminidase de la grippe. Elle concerne également des formulations les contenant, des techniques et des produits intermédiaires permettant de préparer lesdits composés, ainsi que des procédés d'utilisation de ces composés, y compris la prévention et le traitement de maladies causées par des micro-organismes ayant ladite enzyme neuraminidase.
PCT/US2000/026119 1999-10-19 2000-09-22 Acide 1-cyclohexene-1-carboxylique et 1-cyclohexene1-1carboxylates comme inhibiteurs de la neuraminidase WO2001028981A1 (fr)

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Application Number Priority Date Filing Date Title
AU76081/00A AU7608100A (en) 1999-10-19 2000-09-22 1-cyclohexene-1-carboxylic acid and 1-cyclohexene-1-carboxylates as neuraminidase inhibitors
BR0010525-2A BR0010525A (pt) 1999-10-19 2000-09-22 cido 1-ciclo-hexeno-1-carboxìlico e 1-ciclo-hexeno-1carboxilatos como inibidores de neuraminidase

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US42107799A 1999-10-19 1999-10-19
US09/421,077 1999-10-19
US42809399A 1999-10-27 1999-10-27
US09/428,093 1999-10-27

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WO2001028981A1 true WO2001028981A1 (fr) 2001-04-26

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PCT/US2000/026119 WO2001028981A1 (fr) 1999-10-19 2000-09-22 Acide 1-cyclohexene-1-carboxylique et 1-cyclohexene1-1carboxylates comme inhibiteurs de la neuraminidase

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EP1127872A1 (fr) * 2000-02-22 2001-08-29 F. Hoffmann-La Roche Ag Tamiflu par une réaction de Diels-Alder
US7122684B2 (en) 2003-03-13 2006-10-17 Roche Colorado Corporation Process for preparing 1,2-diamino compounds
US7410666B2 (en) 2001-09-14 2008-08-12 Asm International N.V. Metal nitride carbide deposition by ALD
US20120010254A1 (en) * 2008-12-30 2012-01-12 Simon Fraser University Compounds and methods for treatment of influenza
CN111470999A (zh) * 2020-05-18 2020-07-31 中山万汉制药有限公司 N-环己烯基-脂肪酰胺类化合物及其制备方法、组合物与用途
CN116354869A (zh) * 2023-02-13 2023-06-30 北京恒创星远医药科技有限公司 一种环己烯类抗病毒化合物的合成工艺

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1127872A1 (fr) * 2000-02-22 2001-08-29 F. Hoffmann-La Roche Ag Tamiflu par une réaction de Diels-Alder
US6403824B2 (en) 2000-02-22 2002-06-11 Hoffmann-La Roche Inc. Process for the preparation for 4,5-diamino shikimic acid derivatives
KR100743305B1 (ko) * 2000-02-22 2007-07-26 에프. 호프만-라 로슈 아게 4,5-디아미노 시킴산 유도체의 제조 방법
US7410666B2 (en) 2001-09-14 2008-08-12 Asm International N.V. Metal nitride carbide deposition by ALD
US7122684B2 (en) 2003-03-13 2006-10-17 Roche Colorado Corporation Process for preparing 1,2-diamino compounds
US20120010254A1 (en) * 2008-12-30 2012-01-12 Simon Fraser University Compounds and methods for treatment of influenza
CN111470999A (zh) * 2020-05-18 2020-07-31 中山万汉制药有限公司 N-环己烯基-脂肪酰胺类化合物及其制备方法、组合物与用途
CN116354869A (zh) * 2023-02-13 2023-06-30 北京恒创星远医药科技有限公司 一种环己烯类抗病毒化合物的合成工艺

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BR0010525A (pt) 2002-11-26

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