WO1999054290A1 - Inhibiteurs de neuraminidases - Google Patents

Inhibiteurs de neuraminidases Download PDF

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Publication number
WO1999054290A1
WO1999054290A1 PCT/US1999/007949 US9907949W WO9954290A1 WO 1999054290 A1 WO1999054290 A1 WO 1999054290A1 US 9907949 W US9907949 W US 9907949W WO 9954290 A1 WO9954290 A1 WO 9954290A1
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Prior art keywords
hydrogen
alkyl
alkenyl
loweralkyi
heterocyclic
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PCT/US1999/007949
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English (en)
Inventor
Clarence J. Maring
Yu-Gui Gu
Yuanwei Chen
David A. Degoey
Vincent L. Giranda
David J. Grampovnik
Warren M. Kati
Dale J. Kempf
April Kennedy
Zhen Lin
Darold L. Madigan
Steven W. Muchmore
Hing L. Sham
Kent D. Stewart
Vincent S. Stoll
Minghua Sun
Gary T. Wang
Sheldon Wang
Ming C. Yeung
Chen Zhao
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Abbott Laboratories
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Priority to CA002329660A priority Critical patent/CA2329660A1/fr
Priority to JP2000544631A priority patent/JP2002521312A/ja
Priority to EP99918495A priority patent/EP1087938A1/fr
Publication of WO1999054290A1 publication Critical patent/WO1999054290A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase.
  • the invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.
  • neuraminidase 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 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. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains.
  • a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus.
  • Compounds which are influenza neuraminidase inhibitors will be useful for the
  • siastatin B analogs which are useful as neuraminidase inhibitors: Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and
  • An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.
  • An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.
  • Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.
  • Another object of the invention is to provide treatment of influenza infection in humans and other mammals.
  • Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
  • Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
  • the present invention discloses compounds having Formula I, II or III
  • R 11 is selected from the group consisting of
  • R 2 and R 36 are independently selected from the group consisting of
  • X is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • C1-C 3 loweralkyi hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
  • Z' is -O-, -S-, or C(R D ) 2 ;
  • R 3 and R 4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f) -Z-R 14 wherein Z is
  • R 3 7a R 3 7b R 7 and R 4 8 gt each occurrence are independently selected from the group consisting of
  • R 37c at each occurrence is independently selected from the group consisting of
  • N(R 37c ) and R 14 when taken together are an azido group
  • N(O)(R 37c ) and R 14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
  • R 5 is selected from the group consisting of
  • R 3 and R 4 taken together, with the atom to which they are attached, form a carbocyciic or heterocyclic ring having from 3 to 8 ring atoms;
  • R 5 at each occurrence is independently selected from the group consisting of
  • R 5 is -O-R 40 or -N(R 19 ) 2 , ' then the other R 5 is other than -O-R 40 or -N(R 19 ) 2 ; wherein Q 1 is O, S, or N(R 18 );
  • R 17 and R 18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
  • R 19 , R 38 , and R 40 are independently selected, at each occurrence, from the group consisting of
  • R 19 is an N-protecting group
  • Y is selected from the group consisting of
  • n 0, 1 , or 2;
  • Q 2 is O, S, NR 25 , or CHR 26 ; and
  • Q 3 is NR 41 , or CHR 42 ;
  • R 20 at each occurrence is independently
  • R 23 and R 39 are independently hydrogen or methyl
  • R 4 and R 42 are independently hydrogen, methyl, or ethyl
  • R 24 is selected from the group consisting of
  • Q 4 is O, S, or N(R 33 );
  • R 25 is hydroxy, methyl, ethyl, amino, -CN, or -N0 2 ;
  • R 26 group is hydrogen, methyl or ethyl ;
  • R 28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH 3 , -N(CH 3 ) 2 , methoxy, ethoxy, or -CN;
  • R 28b is hydrogen, methyl or ethyl
  • R 28a , R 28b and the nitrogen to which they are bonded taken together represent azetidinyl
  • R 29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
  • R 30 group is hydrogen, methyl, ethyl, -OR 34 , -SR 34 , -N(R 35 ) 2 , -NHOH, -NHNH 2 , -N(CH 3 )NH 2 , or -N(CH 2 CH 3 )NH 2 ;
  • R 31 and R 32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl
  • R 33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -N0 2 ;
  • R 34 group is methyl or ethyl
  • R 35 group is independently hydrogen, methyl or ethyl
  • R 22 is selected from the group consisting of hydrogen, -CH 3 , -C 2 H 5 , -C 3 H 7 , -OCH 3 , -SCH 3 , -0-C 2 H 5 , and -S-C 2 H 5 ;
  • R 6 and R 7 are independently selected from the group consisting of
  • R >8 , D R9 , and R ,10 are independently selected from the group consisting of
  • Preferred compounds of the invention include compounds wherein R 3 and R 4 are not the same and which have the relative stereochemistry depicted by Formula IV, V, VI, VII, VIII or IX:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X , Y and Z 1 are as defined above.
  • C 1 -C 3 loweralkyi hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • Z 1 is -0-, -S- or -CH(R 5 )- wherein R 5 is hydrogen, loweralkyi or - (CH 2 )rN(R 9 ) 2 wherein r and R 19 are defined as above; or R 5 is hydrogen, loweralkyi or -(CH 2 ) r N(R 19 ) 2 wherein r and R 19 are defined as above;
  • R 6 and R 7 are independently hydrogen or loweralkyi
  • R 8 and R 9 are independently hydrogen, fluoro or loweralkyi
  • R 10 is hydrogen, fluoro or loweralkyi
  • More preferred compounds of the invention are compounds having Formula I, II, III. IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R 1 is defined as above;
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • Z 1 is -0-, -S- or -CH(R 5 )- wherein R 5 is hydrogen, loweralkyi or - (CH 2 )rN(R 19 ) 2 wherein r and R 19 are defined as above; or R 5 is hydrogen, loweralkyi or -(CH 2 ) r N(R 19 ) 2 wherein r and R 19 are defined as above;
  • R 6 and R 7 are independently hydrogen or loweralkyi
  • R 8 and R 9 are independently hydrogen or loweralkyi
  • R 10 is hydrogen or loweralkyi
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • Z 1 is -0-, -S- or -CH(R 5 )- wherein R 5 is hydrogen, loweralkyi or - (CH 2 ) r N(R 19 ) 2 wherein r and R 9 are defined as above; or R 5 is hydrogen, loweralkyi or -(CH 2 ) r N(R 19 ) 2 wherein r and R- ⁇ 9 are defined as above;
  • R 6 and R 7 are independently hydrogen or loweralkyi
  • R 8 and R 9 are independently hydrogen or loweralkyi
  • R 10 is hydrogen or loweralkyi
  • Y is C 2 -C 5 alkenyl, C 2 -C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R 1 is -C0 2 H;
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • Z 1 is -0-, -S- or -CH 2 -; or R 5 is hydrogen;
  • R 6 and R 7 are independently hydrogen or loweralkyi
  • R 8 and R 9 are hydrogen independently hydrogen or loweralkyi
  • R 10 is hydrogen or loweralkyi
  • Y is C 2 -C ⁇ alkenyl, C 2- C haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R 1 is -C0 2 H;
  • R 4 is hydrogen or ioweralkyl and R 3 is heterocyclic or -Z-R 14 wherein Z and R 14 are defined as above;
  • Z 1 is -0-, -S- or -CH 2 -; or R 5 is hydrogen;
  • R 6 and R 7 are hydrogen
  • R 10 is hydrogen
  • Y is C 2 -C 5 alkenyl, C 2 .C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • R 4 is hydrogen or loweralkyi and R 3 is (a) heterocyclic, (b) alkyl,
  • R 37a and R 37b are independently selected from the group consisting of
  • Z 1 is -0-, -S- or -CH 2 -; or R 5 is hydrogen;
  • R 8 and R 9 are hydrogen
  • R 10 is hydrogen
  • Y is C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • Most highly preferred compounds of the invention are compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R 1 is -CO 2 H;
  • R 4 is hydrogen and R 3 is (a) heterocyclic, (b) alkyl or (c) -C(R 37a )(0R 37c )- R 14 wherein R 14 is
  • R 37a and R 37b are independently selected from the group consisting of
  • Z 1 is -0-, -S- or -CH 2 -; or R 5 is hydrogen;
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen ;
  • R 10 is hydrogen
  • Y is C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • R 4 is hydrogen and R 3 is (a) heterocyclic, (b) alkyl or (c) -C(R 37a )(OR 37c )- R 14 wherein R 14 is
  • Z is -0-, -S- or -CH 2 -; or R 5 is hydrogen;
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen
  • R 10 is hydrogen
  • -26- Y is C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • R 4 is hydrogen and R 3 is -C(R 37a )(OR 37c )-R 14 wherein R 14 is
  • Z 1 is -0-, -S- or -CH 2 -; or R 5 is hydrogen;
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen
  • R 10 is hydrogen
  • Y is C 2 -C 5 alkenyl, C 2 -C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • Preferred substituents R 1 include -C0 2 H or esters or prodrugs thereof.
  • Preferred esters include C 2 -C 6 loweralkyi esters or substituted or unsubstituted
  • R 1 include -C0 2 H or esters or prodrugs thereof.
  • Most highly preferred esters include C 2 -C ⁇ loweralkyi esters or substituted or unsubstituted benzyl esters.
  • C 1 -C 3 loweralkyi hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.
  • Preferred substituents Z 1 include -0-, -S- or -CH(R 5 )- wherein R 5 is hydrogen, loweralkyi or -(CH 2 ) r N(R 19 ) 2 wherein r and R-ig are defined as above; or R 5 is hydrogen, loweralkyi or -(CH 2 ) r N(R 19 ) 2 wherein r and Rig are defined as above;
  • substituents Z 1 are -0-, -S- or -CH(R 5 )- wherein R 5 is hydrogen or loweralkyi.
  • substituents Z 1 are -O-, -S- or -CH2-.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, heterocyclic and -Z-R 14 wherein Z and R 14 are defined as most broadly defined previously herein and wherein one of R 3 and R 4 is other than hydrogen.
  • substituent R 4 is hydrogen or loweralkyi and R 3 includes heterocyclic or -Z-R 14 wherein Z and R 14 are defined as most broadly defined previously herein.
  • substituent R 4 is hydrogen or loweralkyi and R 3 includes
  • R 37a and R 37b are independently selected from the group consisting of
  • R 37c is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl.
  • substituent R 4 is hydrogen and R 3 includes
  • R 37a and R 37b are independently selected from the group consisting of
  • R 37c is (i) hydrogen, (ii) d-d loweralkyi or (iii) allyl.
  • substituent R 4 is hydrogen and R 3 includes
  • R 37a is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl
  • R 37c is (i) hydrogen, (ii) d-d loweralkyi or (iii) allyl.
  • substituent R 4 is hydrogen and R 3 includes
  • R 14 is loweralkyi or loweralkenyl
  • R 37a is loweralkyi or loweralkenyl
  • R 37c is hydrogen, d-C 3 loweralkyi or allyl, and especially, wherein R 37c is hydrogen or methyl.
  • Preferred substituents R 5 include those independently selected from hydrogen, loweralkyi and -(CH 2 ) r N(R 9 ) 2 wherein r and R 19 are defined as above.
  • R 5 are independently selected from hydrogen, loweralkyi and -(CH 2 ) r N(R 19 ) 2 wherein r is 0 or 1 and one R 19 is hydrogen or loweralkyi and the other R 19 is hydrogen, loweralkyi or an N-protecting group.
  • substituents R 5 are independently selected from hydrogen and loweralkyi.
  • R 5 is hydrogen
  • R 6 and R 7 include independently hydrogen and loweralkyi. Most highly preferred, R 6 and R 7 are hydrogen.
  • R 8 , R 9 and R 10 include independently hydrogen, fluoro and loweralkyi. Most highly preferred, R 8 , R 9 and R 0 are hydrogen.
  • Preferred substituent Y includes C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl,
  • More preferred substituent Y includes C 2 -C 5 alkenyl
  • substituent Y includes C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • Representative alkenyl and haloalkenyl substituents Y include:
  • -CF CCIBr
  • -C(CH 3 ) CH 2 .
  • -C(CH 3 ) CHF
  • -C(CH 3 ) CH-CH 3
  • -C(CH 3 ) CH-CF 3 ,
  • Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:
  • substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
  • substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
  • acid protecting group refers to groups used to protect acid groups (for example, -C0 2 H, -S0 3 H, -S0 2 H, -PO 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). Most frequently, such acid protecting groups are esters.
  • esters include:
  • alkyl esters especially loweralkyi 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;
  • -34- 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, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like; and the like.
  • Preferred acid protecting groups are loweralkyi 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- trichiorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoiine derived esters 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.
  • 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 loweralkyi groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, e/f-butoxy, and the like.
  • alkoxyalkoxy refers to groups having the formula -0-R 96 -0-R 97 wherein R 97 is loweralkyi, as defined herein, and R 96 is a lower alkylene group.
  • Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, f-butoxymethoxy and the like.
  • alkoxyalkyl refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
  • alkyl refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms.
  • loweralkyi 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, so-propyl, n-butyl, /so-butyl, sec-butyl, -butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethyl- propyl, 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, loweralkyi, 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 loweralkyi 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
  • lower alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms.
  • alkylene groups include groups such as, for example, methylene (-CH 2 -), 1 ,2-ethylene (-CH 2 CH 2 -), 1 ,1-ethylene
  • hydrocarbon chains in 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, loweralkyi, 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 loweralkyi groups.
  • alkylsulfonyiamino 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 loweralkyi 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
  • lower alkynylene refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms.
  • alkynylene groups include groups such as, for example, -C ⁇ C-, -CH 2 -C ⁇ C-, -CsC-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 loweralkyi, 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, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.
  • (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 loweralkyi 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 ⁇ -COOH, 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, norbomene 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 loweralkyi.
  • Preferred substitutents are independently selected from loweralkyi, 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, cyclobutyi, cyclopentyl, cyclohexyl, cycloheptyl, norbomane, 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 loweralkyi.
  • Preferred substitutents are independently selected from loweralkyi, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
  • (cycloalkyl)alkyl refers to a cycloalkyl group appended to a loweralkyi 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.
  • halo 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 loweralkyi 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, pentafluoroethyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein, 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, thiazo
  • X * is -CH 2 or -O- and Y * is -C(O)- or [-C(R 92 ) 2 -]v
  • 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 loweralkyi, 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.
  • heterocyclicalkyl refers to a heterocyclic group appended to a loweralkyi 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.
  • heterocyclicoxy 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). 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-1-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;
  • -45- 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, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-meth- oxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
  • N-protecting groups are 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 loweralkyi 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,
  • 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
  • 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. For example, 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.
  • any variable for example R , 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
  • 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 I, II, III, IV, V, VI, VII, VIII or IX 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 vitro.
  • R 1 is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R 1 substituents can (a) be obtained either from the carboxylic acid or carboxylic acid ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.
  • R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
  • N-protected amino acid 1 (P 1 is an N-protecting group, for example, t-butoxycarbonyl or the like) can be prepared by N-protection of amino acid (( ⁇ )-(2R,3S)-2-Amino-bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; Stajer, G. et al. Tetrahedron, 40, 2385 (1984)). Formation of an anhydride derivative of the acid (for example, by reaction with ethyl chloroformate or the like), followed by reduction (for example, with sodium borohydride or the like) provides alcohol 2.
  • P 1 is an N-protecting group, for example, t-butoxycarbonyl or the like
  • N-protection of amino acid (( ⁇ )-(2R,3S)-2-Amino-bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; Stajer, G. et al. Tetrahedron, 40, 2385
  • the alcohol group is oxidized (for example, by Swern oxidation or the like) to provide aldehyde 3.
  • Reductive amination of the aldehyde (for example with benzyl amine and Na(AcO)sBH or the like) provides N- protected amine 4 (P 2 is an N-protecting group, such as benzyl and the like).
  • a second N-protecting group can be introduced to give 5 (P 3 is an N-protecting group, for example, benzyloxycarbonyl or the like).
  • the mono- protected amino group can be alkylated (for example, by reaction with a non- nucleophilic base and an alkyl halide).
  • the bicyclic ring is oxidatively cleaved (for example, with Ru0 2 and Nal0 or the like) to give a diacid which is esterified to give diester 6
  • P 4 is a carboxylic acid protecting group, for example, loweralkyi, such as methyl, ethyl or the like).
  • the N-protecting groups P 2 and P 3 are selectively removed (for example, by hydrogenation or the like) to provide amine 7.
  • Amine 7 can be further functionalized to complete the introduction of the R 2 - X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like) to give 8.
  • Removal of the acid protecting groups P 4 (for example, by base hydrolysis) provides diacid 9.
  • Diacid 9 can be monoprotected (for example, by treatment with acetic anhydride, followed by methanol and triethylamine) and chromatographic separation to give 10 (P 5 is a
  • the acid group of 10 can also be transformed to a variety of substituents Y of the compounds of the invention using methods known to those skilled in the art to give 11, followed by N-deprotection, to give compounds of the invention 12.
  • substituents R 3 can be introduced via reaction of aldehyde 3 with a Grignard reagent (for example, R 3 MgBr or the like) to give alcohol 13.
  • a Grignard reagent for example, R 3 MgBr or the like
  • Oxidation of alcohol 13 for example, Swern oxidation or the like
  • ketone 14 Reductive amination of ketone 14 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 15.
  • Amine 15 can be further functionaiized to complete introduction of the R 2 -X- substituent (for example, by reaction of the amine with an acyiating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 16a.
  • the other diastereomer (16b) can also be isolated and further transformed according to the scheme.
  • diol 20 is selectively diprotected (Culbertson, et al., Journal of the American Chemical Society 82, 2541-2547 (1960)) by reaction with one equivalent of a hydroxy protecting agent, followed by reaction with a second hydroxy protecting agent, to give 2 .
  • P 6 is a hydroxy protecting group, for example, acetyl or the like
  • P 7 is a hydroxy protecting group, for example, benzyl or the like.
  • Oxidation and esterification provide 22.
  • Removal of protecting group P 7 followed by transformation of the hydroxy group to an amine, which is then N-protected, provides 24. Transformation of 24 in a manner
  • alcohol 31 can be transformed to compounds of the invention 38 in a manner analogous to the transformation of 13 to 19 in Scheme 2.
  • aldehyde 39 can be reacted with a Grignard reagent to introduce substituent R 3 to give 40.
  • Oxidation (for example, by Swern oxidation or the like) provides 41a, which can be epimerized (for example, with sodium methoxide or the like) and 41b can be obtained by chromatography.
  • Ketone 41b can be transformed to compounds of the invention 47 in a manner analogous to the transformation of 14 to 19 in Scheme 2.
  • olefin 48 (P 8 is a hydroxy protecting group) is converted to alcohol 48a (for example, by reaction with borane dimethylsulfide complex and hydrogen peroxide or the like).
  • Oxidation of the alcohol to a carboxylic acid followed by esterification with a carboxylic acid protecting group P 9 and deprotection of the diol, provides 49.
  • Selective protection of the primary alcohol with a hydroxy protecting group P 10 gives 50.
  • Oxidation of 50 (for example, Swern oxidation or the like) provides ketone 5
  • Reductive amination of ketone 51 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 52.
  • Amine 52 can be further functionalized to complete the introduction of the R 2 -X- substituent (for example, by reaction with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 53a.
  • the other diastereomeric amide (53b) can also be isolated and further functionalized according to this scheme.
  • the aldehyde can serve as a precursor for various substituents Y in the compounds of the invention.
  • olefination of 55 (for example, with Ph 3 PCH 2 , or triphenylphosine/methylene chloride/n-BuLi, or rPh 3 P + CH 2 CH 3 /KOtBu, or the like) provides 56 wherein Y is an olefinic substituent. Removal of the P 10 hydroxy protecting group gives alcohol 57.
  • the alcohol can serve as a precursor for a variety of R 3 substituents in the compounds of the invention.
  • the alcohol of 57 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 58.
  • Aldehyde 58 can be reacted with Grignard reagents (R 14 MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R 4 Li or the like) to provide 59 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 59a and the other isomer 59b.
  • Grignard reagents R 14 MgBr or the like
  • organometallic reagents for example, organolithium reagents such as R 4 Li or the like
  • Isomer 59a or the mixture of isomers 59 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 62.
  • Reduction of ketone 62 (for example, with sodium borohydride in ethanol or the like) provides alcohol 59b as the major isomer, which can be isolated by chromatography.
  • Ester hydrolysis provides compounds of the invention 63a or 63b, respectively, wherein Y is an olefinic substituent.
  • Alkylation of alcohol 59a or 59b provides ethers 60a or 60b, respectively.
  • Ester hydrolysis provides compounds of the invention 61a or 61b, respectively, wherein Y is an olefinic substituent.
  • reaction of ketone 62 with with Grignard reagents (R 37a MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R 37a Li or the like) provides alcohols 64a and 64b as a mixture of alcohol diastereomers which can be separated chromatographically.
  • Ester hydrolysis provides compounds of the invention 65a or 65b, respectively, wherein Y is an olefinic substituent.
  • Scheme 8 shows the preparation of precursor 74 for compounds of the invention which are substituted tetrahydrofurans.
  • Alcohol 68 is oxidized to a ketone (for example, by Swern oxidation or the like), followed by oxidation of the olefin to a diol (for example, by treatment with Os0 and N-methylmorpholine N- oxide or the like) to give 69.
  • Diol 69 is protected as the acetonide 70.
  • Oxidation of 70 (for example, with MCPBA or the like) provides lactone 71.
  • lodination via the enolate of 71 provides 72- Reaction of 72 with potassium carbonate and methanol provides ester 73. Reduction of the ester provides aldehyde 74.
  • the aldehyde provides a functional group via which substituents R 3 and R 2 -X- can be introduced.
  • Deprotection of the diol and oxidation of the diol provides functional groups via which substituents Y and R 1 can be introduced.
  • Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
  • 56 Y is an alkene 57 or haloalkene
  • 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. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
  • the title compound was synthesized from norbornadiene by a cycloaddition reaction with chlorosulfonyl isocyanate followed by a reduction and acidic hydrolysis as reported by Stajer, G. et al. Tetrahedron. . 40, 2385 (1984).
  • the reaction mixture was diluted with 100 mL of chloroform, and washed successively with 0.1 N HCI and brine. The solution was dried over MgS0 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform/methanol/acetic acid (97:2:1) to provide the title compound (yield: 155 mg, 30 %).
  • Ruthenium dioxide hydrate (43mg, 0.32 mmole) was added to a vigorously stirred mixture of Nal0 4 (7.12 g, 33 mmole) in 33 mL of acetonitrile, 33 mL of carbon tetrachloride and 58 mL of water. The mixture was stirred at room temperature for 5 minutes or until a homogeneous yellow color was attained.
  • THF tetrahydrofuran
  • Methanesulfonyl chloride (1.3 mL, 17.0 mmole) was added slowly to a solution of ( ⁇ )-(1 S,2S,3S,4R)-2-(f-butyloxycarbonylamino)-3-(hydroxymethyl)- cyclopentane-1 ,4-dicarboxylic acid dimethyl ester (2.76g, 8.34 mmole) and triethylamine (2.4 mL, 17.0 mmole) in 80 mL of 1 :1 dichloromethane:tetrahydrofuran, maintained at -30 °C.
  • the reaction mixture was stirred for 2.5 hours, at -30 °C then diluted with ethyl acetate washed with 0.1 N HCI and brine, dried over MgS0 4 , filtered and concentrated in vacuo to provide the crude mesylate.
  • the mesylate and lithium azide (4 g) were reacted in 35 mL of N.N-dimethylformamide for 1 hour, at 90 °C.
  • the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS0 , filtered and concentrated.
  • the crude product was purified by silica gel chromatography using 20% ethyl acetate in hexanes to provide the title compound, (yield: 1.8 g, 48%)
  • the crude diacid, ( ⁇ )-(1S,2S,3R,4R)-2-(f-butyloxycarbonylamino)-3- (acetamidomethyl)-cyclopentane-1 ,4-dicarboxylic acid, prepared in Example 4G was reacted with acetic anhydride (20 mL) for approximately 1 hour at 60 °C to provide the bicyclic anhydride.
  • the reaction mixture was concentrated in vacuo and the crude anhydride was treated with methanol (50 mL) and triethylamine (2- 3 equivalents) at room temperature for 3 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with 0.5N HCI and brine.
  • the crude benzylated product was reacted with acetic anhydride (0.7 mL), triethylamine (3 mL) and N,N-dimethylaminopyridine (catalytic) in dichloromethane (20 mL) at room temperature for 1 hour.
  • the reaction mixture was concentrated in vacuo and purified by silica gel chromatography using 10% ethyl acetate in hexanes to provide the title compound (yield: .845 g, 74%).
  • the reaction mixture was concentrated in vacuo.
  • the crude product was treated with methanol (10 mL) and triethylamine (.250 mL) for 16 hours.
  • the reaction mixture was concentrated and partitioned between ethyl acetate and 0.1 N HCI.
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the diastereomeric mixture of methyl esters (174 mg) was chromatographed on silica gel using (5-10%) methanol in chloroform and acetic acid (0.5%) to provide the title compound, (yield: 72 mg, 32%)
  • the title compound was prepared in two steps starting by reacting ( ⁇ )- (1 S,2S,3R,4R)-2-(N-Nbutyloxycarbonylamino)-3-(acetamidomethyl)- cyclopentane-1 ,4-dicarboxylic acid in place of ( ⁇ )-(1S,2S,3R,4R)-2-(f- butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1 ,4-dicarboxyiic acid, according to the method described in Example 4H, and substituting anhydrous liquid ammonia for methanol and triethylamine.

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Abstract

L'invention concerne les composés représentés par les formule (I), (II) et (III). Ces composés servent à inhiber les neuraminidases dans des micro-organismes pathogènes, en particulier la neuraminidase de la grippe. L'invention concerne également des compositions et des procédés permettant de prévenir et de traiter les maladies causées par des micro-organismes comprenant une neuraminidase, des procédés de préparation de ces composés et des intermédiaires de synthèse utilisés dans ces procédés.
PCT/US1999/007949 1998-04-23 1999-04-12 Inhibiteurs de neuraminidases WO1999054290A1 (fr)

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CA002329660A CA2329660A1 (fr) 1998-04-23 1999-04-12 Inhibiteurs de neuraminidases
JP2000544631A JP2002521312A (ja) 1998-04-23 1999-04-12 ノイラミニダーゼの阻害剤
EP99918495A EP1087938A1 (fr) 1998-04-23 1999-04-12 Inhibiteurs de neuraminidases

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028979A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs des neuraminidases
WO2001028996A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de neuraminidases
US6410594B1 (en) 1996-06-14 2002-06-25 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
US6503745B1 (en) 1998-11-05 2003-01-07 Biocryst Pharmaceuticals, Inc. Cyclopentane and cyclopentene compounds and use for detecting influenza virus
US6562861B1 (en) 1997-12-17 2003-05-13 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
CN102964267A (zh) * 2011-09-01 2013-03-13 中山大学 一种具有流感病毒神经氨酸酶抑制活性的环己烯化合物及其制备方法以及其应用
KR101566157B1 (ko) 2015-02-26 2015-11-05 전남대학교산학협력단 대장균에서 조류인플루엔자 바이러스의 뉴라미니다제 ｎ1을 발현하기 위한 벡터 및 방법, 이의 사용방법, 및 뉴라미니다제 저해제
KR101566156B1 (ko) 2015-02-26 2015-11-05 전남대학교산학협력단 대장균에서 조류인플루엔자 바이러스의 뉴라미니다제 ｎ1을 발현하기 위한 벡터 및 방법, 이의 사용방법, 및 뉴라미니다제 저해제
KR101568974B1 (ko) 2015-02-26 2015-11-13 전남대학교산학협력단 대장균에서 조류인플루엔자 바이러스의 뉴라미니다제 ｎ1을 발현하기 위한 벡터 및 방법, 이의 사용방법, 및 뉴라미니다제 저해제
WO2018049003A1 (fr) * 2016-09-08 2018-03-15 The Texas A&M University System Composés inhibiteurs de sialidase anti-fibrotique et leurs méthodes d'utilisation
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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US8048147B2 (en) * 2007-06-27 2011-11-01 Aga Medical Corporation Branched stent/graft and method of fabrication
CN104387288B (zh) * 2014-11-25 2016-04-20 广东东阳光药业有限公司 作为神经氨酸酶抑制剂的化合物及其在药物中的应用
CN104496839B (zh) * 2014-12-03 2016-04-20 广东东阳光药业有限公司 取代环丁烷类神经氨酸酶抑制剂及其使用方法和用途
CN104496838B (zh) * 2014-12-03 2016-04-20 广东东阳光药业有限公司 取代环丁烷类神经氨酸酶抑制剂及其使用方法和用途

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WO1995018800A1 (fr) * 1994-01-07 1995-07-13 Biota Scientific Management Pty Ltd Derives de l'acide 2-desoxy-2,3-deshydro-n-acetylneuraminique (dana)
WO1997006157A1 (fr) * 1995-08-08 1997-02-20 Biota Scientific Management Pty Ltd Derives de dihydropyranne utilises comme inhibiteurs de la neuraminidase virale
US5648379A (en) * 1990-04-24 1997-07-15 Biota Scientific Management Pty., Ltd. Derivatives and analogues of 2-deoxy-2,3-didehydro-n-acetyl neuraminic acid and their use as antiviral agents
WO1997047194A1 (fr) * 1996-06-14 1997-12-18 Biocryst Pharmaceuticals, Inc. Composes cyclopentane substitues convenant comme inhibiteurs des neuraminidases
WO1999033781A1 (fr) * 1997-12-17 1999-07-08 Biocryst Pharmaceuticals, Inc. Composes des cyclopentane et cyclopentene convenant comme inhibiteurs de neuraminidase

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US5648379A (en) * 1990-04-24 1997-07-15 Biota Scientific Management Pty., Ltd. Derivatives and analogues of 2-deoxy-2,3-didehydro-n-acetyl neuraminic acid and their use as antiviral agents
WO1995018800A1 (fr) * 1994-01-07 1995-07-13 Biota Scientific Management Pty Ltd Derives de l'acide 2-desoxy-2,3-deshydro-n-acetylneuraminique (dana)
WO1997006157A1 (fr) * 1995-08-08 1997-02-20 Biota Scientific Management Pty Ltd Derives de dihydropyranne utilises comme inhibiteurs de la neuraminidase virale
WO1997047194A1 (fr) * 1996-06-14 1997-12-18 Biocryst Pharmaceuticals, Inc. Composes cyclopentane substitues convenant comme inhibiteurs des neuraminidases
WO1999033781A1 (fr) * 1997-12-17 1999-07-08 Biocryst Pharmaceuticals, Inc. Composes des cyclopentane et cyclopentene convenant comme inhibiteurs de neuraminidase

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6410594B1 (en) 1996-06-14 2002-06-25 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
US6562861B1 (en) 1997-12-17 2003-05-13 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
US6518305B1 (en) 1998-04-23 2003-02-11 Abbott Laboratories Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases
US6455571B1 (en) 1998-04-23 2002-09-24 Abbott Laboratories Inhibitors of neuraminidases
US6503745B1 (en) 1998-11-05 2003-01-07 Biocryst Pharmaceuticals, Inc. Cyclopentane and cyclopentene compounds and use for detecting influenza virus
WO2001028979A3 (fr) * 1999-10-19 2001-12-27 Abbott Lab Inhibiteurs des neuraminidases
WO2001028996A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de neuraminidases
WO2001028996A3 (fr) * 1999-10-19 2001-11-29 Abbott Lab Inhibiteurs de neuraminidases
WO2001028979A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs des neuraminidases
CN102964267A (zh) * 2011-09-01 2013-03-13 中山大学 一种具有流感病毒神经氨酸酶抑制活性的环己烯化合物及其制备方法以及其应用
CN102964267B (zh) * 2011-09-01 2015-06-10 中山大学 一种具有流感病毒神经氨酸酶抑制活性的环己烯化合物及其制备方法以及其应用
KR101566157B1 (ko) 2015-02-26 2015-11-05 전남대학교산학협력단 대장균에서 조류인플루엔자 바이러스의 뉴라미니다제 ｎ1을 발현하기 위한 벡터 및 방법, 이의 사용방법, 및 뉴라미니다제 저해제
KR101566156B1 (ko) 2015-02-26 2015-11-05 전남대학교산학협력단 대장균에서 조류인플루엔자 바이러스의 뉴라미니다제 ｎ1을 발현하기 위한 벡터 및 방법, 이의 사용방법, 및 뉴라미니다제 저해제
KR101568974B1 (ko) 2015-02-26 2015-11-13 전남대학교산학협력단 대장균에서 조류인플루엔자 바이러스의 뉴라미니다제 ｎ1을 발현하기 위한 벡터 및 방법, 이의 사용방법, 및 뉴라미니다제 저해제
WO2018049003A1 (fr) * 2016-09-08 2018-03-15 The Texas A&M University System Composés inhibiteurs de sialidase anti-fibrotique et leurs méthodes d'utilisation
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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CA2329660A1 (fr) 1999-10-28
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