WO1999054299A1 - Pyrrolidines as inhibitors of neuraminidases - Google Patents

Pyrrolidines as inhibitors of neuraminidases Download PDF

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Publication number
WO1999054299A1
WO1999054299A1 PCT/US1999/007945 US9907945W WO9954299A1 WO 1999054299 A1 WO1999054299 A1 WO 1999054299A1 US 9907945 W US9907945 W US 9907945W WO 9954299 A1 WO9954299 A1 WO 9954299A1
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WIPO (PCT)
Prior art keywords
pyrrolidine
acetamido
carboxylic acid
hydrogen
propen
Prior art date
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PCT/US1999/007945
Other languages
English (en)
French (fr)
Inventor
Clarence J. Maring
Yu-Gui Gu
Hui-Ju Chen
Yuanwei Chen
David A. Degoey
William J. Flosi
Vincent L. Giranda
David J. Grampovnik
Warren M. Kati
Dale J. Kempf
Larry L. Klein
Allan C. Krueger
Zhen Lin
Darold L. Madigan
Keith F. Mcdaniel
Steven W. Muchmore
Hing L. Sham
Kent D. Stewart
Vincent S. Stoll
Minghua Sun
Gary T. Wang
Sheldon Wang
Yibo Xu
Ming C. Yeung
Chen Zhao
April Kennedy
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Abbott Laboratories
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Filing date
Publication date
Priority to IL13860199A priority Critical patent/IL138601A0/xx
Priority to BR9909870-9A priority patent/BR9909870A/pt
Priority to EP99917414A priority patent/EP1315698A1/en
Priority to HU0101224A priority patent/HUP0101224A3/hu
Priority to CA002329422A priority patent/CA2329422A1/en
Priority to SK1509-2000A priority patent/SK15092000A3/sk
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to PL99343678A priority patent/PL343678A1/xx
Priority to JP2000544640A priority patent/JP2002512224A/ja
Priority to AU35545/99A priority patent/AU3554599A/en
Publication of WO1999054299A1 publication Critical patent/WO1999054299A1/en
Priority to NO20005301A priority patent/NO20005301L/no
Priority to BG104962A priority patent/BG104962A/bg

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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—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
    • 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
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    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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    • C07F9/572—Five-membered rings

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 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 ofthe 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,
  • 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 prevention of influenza infection and will be useful for the treatment of influenza infection.
  • 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:
  • R 1 is selected from the group consisting of
  • R 11 is selected from the group consisting of
  • R 12 and R 36 are independently selected from the group consisting of (i) hydrogen, (ii) C ⁇ -C ⁇ 2 alkyl, (iii) C 2 -C ⁇ 2 alkenyl, (iv) cycloalkyl, (v) (cycioalkyl)alkyl, (vi) (cycloalkyi)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl
  • X is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • C1-C3 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 the group consisting of
  • R 3 7 a ⁇ R 3 7 R 47 ⁇ and R 4 8 at eacn 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 15 is selected from the group consisting of
  • R 5 is selected from the group consisting of
  • 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
  • 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 21 is hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
  • R 23 and R 39 are independently hydrogen or methyl
  • R 41 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 hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO 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 -NO 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 5l -C 3 H 7 , -OCH 3> -SCH 3 , -O-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 , R 9 , and R 10 are independently selected from the group consisting of
  • -17- Preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula II:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined above and wherein R 3 and R 4 are not both the same.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined above and wherein R 3 and R 4 are not both the same.
  • C- ⁇ -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
  • R 5 is hydrogen or loweralkyi
  • 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 or II or III 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
  • R 5 is hydrogen or loweralkyi
  • 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
  • R 5 is hydrogen or loweralkyi
  • 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
  • -21- 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.
  • More highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R 1 is -CO 2 H;
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • R ⁇ is hydrogen or loweralkyi
  • R 6 and R 7 are hydrogen 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 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 heterocyclic or -Z-R 14 wherein Z and R 14 are defined as above;
  • 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.
  • 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
  • -23- 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, C2-C5 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 or II or III 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 )(OR 37c )- R 14 wherein R 14 is
  • R 37a and R 37b are independently selected from the group consisting of
  • 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.
  • 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
  • R 5 is hydrogen
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen
  • R 10 is hydrogen
  • -25- 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
  • R 5 is hydrogen
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen
  • R 0 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 -CO 2 H or esters or prodrugs thereof.
  • Preferred esters include C 2 -C 6 loweralkyi esters or substituted or unsubstituted
  • R 1 include -CO 2 H or esters or prodrugs thereof.
  • Most highly preferred esters include C 2 -C 6 loweralkyi esters or substituted or unsubstituted benzyl esters.
  • C ⁇ -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 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) C C 3 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) C 1 -C 3 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, C 1 -C 3 loweralkyi or allyl, and especially, wherein R 37c is hydrogen or methyl.
  • R 5 include hydrogen or loweralkyi. Most highly preferred, 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 incude independently hydrogen, fluoro and loweralkyi. Most highly preferred, R 8 , R 9 and R 10 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.
  • Preferred compounds of the invention include compounds selected from the group consisting of:
  • More preferred compounds of the invention include compounds selected from the group consisting of:
  • acid protecting group refers to groups used to protect acid groups (for example, -CO 2 H, -SO 3 H, -SO 2 H, -PO 3 H 2 , -PO 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. uts, 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 ofthe 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, 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-hydroxybenzotriazoie derived esters, N-hydroxy-5-norbomene-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.
  • 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.
  • alkoxy groups include groups such as, for example, methoxy, ethoxy, ferf-butoxy, and the like.
  • alkoxyalkoxy refers to groups having the formula -O-R 96 -O-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, £-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, f-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
  • alkylamino refers to groups having the formula -NHR 91 wherein R 91 is an alkyl group. Preferred R 9 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 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.
  • alkylene groups include groups such as, for example, methylene (-CH2-), 1,2-ethylene (-CH 2 CH 2 -), 1 ,1-ethylene (-CH(CH 3 )-), 1 ,3-propylene (-CH 2 CH 2 CH 2 -), 2,2-dimethylpropylene (-CH 2 C(CH 3 ) 2 CH 2 -), and the like.
  • 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, -SO 2 -R 78 , where R 78 is an alkyl group. Preferred groups R 78 are loweralkyi groups.
  • alkylsulfonylamino refers to the group having the formula, -SO 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 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, indenyi and the like.
  • aryl substituents are each independently selected from the group consisting of loweralkyi, halo, haloalkyl, hydroxy, hydroxyalkyi, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro.
  • substituted aryl examples include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methyisulfonylphenyl, and the like.
  • (aryl)alkenyl refers to a lower alkenyl group having appended thereto an aryl group.
  • Representative examples of (aryl)alkenyi groups include groups such as, for example phenylethylenyl, phenyipropenyl, 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.
  • cyanoalkyi 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 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, cyclobutyl, 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, CI, 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,
  • X * is -CH 2 or -O- and Y * is -C(O)- or [-C(R 92 ) 2 -] V
  • R 92 is hydrogen or C 1 -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.
  • heterocyclicalkynyl 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 (-O-).
  • 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;
  • 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, trichioroacetate, 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.
  • hydroxyalkyi 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, CI, 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,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyi, 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. As a result, all stereoisomers of the compounds of the invention
  • -53- 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.
  • 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. 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.
  • soivates and hydrates of the compounds of Formula I and II and III 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 I and II and III 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 8 , 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.
  • reaction of acrolein with an N-protected ⁇ -amino acid ester 1 (P 1 is an N-protecting group, preferably a benzyl group or the like and P 2 is a carboxylic acid protecting group, preferably a t-butyl group or the like) in an inert solvent (for example, toluene and the like) in the presence of an acid catalyst (for example, acetic acid and the like), followed by equilibration with a base (for example, with triethylamine or the like) and separation of the isomers by chromatography, provides substituted pyrrolidine 2.
  • P 1 is an N-protecting group, preferably a benzyl group or the like and P 2 is a carboxylic acid protecting group, preferably a t-butyl group or the like
  • an inert solvent for example, toluene and the like
  • an acid catalyst for example, acetic acid and the like
  • Alcohol 3 can be protected with an hydroxy protecting group P 3 (preferably with a silyl protecting group, for example, t-butyldimethylsilyl or the like) using standard alcohol protection methods to provide 4.
  • Oxidation of the vinyl group of compound 4 to an aldehyde is accomplished by reacting compound 4 with OsO 4 and N-methylmorpholine N-oxide to give the corresponding diol. The diol is then treated with sodium periodate to provide aldehyde 5.
  • Substituents R 3 can be introduced via reaction of aldehyde 5 with a Grignard reagent (for example, R 3 MgBr or the like) to give alcohol 6.
  • Oxidation of alcohol 6 for example, Swern
  • ketone 7 Reductive amination of ketone 7 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 8.
  • Amine 8 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 or by other acylation methods), followed by chromatographic separation of the diastereomers to give 9a.
  • the other diastereomeric amine (9b) can also be isolated and further transformed according to Scheme 1.
  • hydroxy protecting group P 3 for example, by reaction with a fluoride ion source, such as tetrabutylammonium fluoride or the like, when P 3 is a silyl protecting group
  • a fluoride ion source such as tetrabutylammonium fluoride or the like
  • Transformation of the hydroxy group of alcohol 10 allows introduction of various substituents Y.
  • alkylation of the hydroxy group provides ethers H.
  • N- deprotection for example, where P 1 is a benzyl group, by hydrogenation
  • ester hydrolysis for example, with acid such as HCl
  • Oxidation of the hydroxy group of 0 (for example, Swern oxidation or the like) provides aldehyde 13.
  • Oxidation of aldehyde 13 (for example, with NaCIO 2 or the like) provides carboxylic acid 14.
  • the carboxylic acid substituent of 14 can be used to introduce a variety of other functional groups in substituent Y.
  • N-deprotection (for example, where P 1 is a benzyl group, by hydrogenation) gives 16 ⁇ , followed by ester hydrolysis (for example, with acid such as HCl), provides compound IjT of the invention.
  • aldehyde group of 13 or the carboxylic acid group of 14 can be used to introduce substituents Y which are -CN or various heterocycles, according to methods known to those skilled in the art and according to the specific methods exemplified herein.
  • aldehyde 13 for example, with Ph 3 PCH 2 or the like
  • hydrogenation causing N-deprotection (for example, where P 1 is a benzyl group) and olefin saturation
  • ester hydrolysis for example,
  • Olefination of 26a (for example, with Ph 3 PCH 2 , or triphenylphosine/methylene chloride/n-BuLi, or l " Ph 3 P + CH 2 CH3/KOtBu, or the like) provides 27 wherein Y is an olefinic substituent.
  • N-deprotection of the P 5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 28 wherein Y is an olefinic substituent.
  • the hydroxy group of alcohol 3 is protected with a base-labile hydroxy protecting group P 6 (for example, acetyl or the like) to give compound 29.
  • a base-labile hydroxy protecting group P 6 for example, acetyl or the like
  • Oxidation of the vinyl group of 29 with OsO 4 and N-methylmorpholine N-oxide provides diol 30.
  • Removal of the P 1 protecting group (for example, by hydrogenation or the like) provides pyrrolidine 3 .
  • Reprotection with an acid-labile N-protecting group P 5 (for example, t-butoxycarbonyl or the like) provides 32.
  • a hydroxy protecting group P 7 for example, a silyl protecting group such as triisopropylsilyl or the like
  • a hydroxy protecting group P 7 for example, a silyl protecting group such as triisopropylsilyl or the like
  • Oxidation of 33 for example, Swern oxidation or the like
  • ketone 34- Reductive amination of ketone 34 for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like gives amine 35.
  • -60- Amine 35 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 or by other acylation methods), followed by chromatographic separation of the diastereomers to give 36a.
  • the other diastereomeric amine (36b) can also be isolated and further transformed according this scheme.
  • the alcohol can serve as a precursor for a variety of R 3 substituents in the compounds of the invention.
  • the alcohol of 40 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 4 . .
  • Aldehyde 4_1 can be reacted with Grignard reagents (R 14 MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R 14 Li or the like) to provide 42 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 42a and the other isomer 42b.
  • Grignard reagents R 14 MgBr or the like
  • organometallic reagents for example, organolithium reagents such as R 14 Li or the like
  • Isomer 42a or the mixture of isomers 42 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 43.
  • Reduction of ketone 43 (for example, with sodium borohydride in ethanol or the like) provides alcohol 42b as the major isomer, which can be isolated by chromatography.
  • reaction of ketone 43 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 46a and 46b as a mixture of alcohol diastereomers which can be separated chromatographically.
  • organolithium reagents such as R 37a Li or the like
  • Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
  • R 22 ⁇ )- is an ester or amide
  • R 22 is loweralkyi or loweralkenyl o
  • Y is an alkene
  • Y is an alkene 40 or haloalkene
  • P 1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P 2 is a carboxylic acid protecting group (preferrably, a loweralkyi group, especially t-butyl); preferrably, P 1 and P 2 can be selectively deprotected/removed; or a salt thereof;
  • P 1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P 2 is a carboxylic acid protecting group (preferably, a
  • P , P 2 and P 3 can be selectively deprotected/removed; or a salt thereof;
  • P 1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P 2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P 4 is hydrogen or an N-protecting group (preferably, a carbamate N-protecting group, for example, benzyloxycarbonyl and the like); preferrably, P 1 , P 2 and P 4 can be selectively deprotected/removed; or a salt thereof;
  • P 5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P 2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P 6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P 7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); preferrably, P 2 , P 5 , P 6 and P 7 can be selectively deprotected/removed; or a salt thereof; and
  • P 5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P 2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P 6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P 7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); and R 2 is defined as herein (preferably, loweralkyi or haloloweralkyl; most preferably, methyl or trifluoromethyl); preferrably, P 2 , P 5 , P 6 and P 7 can be selectively deprotected/removed; or a salt thereof.
  • N-protecting group preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like
  • 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, WI, 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.
  • Acrolein (8 mL, 120 mmole) was added to a solution of f-butyl N-benzyl- glycinate (4.34 g, 19.6 mmole) and acetic acid (5 drops) in toluene (100 mL). The solution was heated at reflux. After 1 hour, the reaction was cooled to about 50 °C and an additional 3 mL of acrolein were added. The reaction was heated at reflux for an additional 2 hours and concentrated in vacuo.
  • the residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide a mixture of ( ⁇ )-(2S,3R,5R)- and ( ⁇ )-(2S,3S,5R)-1-benzyl-2-vinyl-3- formyl-pyrrolidine-5-carboxylic acid -butyl esters as an oil (yield: 2.78 g, 45%).
  • the mixture of aldehydes was equilibrated to an 8:1 ratio by stirring the crude product with triethylamine (0.5 mL) in ethyl acetate at room temperature followed by evaporation of the solvents.
  • the crude diol was dissolved in 6:1 tetrahydrofuran (THF)/water (50 mL) and treated with sodium periodate (3.0 g, 14.0 mmole). The mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate, washed with water, dried over MgSO , filtered, and concentrated in vacuo.
  • the crude aldehyde was purified by chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 1.6 g, 46%).
  • reaction mixture was cooled to -30 °C and ( ⁇ )-(2R,3R,5R)-1-benzyl-2-formyl- 3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (0.5 g, 1.15 mmole) in of THF (6 mL) was added, dropwise.
  • the reaction was slowly warmed to -10 °C, over a period of about 2 hours, and quenched with aqueous ammonium chloride.
  • the resultant slurry was diluted with ethyl acetate and washed with water, brine, and dried over MgSO 4 and concentrated.
  • DiazaldTM (0.5 g, 2.33 mmole) in 5 mL of ether was added slowly to a solution of aqueous KOH (0.5 g in 1 mL of water) and 1 mL of ethanol maintained at 65 °C.
  • Diazomethane was distilled into a receiving flask charged with a solution of ( ⁇ )-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (30 mg, 0.065 mmole) in 3 mL of THF.
  • the receiving flask was cooled to 0 °C in an ice/water bath.
  • the condenser was cooled with dry ice/acetone and 3 mL of ether was added the distilling flask until the distillate was colorless.
  • the reaction was stirred for an additional 0.5 hours at 0 °C.
  • the yellowish reaction mixture was quenched with acetic acid (0.1 mL ) and diluted with ethyl acetate.
  • the organic layer was washed with 10% NaHCO 3 and brine, dried with MgSO and concentrated in vacuo.
  • the residue was purified by chromatography on silica gel using 50 % ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 20 mg, 65%).
  • the title compound is prepared by reacting a solution of ( ⁇ )- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester with hydroxylamine hydrochloride and 10% aqueous potassium carbonate in methanol according to the procedure described by Chelucci et al., Tetrahedron: Asymmetry 5:1973 (1994).
  • the title compound is prepared by reacting a solution of ( ⁇ )- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hydroxyiminoformyl)- pyrrolidine-5-carboxyiic acid f-butyl ester with 1 ,1'-carbonyldiimidazole in dichloromethane according to the procedure described by Cheiucci et al., Tetrahedron: Asymmetry 5:1973 (1994).
  • the title compound is prepared according to the method described in Example U, substituting ( ⁇ )-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of ( ⁇ )- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxyiic acid f-butyl ester.
  • the title compound is prepared according to the method described in Example 1 K, substituting ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of ( ⁇ )-(2R,3R,5R,1'S)-2- (1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrroiidine-5-carboxylic acid f- butyl ester.
  • the title compound was prepared according to the method described in Example 1 K, substituting ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3- ethyl)pentyl-3-(N-methylcarbamoyl)pyrroiidine-5-carboxylic acid f-butyl ester in place of ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester.
  • the title compound was prepared according to the method described in Example 1 K, substituting ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(N- (t-butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of ( ⁇ )-(2R,3R,5R,1 'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester.

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PCT/US1999/007945 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases WO1999054299A1 (en)

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BR9909870-9A BR9909870A (pt) 1998-04-23 1999-04-12 Pirrolidinas como inibidores de neuraminidases
EP99917414A EP1315698A1 (en) 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases
HU0101224A HUP0101224A3 (en) 1998-04-23 1999-04-12 Pyrrolidine derivatives as inhibitors of neuraminidases and pharmaceutical compositions containing them
CA002329422A CA2329422A1 (en) 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases
SK1509-2000A SK15092000A3 (sk) 1998-04-23 1999-04-12 Pyrolidíny ako inhibítory neuraminidáz
IL13860199A IL138601A0 (en) 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases
PL99343678A PL343678A1 (en) 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases
JP2000544640A JP2002512224A (ja) 1998-04-23 1999-04-12 ノイラミニダーゼの阻害剤としてのピロリジン
AU35545/99A AU3554599A (en) 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases
NO20005301A NO20005301L (no) 1998-04-23 2000-10-20 Pyrrolidiner som inhibitorer av neuraminidaser
BG104962A BG104962A (bg) 1998-04-23 2000-11-17 Пиролидини като инхибитори на неуроаминидази

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WO2001028996A2 (en) * 1999-10-19 2001-04-26 Abbott Laboratories Pyrrolidine derivatives, their preparation and their use as inhibitors of neuraminidases
WO2001080892A1 (fr) * 2000-04-25 2001-11-01 Sankyo Company, Limited Substances preventives de la grippe
US6410594B1 (en) 1996-06-14 2002-06-25 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
WO2002081441A1 (en) * 2001-04-03 2002-10-17 Abbott Laboratories Process for the preparation of substituted pyrrolidine neuraminidase inhibitors
US6503745B1 (en) 1998-11-05 2003-01-07 Biocryst Pharmaceuticals, Inc. Cyclopentane and cyclopentene compounds and use for detecting influenza virus
US6518299B1 (en) 2000-10-20 2003-02-11 Biocryst Pharmaceuticals, Inc. Substituted pyrrolidine compounds useful as neuraminidase inhibitors
WO2003037894A1 (en) * 2001-11-02 2003-05-08 Glaxo Group Limited 4-(5-membered)-heteroaryl acyl pyrrolidine derivatives as hcv inhibitors
WO2003037895A1 (en) * 2001-11-02 2003-05-08 Glaxo Group Limited 4-(6-membered)-heteroaryl acyl pyrrolidine derivatives as hcv inhibitors
US6562861B1 (en) 1997-12-17 2003-05-13 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
WO2004037818A1 (en) * 2002-10-24 2004-05-06 Glaxo Group Limited 1-acyl-pyrrolidine derivatives for the treatment of viral infections
CN104402754A (zh) * 2014-11-25 2015-03-11 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

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WO1996026933A1 (en) * 1995-02-27 1996-09-06 Gilead Sciences, Inc. Novel selective inhibitors of viral or bacterial neuraminidases
WO1997047194A1 (en) * 1996-06-14 1997-12-18 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
WO1999014191A1 (en) * 1997-09-17 1999-03-25 Biocryst Pharmaceuticals, Inc. Pyrrolidin-2-one compounds and their use as neuraminidase inhibitors

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WO1996026933A1 (en) * 1995-02-27 1996-09-06 Gilead Sciences, Inc. Novel selective inhibitors of viral or bacterial neuraminidases
WO1997047194A1 (en) * 1996-06-14 1997-12-18 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
WO1999014191A1 (en) * 1997-09-17 1999-03-25 Biocryst Pharmaceuticals, Inc. Pyrrolidin-2-one compounds and their use as neuraminidase inhibitors

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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
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
WO2001028996A3 (en) * 1999-10-19 2001-11-29 Abbott Lab Pyrrolidine derivatives, their preparation and their use as inhibitors of neuraminidases
WO2001028996A2 (en) * 1999-10-19 2001-04-26 Abbott Laboratories Pyrrolidine derivatives, their preparation and their use as inhibitors of neuraminidases
WO2001080892A1 (fr) * 2000-04-25 2001-11-01 Sankyo Company, Limited Substances preventives de la grippe
JP2008297320A (ja) * 2000-04-25 2008-12-11 Daiichi Sankyo Co Ltd インフルエンザ予防剤
US6518299B1 (en) 2000-10-20 2003-02-11 Biocryst Pharmaceuticals, Inc. Substituted pyrrolidine compounds useful as neuraminidase inhibitors
WO2002081441A1 (en) * 2001-04-03 2002-10-17 Abbott Laboratories Process for the preparation of substituted pyrrolidine neuraminidase inhibitors
WO2003037894A1 (en) * 2001-11-02 2003-05-08 Glaxo Group Limited 4-(5-membered)-heteroaryl acyl pyrrolidine derivatives as hcv inhibitors
US7259163B2 (en) 2001-11-02 2007-08-21 Glaxo Group Limited 4-(6-membered)-heteroaryl acyl pyrrolidine derivatives as HCV inhibitors
WO2003037895A1 (en) * 2001-11-02 2003-05-08 Glaxo Group Limited 4-(6-membered)-heteroaryl acyl pyrrolidine derivatives as hcv inhibitors
WO2004037818A1 (en) * 2002-10-24 2004-05-06 Glaxo Group Limited 1-acyl-pyrrolidine derivatives for the treatment of viral infections
US7304087B2 (en) 2002-10-24 2007-12-04 Glaxo Group Limited 1-acyl-pyrrolidine derivatives for the treatment of viral infections
CN104402754A (zh) * 2014-11-25 2015-03-11 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

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HUP0101224A2 (hu) 2001-08-28
IL138601A0 (en) 2001-10-31
TR200003065T2 (tr) 2001-02-21
CN1328546A (zh) 2001-12-26
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