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WO2012085003A1 - 2 -hydroxyisoquinoline- 1, 3 ( 2h, 4h) - diones et composés associés servant d'inhibiteurs de la réplication du vih - Google Patents

2 -hydroxyisoquinoline- 1, 3 ( 2h, 4h) - diones et composés associés servant d'inhibiteurs de la réplication du vih Download PDF

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Publication number
WO2012085003A1
WO2012085003A1 PCT/EP2011/073480 EP2011073480W WO2012085003A1 WO 2012085003 A1 WO2012085003 A1 WO 2012085003A1 EP 2011073480 W EP2011073480 W EP 2011073480W WO 2012085003 A1 WO2012085003 A1 WO 2012085003A1
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WIPO (PCT)
Prior art keywords
het
civ
alkyl
halo
carboxamide
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PCT/EP2011/073480
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English (en)
Inventor
Fabrice BAILLY
Muriel BILLAMBOZ
Frauke Christ
Philippe COTELLE
Zeger Debyser
Cédric LION
Virginie SUCHAUD
Original Assignee
Katholieke Universiteit Leuven, K.U. Leuven R&D
Universite De Lille
Centre National De Recherche Scientifique
Ecole Nationale Superieure De Chimie De Lille
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Application filed by Katholieke Universiteit Leuven, K.U. Leuven R&D, Universite De Lille, Centre National De Recherche Scientifique, Ecole Nationale Superieure De Chimie De Lille filed Critical Katholieke Universiteit Leuven, K.U. Leuven R&D
Publication of WO2012085003A1 publication Critical patent/WO2012085003A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds and compositions containing said compounds acting as inhibitors of HIV integrase.
  • the invention also provides processes for the preparation of the disclosed compounds and compositions and methods of using them, for instance as a medicine. BACKGROUND OF THE INVENTION
  • HIV-1 Human immunodeficiency virus type 1
  • NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
  • NRTIs non- nucleoside reverse transcriptase inhibitors
  • protease inhibitors Pis
  • entry inhibitors NRTIs
  • the standard combination therapy consists of a PI compound or a NNRTI compound combined with two NRTIs compounds.
  • HAART can suppress virus titers to undetectable levels but the virus persists in reservoirs such as peripheral blood mononuclear cells or resting T-lymphocytes. While HAART is undeniably effective, it is strongly limited by several factors like lack of therapy adherence, occurrence of important side effects and the development of resistance (multidrug resistance and cross-resistance) causing the loss of drug effectiveness. In the last decade, viral entry inhibitors and, most importantly, HIV-1 integrase inhibitors have been pursued as novel anti-HIV agents.
  • HIV-1 integrase has emerged as an attractive target since it is necessary for stable infection and has no cellular equivalent.
  • This enzyme is essential for viral replication, and mediates the insertion of viral DNA within the host cell genome via a multistep process that occurs in discrete biochemical stages: (i) assembly of a stable-DNA enzyme complex with specific DNA sequences at the end of the HIV-1 long terminal repeat (LTR) regions, (ii) endonucleolytic process of the viral DNA to remove the terminal dinucleotide from each 3 '-end (3 '-processing), (iii) strand transfer in which the viral DNA 3 '-ends are covalently linked to the cellular DNA, (iv) removal of the two unpaired nucleotides at the 3 '-ends of the viral DNA and (v) gap-filling, probably accomplished by cellular enzymes.
  • LTR long terminal repeat
  • WO200400472 published on 15 January 2004 discloses 3,4-dihydroisoquinolin-l-one derivatives as inducers of apoptosis.
  • WO200707578 published on 5 July 2005 discloses substituted isoquinoline-l,3(2H, 4H> diones for the prevention of cancer.
  • Billamboz et al. J. Med. Chem. 2008, 51, 7717-7730 disclose the design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-l,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain.
  • the present novel hydroxyisoquinolineidiones derivatives act as selective inhibitors of HIV- 1 integrase. They inhibit the overall catalytic activity of HIV-integrase and act as inhibitors of HIV- 1 replication. More in particular they act as strand transfer inhibitors.
  • the present compounds act as 3 'processing inhibitors. Thus they have a strong activity against both strand transfer activity and 3 'processing and inhibit the viral integrase in a unique way.
  • the compounds inhibit the overall integrase reaction, the strand transfer reaction and the 3 'processing reaction with similar potency.
  • the present invention satisfies the urgent need for efficient and non-harmful pharmaceutically compounds and combinations for the treatment of retroviral infections, in particular lentiviral infections, and more particularly HIV infections, in mammals and in humans.
  • new anti-viral, more in particular anti-HIV compounds are provided.
  • the compounds are novel hydroxyisoquinolinediones derivatives of formula (I) and it has been shown that they possess anti-viral activity, more specifically against HIV.
  • the present invention demonstrates that the compounds inhibit the replication of HIV. Therefore, these compounds constitute a new potent class of anti-viral agents that can be used in the treatment and prevention of viral infections in animals, mammals and humans, more specifically for the treatment and prevention of HIV.
  • the present invention relates to novel hydroxyisoquinolinediones derivatives of formula (I).
  • the invention further relates to compounds having anti-viral activity, more specifically to novel hydroxyisoquinolinediones derivatives of formula (I) thereof having viral replication inhibitory properties, more in particular of HIV (Human Immunodeficiency Virus), which is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans, and consequently may be useful for the treatment of individuals infected by HIV.
  • HIV Human Immunodeficiency Virus
  • the present invention also relates to compounds of formula (I) having antiviral activities with respect to other viruses, such as Hepatitis C Virus.
  • Present invention furthermore relates to the use of the compounds of formula (I) as a medicine and more specifically to the use of the compounds of formula (I) as an anti-viral agent.
  • the invention also relates to methods for preparation of all such compounds and pharmaceutical compositions comprising them.
  • the invention further relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection, as well as for treatment of other viral, retroviral or lentiviral infections, treatment of animals suffering from FIV, viral, retroviral, lentiviral infections or treatment of tumour or cancer cells.
  • the present invention also relates to a method of treatment or prevention of viral infections, by using said compounds.
  • One aspect of the present invention is the provision of hydroxyisoquinolinediones derivatives and analogues thereof.
  • the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I),
  • R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • R 1 and R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each Ar 1 , Ar 2 , Ar 3 ; or Ar 4 is independently phenyl or naphtyl and is optionally substituted with 1 to 5 substituents each of which is independently halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 or CF 3 ;
  • each Het 1 , Het 2 , Het 3 or Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S and is optionally substituted with 1 to 4 substituents each of which is independently halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 or CF 3 .
  • the present invention also relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I),
  • R 1 and R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • Ci -6 alkyl optionally substituted with halo, Ci -6 alkyl, -OH, -SH, -CN, -N0 2 ,
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 ;
  • One embodiment of the present invention relates to the compounds of formula (I) or ( ⁇ ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, or for use as a treatment of infection by HIV, or for treating AIDS.
  • One embodiment of the present invention relates to the compounds of formula (I) or ( ⁇ ) as defined just hereinbefore or 2-Hydroxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide, or 2-Hydroxy-6,7-dimethyl-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide for use as an antiviral agent, or for use as a treatment of infection by HIV, or for treating AIDS.
  • One aspect of the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I), or a tautomer ( ⁇ ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
  • R 1 is selected from:
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • One embodiment of the present invention relates to the compounds of formula (I) or ( ⁇ ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (X),
  • R 1 is selected from:
  • R 2 is selected from:
  • R 5 is selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ; and
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • substituents for example 1, 2, 3 or 4 substituents
  • One embodiment of the present invention relates to the compounds of formula (X) or ( ⁇ ') as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention is the provision of 2-benzyloxy-4- carboxamidoisoquinoline-l ,3(2H,4H)-diones of formula (II) or ( ⁇ ) wherein the substituents R 1 , R 2 , R 3 , R 4 , R s and R 6 , are as defined above.
  • One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-l,3(2H,4H)- dioxoisoquinoline-4-carboxamides of formula (II) or (IF) wherein the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , are as defined above, provided that the following compounds are excluded:
  • One embodiment of the present invention relates to the compounds of formula (II) or (II ') as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-4-carboxamidoisoquinoline- l,3(2H,4H)-diones of formula (II) or a tautomer ( ⁇ ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof,
  • R 1 is selected from:
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and - CF 3 .
  • substituents for example 1, 2, 3 or 4 substituents
  • One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-4-carboxamidoisoquinoline- l,3(2H,4H)-diones of formula (II) or a tautomer (IF) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each R 9 is hydrogen; OH; C
  • each R 10 , R U , and R 12 is independently selected from hydrogen; OH; Cuealkyl optionally substituted with halo, C
  • each of Ar 1 , Ar 2 , Ar 3 , and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, OH, Ci-6alkyloxy, N0 2 , -OCF3, and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-ealkyl, OH, Ci-ealkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-l ,3(2/ ,4/_')- dioxoisoquinoline-4-carboxamides of formula (XI)
  • R 1 is selected from:
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • Ar 1 Het 1 ;
  • R 1 and R 2 together form a bivalent radical of formula
  • R 5 is selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • One embodiment of the present invention relates to the compounds of formula (XI) or ( ⁇ ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • R 2 is hydrogen or Ci- 6 alkyl
  • R 1 and R 2 together form the bivalent radical of formula (a-3);
  • R 7 and R 8 are each, independently, hydrogen or Ci- 6 alkyl
  • R 9 is Ci -6 alkoxy
  • Ar 1 and Ar 3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci-6alkyl, OH, and Ci-6alkyloxy;
  • Het 2 is pyridinyl
  • Het 3 is thienyl.
  • interesting group of compounds are those compounds of formula (I), (F), (II), or (IF) wherein
  • substituents for example 1, 2, 3 or 4 substituents
  • R 2 is hydrogen, methyl, or ethyl
  • R 1 and R 2 together form the bivalent radical of formula (a-3);
  • R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, N0 2 , or H 2 , methyloxy, - HCOCH 3 , - HCOCH 2 phenyl, - HCOphenyl, - HCOpyridinyl, or - HCOCH 2 thienyl; and
  • each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy.
  • One embodiment of the present invention relates to the compounds of formula (I), ( ⁇ ), (II), or ( ⁇ ), as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • R 1 is hydrogen, Ci-i 2 alkyl, phenylmethyl, phenylethyl, or phenyl;
  • R 2 is hydrogen
  • R 5 is hydrogen, methyloxy, - HCOCH 2 phenyl, -NHCOphenyl, -NHCOpyridinyl, or -NHCOCH 2 thienyl;
  • each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy.
  • One embodiment of the present invention relates to the compounds of formula (I), ( ⁇ ), (X), ( ⁇ '), (II), (IF), (XI), or (XT), as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • R 2 is hydrogen or Ci- 6 alkyl
  • R 3 , R 4 , R 5 and R 6 are each hydrogen, halo, N0 2 or -NR 7 R 8 ;
  • R 7 andR 8 are each Ci -6 alkyl
  • R 9 is Ci-6 alkoxy
  • Ar 1 and Ar 3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci- 6 alkyl, OH, or Ci- 6 alkyloxy.
  • R 2 is hydrogen or ethyl
  • R 3 , R 4 , R 5 and R 6 are each hydrogen, halo, N0 2 or H 2 ;
  • R 9 is ethyl oxy
  • each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, or methyloxy.
  • R 1 is hydrogen
  • R 2 is halophenylmethyl
  • R 5 is hydrogen or N0 2 .
  • Preferred compounds are those compounds of formula (I), (F), (II), or (IF) wherein
  • R 2 is hydrogen or Ci -6 alkyl;
  • R 1 and R 2 together form the bivalent radical of formula (a-3);
  • R 3 , R 4 , R 5 and R 6 are each hydrogen, N0 2 or - R 7 R 8 ;
  • R 7 and R 8 are each Ci -6 alkyl;
  • R 9 is Ci -6 alkoxy;
  • Ar 1 and Ar 3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci- 6 alkyl, OH, or Ci- 6 alkyloxy.
  • the most preferred compounds are selected from:
  • One embodiment of the present invention relates to a compound of formula (I),
  • R 1 and R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 ;
  • R 1 and R 2 are each independently selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each R 9 is hydrogen; OH; Ci- 6 alkyl optionally substituted with halo, -OH, -SH, -CN, -N0 2 ,
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1 , 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and
  • the invention relates the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, for use as a medicine, more particularly as antiviral compounds, even more particularly as compounds active against HIV.
  • the invention also relates to the use of the compounds of the formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, for the manufacture of a medicament or as a pharmaceutically active ingredient, especially as a virus replication inhibitor, preferably a retrovirus replication inhibitor, for instance for the manufacture of a medicament or pharmaceutical composition having antiviral activity for the prevention and/or treatment of viral, preferably retroviral, infections in humans and mammals.
  • a virus replication inhibitor preferably a retrovirus replication inhibitor
  • the present invention further relates to a method of treatment of a viral infection, preferably a retroviral infection in a mammal, including a human, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, as an active ingredient, preferably in admixture with at least a pharmaceutically acceptable carrier.
  • a viral infection preferably a retroviral infection in a mammal, including a human
  • the invention further relates to methods for the preparation of compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof.
  • the invention also relates to pharmaceutical compositions comprising the compounds of the invention according to formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, in admixture with at least a pharmaceutically acceptable carrier, the active ingredient preferably being in a concentration range of about 0.1 to 100% by weight, and to the use of these derivatives namely as drugs useful for the treatment of subjects suffering from HIV infection.
  • the invention further relates to the use of a composition
  • a composition comprising (a) one or more derivatives of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, and (b) one or more viral inhibitors as biologically active agents in respective proportions such as to provide a synergistic effect against a viral infection, preferably a lentiviral infection and more preferably a retroviral infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in retroviral infection therapy.
  • the retroviral enzyme inhibitors used as a therapeutically active ingredients (b) may belong to categories already known in the art and include, among others,
  • HIV integrase inhibitors such as for instance, elvitegravir and raltegravir,
  • nucleoside, non-nucleoside and nucleotide reverse transcriptase inhibitors such as for instance, dideoxyadenosine, stavudine, zalcitabine, zidovudine, lamivudine, didanosine, nevirapine, delavirdine, efavirenz, tenofovir, foscamet sodium and the like,
  • HIV protease inhibitors such as for instance saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and the like,
  • the present invention also relates to a pharmaceutical composition according to the invention further comprising a therapeutically effective amount of an HIV/ AIDS treatment agent selected from the group consisting of: an HIV/ AIDS antiviral agent; an anti-infective agent; and an immunomodulator.
  • an HIV/ AIDS treatment agent selected from the group consisting of: an HIV/ AIDS antiviral agent; an anti-infective agent; and an immunomodulator.
  • the invention also relates to a process for preparing a pharmaceutical composition of the invention wherein a therapeutically effective amount of a compound of formula (I) is intimately mixed with a pharmaceutically acceptable carrier.
  • the invention also relates to a process for preparing a pharmaceutical composition of the invention wherein a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of an HIV/AIDS treatment agent as defined herein are intimately mixed with a pharmaceutically acceptable carrier
  • the invention also relates to the compounds of the invention according to formula (I) being used for inhibition of the proliferation of other viruses than HIV, preferably the inhibition of viral activity of hepatitis B virus, hepatitis C virus or flaviviruses, with in particular yellow fever virus or Dengue virus. More generally, the invention relates to the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, being useful as agents having biological activity (preferably antiviral or antitumoral activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, more in particular having antiviral activity, yet more in particular against HIV.
  • a further aspect of the invention provides for a method of treatment or prevention of a viral infection in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the compounds of the present invention can act as inhibitors of HIV- 1 integrase, strand transfer inhibitors and/or 3 'processing inhibitors. Accordingly the present invention includes a method of inhibiting HIV- 1 integrase in a subject in need of such inhibition which comprises administering to the subject an effective amount of a compound of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof.
  • the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
  • Ci- 6 alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • Representative examples of Ci- 6 alkyl include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.
  • C 7- nalkyr refers to a straight or branched chain hydrocarbon containing from 7 to 11 carbon atoms.
  • C 7- nalkyl include, but are not limited to 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undyl, and the like.
  • Ci-nalkyl refers to a straight or branched chain hydrocarbon containing from 1 to 12 carbon atoms and includes but is not limited to Ci- 6 alkyl, the examples given under these definitions, include, but are not limited to, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undyl, and the like.
  • C2- 6 alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbons, and containing at least one carbon-carbon double bond, formed structurally, for example, by the replacement of two hydrogens.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, and the like.
  • C 2 - 6 alkynyl refers to a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms, and containing at least one carbon- carbon triple bond.
  • alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
  • C3-iocycloalkyl means a monocyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkylene refers to a cyclic hydrocarbon radical of 3-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane; i.e.
  • C 3- iocycloalkenyl refers to a cyclic hydrocarbon having 3 to 10 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp2 double bond.
  • monocyclic heterocyclic ring system refers to any 5 or 6 member ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S.
  • the 5 member ring has from 0 to 2 double bonds, and the 6 member ring has from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,
  • bicyclic heterocyclic ring system refers to any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxane, 1,3- benzodioxane, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like.
  • C 1-6 alkoxy refers to substituents wherein a Ci -6 alkyl radical Ar or Het radical (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
  • halo means any atom selected from the group consisting of fluorine (F), chlorine (CI), bromine (Br) and iodine (I).
  • Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
  • the compounds of the invention optionally are bound covalently to an insoluble matrix and used for affinity chromatography separations, depending on the nature of the groups of the compounds, for example compounds with aryl are useful in hydrophobic affinity separations.
  • the present invention encompasses compounds of formula (I) or ( ⁇ ), wherein
  • R 1 and R 2 are each independently selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 are each independently selected from:
  • C 3 -iocycloalkyl or C 3 -iocycloalkenyl which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci -6 alkyl, -OH, and Ar 3 ;
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , and R 6 are each independently selected from:
  • R 5 is selected from: hydrogen; halo; -OH; -SH; -CN; -N0 2 ; -NR 7 R 8 ; -OCF 3 ; CF 3 ;
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents independently selected from halo, Ci-6alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ; preferably each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 , is independently phenyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl,
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and - CF 3 ; preferably each of Het 1 , Het 2 , Het 3 , and Het 4 , is independently a mono- or bicyclic heterocyclic ring system containing 1 or 2 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 ,
  • Another embodiment of the present invention is a process for preparing compounds of formula (I). They can be readily prepared according to the following reaction scheme and examples, or modifications thereof, using readily available starting materials and reagents. In the reactions below, it is possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction scheme and examples.
  • Bn benzyl
  • BOP (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
  • DMSO dimethyl sulfoxide
  • ESI-MS electrospray ionization mass spectrometry
  • EtOAc ethyl acetate
  • h hour(s)
  • LDA lithium diisopropyl amide
  • MeOH methanol
  • MM 4- methylmorpholine
  • MR nuclear magnetic resonance
  • rt room temperature
  • THF tetrahydrofuran.
  • the present invention encompasses a process for making a compound of formula (I) wherein
  • the 4-carboxamido-2-hydroxyisoquinoline-l,3(2H,4H)-diones of formula (I) can be prepared by reacting an intermediate of formula (II) with a boron halide (BX 3 ) such as for example boron tribromide or boron trichloride at room or low temperature.
  • BX 3 boron halide
  • Use of boron tribromide allows for a complete deprotection of the intermediates of formula (II) (deprotection of the benzyloxy function as well as of the alkoxy functions in aromatic rings) whereas boron trichloride only affects the benzyloxy function. Deprotection may also be performed by catalytic hydrogenation on Pd/C 5%.
  • the 4-carboxamido-2-hydroxyisoquinoline-l,3(2H,4H)-diones of formula (I) wherein R 3 , R 4 and R 6 are hydrogen and R 5 is aminated herein referred to as compounds of formula (I- b) can be prepared by catalytic hydrogenation on Pd/C of an intermediate of formula (Il-a).
  • the basic treatment of an intermediate of formula (IV) does not yield an homophthalic acid derivative but a cyclized 2-benzyloxy-4-methoxycarbonylisoquinoline- l,3(2H,4H)-dione of formula (III).
  • the intermediates of formula (III) can be prepared by cyclization of an intermediate of formula (IV). This cyclization can be performed quantitatively using 2.5 M potassium hydroxide in a suitable solvent such as aqueous methanol, at room temperature for 5 min.
  • he benzyloxycarboxamide of formula (IV) can be prepared by coupling the intermediate of formula (V) with O-benzylhydroxylamine, after activation with the BOP reagent and N- methylmorpholine.
  • the coupling can be performed in a suitable solvent such as CH 2 CI 2 .
  • ⁇ he benzyloxycarboxamide of formula (IV) wherein R 3 , R 4 and R 6 are hydrogen and R 5 is a nitro function herein referred to as compounds of formula (IV-a) can be prepared by coupling the intermediate of formula (VIII), wherein R 3 , R 4 and R 6 are hydrogen and R 5 is a nitro function with O-benzylhydroxylamine by refluxing in toluene using a Dean Stark apparatus.
  • the methyl 2-(2-methoxycarbonylphenyl) malonate monoester of formula (V) can be prepared by reacting the anion of the homophthalic diester of formula (VI) with carbon dioxide. This reaction is possible after treatment of the homophthalic diester of formula
  • reaction can be performed in a suitable solvent such as for example tetrahydrofuran.
  • the triester of formula (VIII) can be prepared by aromatic nucleophilic substitution of intermediate (IX) with methylmalonate in the presence of NaH and under reflux in a suitable solvent such as, for example, THF.
  • he methyl diester of formula (VI) can be prepared by reacting the commercially available homophthalic acid of formula (VII) with thionyl chloride in a suitable solvent such as, for example, methanol.
  • the intermediate of formula (IX) can be prepared by esterifi cation of 2-fluoro-5- nitrobenzoic acid with thionyl chloride in a suitable solvent such as, for example, methanol.
  • 2-fluoro-5-nitrobenzoic acid can be prepared by nitrating the commercial 2- fluorobenzoic acid in a mixture of sulfuric acid and nitric acid.
  • the present invention also encompasses an intermediate of formula (II) wherein the substituents R 1 , R 2 , R 3 , 4 , R 5 and R 6 , are as defined hereinabove.
  • the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state, any and all protonated forms of the compounds are intended to fall within the scope of the invention.
  • the resulting compounds may be optionally converted into a pharmaceutically acceptable salt or vice versa according to the methods known by the skilled in the art. Further, the resulting compounds may be converted into each other following art-known functional group transformation reactions. For example, amino groups may be N-alkylated, nitro groups reduced to amino groups, a halo atom may be exchanged for another halo.
  • salts as used herein means the therapeutically active non-toxic salt forms which the compounds according to the formulas of the application like (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + , Ca 2+ and Mg 2+ . Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges.
  • the net charge of the compounds of the invention may be either positive or negative.
  • Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion.
  • the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li + , Na + , and K + . A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups.
  • acids include, for instance, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the salts of the parental compounds with one or more amino acids especially the naturally-occurring amino acids found as protein components.
  • the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the compounds of the invention also include physiologically acceptable salts thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NXf (wherein X is Cl-C4alkyl).
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NXf (wherein X is Cl-C4alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X typically is independently selected from H or a Ci -4 alkyl group).
  • a suitable cation such as Na + and NX 4 + (wherein X typically is independently selected from H or a Ci -4 alkyl group).
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%) and more preferably at least 98%>.
  • isomers as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, may possess, but not including position isomers.
  • the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
  • the compounds of the present invention may also occur as tautomers thereof, such as the following tautomer ( ⁇ ) of a compound of formula (I):
  • the present invention includes all tautomers of 2-hydroxyisoquinoline- l,3(2H,4H)-dione compounds of Formula I (or ⁇ ), as well as the tautomers of its intermediates of Formula II (or ⁇ ), both singly and in mixtures.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds according to the formulas of the application like (I) may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or transconfiguration.
  • stereoisomerically pure or “chirally pure” relates to compounds having a stereoisomeric excess of at least about 80% (i.e. at least 90% of one isomer and at most 10%) of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%.
  • enantiomerically pure and “diastereomerically pure” should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.
  • stereoisomers Separation of stereoisomers is accomplished by standard methods known to those in the art.
  • One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113 :(3) 283-302).
  • Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compounds of the invention.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers can be separated and isolated by normal- and reverse- phase chromatography following methods for separation of atropisomeric naphthyl- isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase.
  • Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives.
  • Commercially available polysaccharide based chiral stationary phases are ChiralCelTM CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP(+) and OT(+).
  • Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.
  • the active ingredients of the compound(s) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra- arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of viral infections in humans and other mammals preferably is a retroviral enzyme inhibiting amount. More preferably, it is a retroviral replication inhibiting amount or a retroviral enzyme inhibiting amount of the derivative(s) of formula (I) as defined herein corresponds to an amount which ensures a plasma level of between ⁇ g/ml and 100 mg/ml, optionally of 10 mg/ml. This can be achieved by administration of a dosage of in the range of 0.001 mg to 2000 mg, in particular 0.01 mg to 1000 mg, more in particular O.
  • the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • the present invention further relates to a method for preventing or treating a viral infection in a subject or patient by administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I).
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of viral infections in humans and other mammals preferably is HIV protein/enzyme inhibiting amount. More preferably, it is a HIV replication inhibiting amount or a HIV enzyme inhibiting amount of the derivative(s) of the formulas as defined herein.
  • Suitable dosage is usually in the range of 0.001 mg to 20 mg, in particular 0.01 mg to 5 mg, more in particular O. lmg to 1 mg per day per kg bodyweight for humans.
  • the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27 ' . Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as CI) defined by the following equation:
  • ED x is the dose of the first or respectively second drug used alone (la, 2a), or in combination with the second or respectively first drug (lc, 2c), which is needed to produce a given effect.
  • Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against viral infection may also be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC 50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC).
  • FIC fractional inhibitory concentration
  • the combination When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FIC X + FIC y ) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as sub synergistic, and when it is lower than 0.5, the combination is defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as sub antagonistic and, when it is higher than 2.0, the combination is defined as antagonistic.
  • This principle may be applied to a combination of different antiviral drugs of the invention or to a combination of the antiviral drugs of the invention with other drugs that exhibit anti-HIV activity.
  • Suitable anti-viral agents for inclusion into the synergistic antiviral compositions or combined preparations of this invention include practically all known anti-HIV compounds known at this moment such as nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors.
  • the pharmaceutical composition or combined preparation with synergistic activity against viral infection may contain the compounds of the present invention over a broad content range depending on the contemplated use and the expected effect of the preparation.
  • the content of the compounds of formula (I) of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.
  • the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of HIV infections.
  • the invention therefore relates to the use of a composition comprising:
  • the active ingredients (f) and (g) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the combined preparation of (f) and (g), especially for the treatment of viral infections in humans and other mammals particularly is a HIV enzyme inhibiting amount. More particularly, it is a HIV replication inhibiting amount of derivative (f) and a HIV enzyme inhibiting amount of inhibitor (g). Still more particularly when the said HIV enzyme inhibitor (g) is a reverse transcriptase inhibitor, its effective amount is a reverse transcriptase inhibiting amount. When the said HIV enzyme inhibitor (g) is a protease inhibitor, its effective amount is a protease inhibiting amount. When the said HIV enzyme inhibitor (g) is an integrase inhibitor, its effective amount is a integrase inhibiting amount.
  • the invention also relates to the compounds of the invention, for inhibition of the proliferation of other viruses than HIV, particularly for the inhibition of other retroviruses and lentiviruses and also for the inhibition of flaviviruses or picornaviruses such as BVDV, HCV, HBV or Coxsackie virus, with in particular yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus.
  • Other viruses may be inhibited such as HSV, CMV and Sars-virus.
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. More generally, the invention relates to the compounds of formula (I) being useful as agents having biological activity (particularly antiviral activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non- medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • the compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the term "pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
  • Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface- active agents may also be prepared by inicronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
  • Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties.
  • Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface- active agents.
  • Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C 10 - 22 ), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil.
  • Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates.
  • Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts.
  • alkaline or alkaline-earth metal salts unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulph
  • Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
  • alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product.
  • phosphates e.g. salts of phosphoric acid ester and an adduct of p- nonylphenol with ethylene and/or propylene oxide, or phospholipids.
  • Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.
  • cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.
  • Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol.
  • non-ionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups.
  • Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
  • non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, poly ethyleneglycol and octylphenoxypolyethoxyethanol.
  • Fatty acid esters of polyethylene sorbitan such as polyoxyethylene sorbitan trioleate
  • glycerol glycerol
  • sorbitan sucrose and pentaerythritol are also suitable non-ionic surfactants.
  • Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy- lower alkyl radicals.
  • C8C22 alkyl radical e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like
  • Compounds of the invention and their physiologically acceptable salts may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration may vary with for example the condition of the recipient.
  • the formulations both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients.
  • the carrier(s) optimally are "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g.
  • the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7%) w/w, etc), preferably 0.2 to 15%> w/w and most preferably 0.5 to 10%> w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30%> w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
  • Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like.
  • the rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers.
  • Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on.
  • the pharmaceutical composition may require protective coatings.
  • Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
  • each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
  • Al-b intermediate 2 3-Methoxy-2 -(methoxycarbonyl)phenyl1-3-oxopropanoic acid
  • the mixture was acidified with 2.0 M HCl and then extracted with CHC1 3 .
  • the combined organic extracts were extracted with 10% Na 2 C0 3 .
  • the basic extracts were made acidic by the careful addition of 2.0 M HCl and the product was extracted into CHCI 3 (3 x 100 mL).
  • the combined CHCI 3 extracts were dried over Na 2 S0 4 .
  • the solvent was removed under reduced pressure to give an oily residue intermediate 2 which crystallized on cooling.
  • Al-d intermediate 4 Methyl 2-(benzyloxy)-L3-dioxo-L2,3,4-tetrahydroisoquinoline
  • Al-e intermediate 5 N-(3-Chloropropyl)-2-benzyloxy-l,3-dioxo-l,2,3,4
  • A2-e intermediate 6 N-Propyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline -4-carboxamide
  • A3-e intermediate 7 N-Butyl-2-benzyloxy-1.3-dioxo-1.2.3.4-tetrahvdroisoquinoline-4- carboxamide
  • A4-e intermediate 8 N-Pentyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A6-e intermediate 10 N-Nonyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A7-e intermediate 11 N-Isopropyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-
  • A8-e intermediate 12 N-7ert-butyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline
  • A9-e intermediate 13 N-Cvclopentyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • AlO-e intermediate 14 N-Allyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A12-e intermediate 16 N-(3-Fluorophenyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A13-e intermediate 17 N-(3-Chloro-4-methoxyphenyl)-2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
  • A14-e intermediate 18 N-(4-Fluorobenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A16-e intermediate 20 N-(2,4-Dimethoxybenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4 tetrahydroisoquinoline-4-carboxamide
  • A18-e intermediate 21 N-(3,4-Dimethoxybenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A20-e intermediate 22 N-((Thiophen-2-vnmethylV2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
  • A21-e intermediate 23 N-r2-(3.4-Dimethoxyphenyl)ethyl1-2-benzyloxy-1.3-dioxo- 1.2.3.4-tetrahydroisoquinoline-4-carboxamide
  • A23-e intermediate 24 (2-Benzylox -l -dioxoisoquinolin-4-yl)(piperidin-l-yl)methanone
  • A24-e intermediate 25 N,N-Diethyl-2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
  • A25-e intermediate 26 N-Butyl-N-methyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A26-e intermediate 27 N-Heptyl-2-benzyloxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A27-e intermediate 28 N-Octyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A29-e intermediate 30 /V-Phenyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A30-e intermediate 31 N-Methyl-N-phenyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A31-e intermediate 32 N-(4-Fluorophenyl)-2-benzyloxy-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A32-e intermediate 33 N-Benzyl-2-benzyloxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A33-e intermediate 34 N-4-Methoxybenzyl-2-benzyloxy-l,3-dioxo-l,2,3,4
  • A34-e intermediate 35 N-(4-Fluorophenethyl)-2-benzyloxy-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A35-a intermediate 36 2-Fluoro- -nitrobenzoic acid
  • Nitric acid 50% solution, 5.0 mL was carefully added to a cooled solution of concentrate sulfuric acid (5.0 mL) so that the temperature did not exceed 10 °C.
  • 2-f uorobenzoic acid 2.1 g, 15.0 mmol was added by small portions while maintaining temperature between 15 and 25 °C. The mixture was stirred for 2 h at room temperature. Ice was added and the precipitate was filtered. After drying at room temperature, intermediate 36 was obtained as a white powder.
  • A35-c intermediate 38 Methyl 2- ⁇ -dimethoxy-L3-dioxopropan-2-yl
  • A35-d intermediate 39 Methyl 2- ⁇ l-r(benzyloxy)amino1-3-methoxy-l -dioxopropan-2- yl I - 5 -nitrob enzoate
  • A35-f intermediate 41 N-(4-Fluorobenzyl)-2-benzyloxy-3-hvdroxy-7-nitro-l-oxo-L2- dihydro- isoquinoline-4-carboxamide
  • A37-a intermediate 42 N-Hexyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
  • A38-a intermediate 43 N-Phenyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-l,2- dihydroisoquinoline-4-carboxamide
  • A40-a intermediate 45 N-Benzyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
  • A41-a intermediate 46 N-(4-Methoxybenzyl)-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
  • A43-a intermediate 48 Methyl 5-amino-2- ⁇ L3-dimethoxy-L3-dioxopropan-2-yl
  • A43-b intermediate 49 Methyl 5-acetamido-2- ⁇ l,3-dimethoxy-l,3-dioxopropan-2- yllbenzoate
  • Acetyl chloride (1.1 mL, 16.0 mmol) was added to a solution of intermediate 48 (3.0 g, 10.7 mmol) in dichloromethane (50 mL). After stirring for 4 h at room temperature, the solution was washed with aqueous 1.0 M HCl. The organic phase was dried over Na 2 S0 4 .
  • A43-c intermediate 50 Methyl 5-acetamido-2- ⁇ 1 (benzyloxy)amino1-3-methoxy-l,3- dioxopropan-2-yl Ibenzoate
  • A43-d intermediate 51 Methyl 7-acetamido-2-(benzyloxy)-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxylate
  • A44-b intermediate 54 Methyl 2- ⁇ l-r(benzyloxy)amino1-3-methoxy-1.3-dioxopropan-2- yl
  • A44-c intermediate 55 Methyl 2-(benzyloxy)- 7-phenylacetamido -1.3-dioxo-l.2.3.4- tetrahydroisoquinoline-4-carboxylate
  • A44-d intermediate 56 N-(4-fluorobenzyl)-2-(benzyloxy)-l,3-dioxo-7-phenylacetamido- 1,2,3, 4-tetrahydroisoquinoline-4-carboxamide
  • A45-b intermediate 58 Methyl 5-benzamido-2- ⁇ l-r(benzyloxy)amino1-3-methoxy-L3- dioxopropan-2-yl Ibenzoate
  • A45-d intermediate 60 N-(4-fluorobenzyl)-7-benzamido-2-(benzyloxy)-L3-dioxo-L2,3,4- tetrah droiso uinoline-4-carboxamide
  • A46-b intermediate 62 Methyl 2- ⁇ l-r(benzyloxy)aminol-3-methoxy-1.3-dioxopropan-2- yll-5-picolinamidobenzoate
  • A46-d intermediate 64 N-(4-fluorobenzyl)- 2-(benzyloxy)-l,3-dioxo-7-picolinamido-
  • A47a intermediate 65 Methyl 2- ⁇ l,3-dimethoxy-l,3-dioxopropan-2-yl
  • A47-b intermediate 66 Methyl 2- ⁇ l-r(benzyloxy)amino1-3-methoxy-L3-dioxopropan-2- yl
  • A47-d intermediate 68 N-(4-fluorobenzyl)- 2-(benzyloxy)-l,3-dioxo-7-(2-(thiophen-2- yl)acetamido)-l,2,3,4-tetrahvdroisoquinoline-4-carboxamide
  • A48-b intermediate 70 Methyl 2- ⁇ l-r(benzyloxy)amino1 -3-methoxy-L3-dioxopropan-2- yll-5-chlorobenzoate
  • A48-d intermediate 72 N-(4-fluorobenzyl)- 2-(benzyloxy -7-chloro-l,3-dioxo-l,2,3,4- tetrah droiso uinoline-4-carboxamide
  • A49-b intermediate 74 Methyl 2- ⁇ l-r(benzyloxy)amino1 -3-methoxy-l,3-dioxopropan-2- yl
  • A49-c intermediate 75 Methyl 2-(benzyloxyV7-bromo-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxylate
  • A49-d intermediate 76 N-(4-fluorobenzyl)- 2-(benzyloxy)-7-bromo-L3-dioxo-L2,3,4- tetrah droiso uinoline-4-carboxamide
  • A50-b intermediate 78 Methyl 2- ⁇ 1 (benzyloxy)amino1-3-methoxy-L3-dioxopropan-2- yll-5 -fluorob enzoate
  • A50-C intermediate 79 Methyl 2-(benzyloxy)-7-fruoro-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxylate
  • A50-d intermediate 80 N-(4-fluorobenzyl)- 2-(benzyloxy)-7-fruoro-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
  • Fuming nitric acid (20.0 mL) was cooled to 0 °C and 6.25 g of homophthalic acid (35.0 mmol) was carefully added while maintaining temperature below 22 °C. After 2 h, ice (20 g) was added. The precipitate was filtered and washed several times with distilled water.
  • A51e intermediate 85 Methyl 2- ⁇ 1 (benzyloxy)amino1 -3-methoxy-L3-dioxopropan-2- yll-5 -methoxyb enzoate
  • A51-f intermediate 86 Methyl 2-(benzyloxy)-7-methoxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxylate

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Abstract

La présente invention concerne des composés et des compositions agissant en tant qu'inhibiteurs d'intégrase du VIH. Le composé de l'invention est de formule (I), ou un tautomère (I') de celui-ci, ou un sel pharmaceutiquement acceptable, ou un solvate dudit composé ou tautomère de celui-ci, R1, R2, R3, R4, R5 et R6 ayant les définitions décrites.
PCT/EP2011/073480 2010-12-22 2011-12-20 2 -hydroxyisoquinoline- 1, 3 ( 2h, 4h) - diones et composés associés servant d'inhibiteurs de la réplication du vih WO2012085003A1 (fr)

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WO2015112902A3 (fr) * 2014-01-23 2015-11-05 Sova Pharmaceuticals, Inc. Inhibiteurs de cystathionine- (gamma)-lyase (cse) pour le traitement de la douleur
CN105153030A (zh) * 2015-10-14 2015-12-16 吉首大学 全氟基团取代的异喹啉-1,3(2h,4h)-二酮及其制法和用途
WO2017097870A1 (fr) * 2015-12-11 2017-06-15 Bayer Cropscience Aktiengesellschaft Amides d'acide malonique substitués utilisés comme insecticides
WO2017161133A1 (fr) * 2016-03-16 2017-09-21 Saint Louis University Inhibiteurs de réplication du vhb de type n-hydroxyisoquinolinedione
CN107286092A (zh) * 2017-05-24 2017-10-24 浙江大学 甲氧基苯甲酰胺和重氮酸酯经碳‑氢官能化制备异喹啉二酮的方法
US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10117871B2 (en) 2015-03-03 2018-11-06 Regents Of The University Of Minnesota 3-hydroxypyrimidine-2,4-dione-5-carboxamides as potent inhibitors of HIV
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10358447B2 (en) 2017-12-04 2019-07-23 Arbutus Biopharma Corporation Substituted 2-N-hydroxy-1,3-dioxo-1,2,3,4-tetrahydronaphthyridines, and methods of making and using same
US10550084B2 (en) 2017-12-04 2020-02-04 Arbutus Biopharma Corporation Substituted 1-hydroxy-pyridin-2(1H)-ones, and methods of making and using same
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3726875A (en) 1967-06-28 1973-04-10 Pfizer 1,3(2h,4h)-dioxoisoquinoline-4-carboxylate esters and process therefor
US3886163A (en) 1967-06-28 1975-05-27 Pfizer 1,3(2H,4H)-dioxoisoquinoline-4-carboxamides
WO1996015111A1 (fr) 1994-11-15 1996-05-23 Regents Of The University Of Minnesota Procede et intermediaires de la synthese de korupensamines
WO2004000472A1 (fr) 2002-06-19 2003-12-31 Solystic Procede de traitement d'objets postaux utilisant la synthese vocale
WO2007007578A1 (fr) 2005-07-13 2007-01-18 Kuraray Co., Ltd Dispersion liquide aqueuse, procédé pour produire celle-ci, une composition, un adhésif et un matériau de revêtement

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3726875A (en) 1967-06-28 1973-04-10 Pfizer 1,3(2h,4h)-dioxoisoquinoline-4-carboxylate esters and process therefor
US3886163A (en) 1967-06-28 1975-05-27 Pfizer 1,3(2H,4H)-dioxoisoquinoline-4-carboxamides
WO1996015111A1 (fr) 1994-11-15 1996-05-23 Regents Of The University Of Minnesota Procede et intermediaires de la synthese de korupensamines
WO2004000472A1 (fr) 2002-06-19 2003-12-31 Solystic Procede de traitement d'objets postaux utilisant la synthese vocale
WO2007007578A1 (fr) 2005-07-13 2007-01-18 Kuraray Co., Ltd Dispersion liquide aqueuse, procédé pour produire celle-ci, une composition, un adhésif et un matériau de revêtement

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
"Chiral Liquid Chromatography", 1989, CHAPMAN AND HALL
"Encyclopaedia of Surfactants", 1981, CHEMICAL PUBLISHING CO.
"Handbook of Pharmaceutical Excipients", 1986
"McCutcheon's Detergents and Emulsifiers Annual", 1981, MC PUBLISHING CROP.
"Tensid-Taschenbucw", 1981, HANSER VERLAG
BABA ET AL., ANTIMICROB. AGENTS CHEMOTHER, vol. 25, 1984, pages 515 - 517
BILLAMBOZ ET AL., EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, 27 November 2010 (2010-11-27), pages 535 - 546
BILLAMBOZ ET AL., J. MED. CHEM., vol. 24, 2008, pages 7717
BILLAMBOZ ET AL., J. MED. CHEM., vol. 51, 2008, pages 7717 - 7730
BILLAMBOZ M ET AL: "2-Hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: Influence of the alkylation of position 4", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 2011 ELSEVIER MASSON SAS FRA LNKD- DOI:10.1016/J.EJMECH.2010.11.033, vol. 46, no. 2, 27 November 2010 (2010-11-27), pages 535 - 546, XP002636355, ISSN: 0223-5234 *
BILLAMBOZ M ET AL: "Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain", JOURNAL OF MEDICINAL CHEMISTRY 20081225 US LNKD- DOI:10.1021/JM8007085, vol. 51, no. 24, 25 December 2008 (2008-12-25), pages 7717 - 7730, XP002636354, ISSN: 0022-2623 *
CHOU ET AL., ADV. ENZYME REG., vol. 22, 1984, pages 27
CHRIST, F.; BUSSCHOTS, K.; HENDRIX, J.; ENGELBORGHS, Y.; DEBYSER, Z.: "Integrase", 2009, article "Assays for the evaluation of HIV-1 integrase enzymatic activity, DNA-binding and co-factor interaction"
DEBYSER, Z. ET AL.: "Methods in Molecular Biology", 2001, HUMANA PRESS INC., article "Assays for the evaluation of HIV-1 integrase inhibitors", pages: 139 - 155
E. L. ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW HILL
ELIEL, E.; WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS
ELION ET AL., J BIOL. CHEM., vol. 208, 1954, pages 477 - 488
HWANG, Y.; D. RHODES; F. BUSHMAN: "Rapid microtiter assays for poxvirus topoisomerase, mammalian type IB topoisomerase and HIV-1 integrase: application to inhibitor isolation", NUCLEIC ACIDS RES., vol. 28, 2000, pages 4884 - 4892
JACOB III., J. ORG. CHEM., vol. 47, 1982, pages 4165
LAZER ET AL., J MED. CHEM., vol. 22, 1979, pages 845
LOCHMULLER, C. H., J. CHROMATOGR., vol. 113, no. 3, 1975, pages 283 - 302
OKAMOTO: "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. OF CHROMATOGR., vol. 513, 1990, pages 375 - 378, XP026488183, DOI: doi:10.1016/S0021-9673(01)89459-0
PAUWELS, R.; J. BALZARINI; M. BABA; R. SNOECK; D. SCHOL; P. HERDEWIJN; J. DESMYTER; E. DE CLERCQ: "Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds", J VIROL METHODS, vol. 20, 1988, pages 309 - 21, XP024105606, DOI: doi:10.1016/0166-0934(88)90134-6

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