WO2004096774A1 - Derives d'acyle isoindoline et d'acyle isoquinoline utilises comme agents antiviraux - Google Patents

Derives d'acyle isoindoline et d'acyle isoquinoline utilises comme agents antiviraux Download PDF

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WO2004096774A1
WO2004096774A1 PCT/EP2004/004660 EP2004004660W WO2004096774A1 WO 2004096774 A1 WO2004096774 A1 WO 2004096774A1 EP 2004004660 W EP2004004660 W EP 2004004660W WO 2004096774 A1 WO2004096774 A1 WO 2004096774A1
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Prior art keywords
methoxy
formula
butylbenzoyl
tetrahydroisoquinoline
carboxylic acid
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PCT/EP2004/004660
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English (en)
Inventor
Gianpaolo Bravi
John Andrew Corfield
David Haigh
Victoria Lucy Helen Lovegrove
Pritom Shah
Martin John Slater
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Glaxo Group Limited
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Priority claimed from GB0310069A external-priority patent/GB0310069D0/en
Priority claimed from GB0310065A external-priority patent/GB0310065D0/en
Priority claimed from GB0310067A external-priority patent/GB0310067D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2004096774A1 publication Critical patent/WO2004096774A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel acyl isoindoline derivatives and novel acyl tetrahydroisoquinoline derivatives useful as anti-viral agents. Specifically, the present invention involves novel HCV inhibitors.
  • HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K.L. (1997) Hepatology 26 (suppl 1): 71S-77S).
  • hepatitis C virus HCV
  • NNBH non-B hepatitis
  • flaviviruses e.g. yellow fever virus and Dengue virus types 1-4
  • pestiviruses e.g.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA- A Publication of the RNA Society. 1(5): 526-537, 1995 Jul.). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931- 960; Raven Press, N.Y.).
  • 3' NTR which roughly consists of three regions: an - 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261 ).
  • the 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • the NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1b isolates) and inter-typically (-85% aa identity between genotype 1a and 1b isolates).
  • the essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al.. (2000) Journal of Virology, 74(4): 2046-2051).
  • inhibition of NS5B RdRp activity is predicted to cure HCV infection.
  • the present invention involves novel acyl isoindoline compounds and novel acyl tetrahydroisoquinoline compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • the present invention provides compounds of Formula (I)
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C ⁇ _ 6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • n 0 or 1 ;
  • R 1 represents C(O)R H and R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • R 1 represents C(O)R H ;
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl; and
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; or
  • R 1 and R 2 independently represent hydrogen, C-
  • R 7 represents C(O)R H
  • R 8 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R A represents hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R c independently represent hydrogen, C 1-6 alkyl, aryl or heteroaryl; or R B and R c together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R D is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R E represents hydrogen or C 1-6 alkyl
  • R F and R G are independently selected from the group consisting of hydrogen, C ⁇ -6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R F and R G together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R H represents hydroxy or NR B BRp'C.
  • R H is hydroxy, which is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than terf-butyl.
  • One embodiment of the invention provides compounds of Formula (I) represented by Formula (la)
  • R H represents hydroxy or NR B R C ;
  • R 2 represents C h alky!, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C-i_ 6 alkyl, halo, OR A , C(O)NR B R c , C(O)R D , CO 2 H, CO 2 R D , NR B R G , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF 3 ; R 5 and R 6 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R A represents hydrogen, C ⁇ . 6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R G independently represent hydrogen, C 1-6 alkyl, aryl or heteroaryl; or R B and R c together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R D is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R E represents hydrogen or C 1-6 alkyl
  • R F and R G are independently selected from the group consisting of hydrogen, C ⁇ alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R F and R G together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R H is hydroxy, which is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-b ty ⁇ .
  • Another embodiment of the invention provides compounds of Formula (l) represented by Formula (lb)
  • R H represents hydroxy or NR B R G ;
  • R 1 and R 2 independently represent hydrogen, C h alky!, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C 1-6 alkyl, halo, OR A , C(O)NR B R G , C(O)R D , CO 2 H, CO 2 R D , NR B R G , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R 8 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R A represents hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R c independently represent hydrogen, C- ⁇ -6 alkyl, aryl or heteroaryl; or R B and R c together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R D is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R E represents hydrogen or C 1-6 alkyl
  • R F and R G are independently selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R F and R G together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R H is hydroxy, which isesterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than fe/f-butyl.
  • a further embodiment of the invention provides compounds of Formula (I) represented by Formula (lc)
  • R H represents hydroxy or NR B BRD'C
  • R 2 represents C ⁇ alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R 3 represents aryl or heteroaryl
  • R 4 represents one or two substituents independently selected from hydrogen, C 1-6 alkyl, halo, OR A , C(O)NR B R G , C(O)R D , CO 2 H, CO 2 R D , NR B R G , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , NR E SO 2 R D , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, heteroaryl, aryl, arylalkyl heteroarylalkyl or CF 3 ;
  • R 5 and R 6 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R A represents hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
  • R B and R G independently represent hydrogen, C 1-6 alkyl, aryl or heteroaryl; or R B and R G together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R D is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R represents hydrogen or C 1-6 alkyl
  • R F and R G are independently selected from the group consisting of hydrogen, C 1- ⁇ alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R F and R G together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R H is hydroxy, which is esterified to form -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tert-butyl.
  • a compound of Formula (I) or a physiologically acceptable salt, solvate or ester thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly HCV infection.
  • references herein to therapy and/or treatment includes, but is not limited to prevention, retardation, prophylaxis, therapy and cure of the disease. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection includes treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.
  • a compound of Formula (I) or a physiologically acceptable salt, solvate or ester thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
  • a method for the treatment of a human or animal subject with viral infection, particularly HCV infection comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a physiologically acceptable salt, solvate or ester thereof.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. All of these racemic compounds, enantiomers and diastereoisomers are contemplated to be within the scope of the present invention.
  • R 3 represents phenyl optionally substituted by halo, C 1-6 alkyl or C 1-3 alkoxy; more preferably terf-butylphenyl optionally 3-substituted by halo, C ⁇ -3 alkyl or C 1-3 alkoxy; especially preferred is 4-fe/f-butylphenyl optionally 3-substituted by halo, C 1-3 alkyl or C-,. 3 alkoxy, especially bromo, chloro, methyl or methoxy; most preferably R 3 is 3-methoxy-4- ferf-butylphenyl.
  • R 4 is positioned on the C6 or C7 positions of the tetrahydroisoquinoline ring.
  • R 4 is a single substituent.
  • R 4 represents hydrogen, OH, -C(O)OH, -OCH 3 , OCH 2 Ph, -OCH-1 ,3-thiazol-4-yl, C(O)NH 2 , - CH 2 C(O)NH 2 , 2-furanyl, -OCH 2 -3-pyhdinyl or 4-pyridinyl.
  • R 5 and R 6 represent hydrogen.
  • R 1 preferably represents C(O)OH and R 2 preferably represents CH 2 Ph or 2-methylpropyl.
  • R 1 preferably represents C(O)OH
  • R 2 preferably represents -CH 2 Ph, 2-methylpropyl or 2-methyl-2-propen-1-yl
  • R 7 and R 8 preferably each represent hydrogen
  • R 1 and R 2 preferably each represent hydrogen
  • R 7 preferably represents C(O)OH
  • R 8 preferably represents -CH 2 Ph, 2-methylpropyl or 2-methyl-2-propen-1-yl.
  • R H respresents hydroxy
  • alkyl refers to an optionally substituted hydrocarbon group.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Where the alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group. Preferably, the group is saturated. Preferred alkyl moieties are C 1-4 alkyl.
  • optional substituents include C 1-6 alkyl, halo, OR A , SR A , C(O)NR B R G , C(O)R D , CO 2 H, CO 2 R D , NR B R C , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , SO 2 NR F R G , SO 2 R D , nitro, cyano, oxo, and heterocyclyl.
  • aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl and biaryl groups, all of which may be optionally substituted. Preferred "aryl” moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • Preferred "aryl" substituents are selected from the group consisting of C 1-6 alkyl, halo, OR A , C(O)NR B R G , C(O)R D , CO 2 H, CO 2 R D , NR B R G , NR E C(O)R D , NR E CO 2 R D , NR E C(O)NR F R G , SO 2 NR F R G , SO 2 R D , nitro, cyano, heterocyclyl, and CF 3 .
  • heteroaryl refers to an optionally substituted, 5 or 6 membered, aromatic group comprising one to four heteroatoms selected from N, O and S, with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Preferred “heteroaryl” moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted pyridyl and thiazolyl.
  • Preferred “heteroaryl” substituents are selected from the group consisting of C ⁇ .
  • heterocyclic and heterocyclyl refer to an optionally substituted, 5 or 6 membered, saturated cyclic hydrocarbon group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, C 1-6 alkyl, C(O)R D , SO 2 R D , aryl or heteroaryl; O; and S, optionally substituted by one or two oxygen atoms.
  • Preferred compounds of Forumula (I) useful in the present invention are selected from the group consisting of: 2-(3-Methoxy-4-teAt-butylbenzoyl)-3-(phenylmethyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid;
  • physiologically acceptable salt complexes also covers the physiologically acceptable salts of the compounds of Formula (I).
  • suitable physiologically acceptable salts of the compounds of Formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, 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 and the like.
  • the present invention also relates to solvates of the compounds of Formula (I), for example hydrates.
  • the present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C 1- alkyl or C 1-4 alkoxy or amino).
  • any alkyl moiety present in such esters preferably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms. Any aryl moiety present in such esters preferably comprises a phenyl group.
  • Compounds of Formula (I) wherein either R 1 or R 7 is C(O)R H and R H is NR B R G may be prepared from a compound of Formula (I) wherein either R 1 or R 7 is C(O)R H and R H is hydroxy using a coupling agent such as HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate) and an amine NHR B R G .
  • a coupling agent such as HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate) and an amine NHR B R G .
  • R 1 or R 7 is C(O)R H and R H is hydroxy
  • R H is an alkoxy, benzyloxy or silyloxy group and n, R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I).
  • R H is methoxy and n, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I), by treatment with an appropriate base, for example aqueous sodium hydroxide, optionally in a solvent such as methanol, tetrahydrofuran or a mixture thereof.
  • an appropriate base for example aqueous sodium hydroxide, optionally in a solvent such as methanol, tetrahydrofuran or a mixture thereof.
  • the temperature is in the range 25 to 100°C, more preferably 50 to 100°C.
  • R H is a methoxy group and n, R 2 , R 3 , R 4 , R 5 R 6 , R 7 and R 8 are as defined above for Formula (I), by treatment with lithium iodide in a suitable solvent such as pyridine, lutidine or collidine, preferably in the temperature range 100-170°C.
  • a suitable solvent such as pyridine, lutidine or collidine
  • R H is ferf-butoxy
  • n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I)
  • an appropriate acid for example trifluoroacetic acid.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 0 to 50°C, more preferably 15 to 30°C.
  • R H is silyloxy
  • n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I)
  • a suitable fluoride source for example tetrabutylammonium fluoride.
  • the reaction is carried out in a suitable solvent, for example tetrahydrofuran.
  • R 1 or R 7 is C(O)R H and R H is hydroxy or a protected form thereof, and n, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for Formula (I); with a suitable acylating agent, for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine and thereafter removing any protecting group.
  • suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts 'Protective Groups in Organic Synthesis', 3 rd Ed (1999), J Wiley and Sons.
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I)
  • a suitable base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, lithium 2,2,6,6- tetramethylpiperidide (LTMP), sodium hydride
  • LTMP 2,2,6,6- tetramethylpiperidide
  • R 2 Y where Y is a halo atom such as chloro, bromo or iodo or Y is a sulphonate leaving group such as mesylate or tosylate, and R 2 is the same as defined above for Formula (I) when n is 0, in a suitable solvent such as tetrahydrofuran.
  • Y is a halo atom such as chloro, bromo or iodo
  • R 4 is as defined above for
  • R H is an alkoxy, benzyloxy or silyloxy group, and R 2 and R 5 are as defined above for Formula (I), in the presence of a suitable base such as LTMP (see for example Tetrahedron Letters (2001) 42, 2245).]
  • P is a suitable nitrogen protecting group such as benzyloxycarbonyl (CBZ), tert- butyloxycarbonyl (BOC), or benzyl
  • a suitable base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, lithium 2,2,6,6- tetramethylpiperidide (LTMP), sodium hydride
  • R H is a protected hydroxy group
  • R 4 , R 5 and R 6 are as defined above for Formula (I)
  • R 2 Y where Y is a halo atom such as chloro, bromo or iodo or Y is a sulphonate leaving group such as mesylate or tosylate, and R 2 is the same as defined above for Formula (I) when n is 0, in a suitable solvent such as tetrahydrofuran, and then removing the protecting group P.
  • R H is an alkoxy, benzyloxy or silyloxy group, and R 4 , R 5 and R 6 are as defined above for Formula (l), with a suitable acylating agent, for example R 3 -C(O)-hal, wherein hal is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine.
  • R H is alkoxy, benzyloxy or siliyloxy and R 2 is defined above for Formula (I) when n is 0, with a compound of Formula R 5 -CHO, where R 5 as defined above for Formula (I), in the presence of a suitable base, for example triethylamine, in a suitable solvent, for example dichloromethane.
  • a suitable base for example triethylamine
  • a suitable solvent for example dichloromethane
  • R H is an alkoxy, benzyloxy or silyloxy group
  • Y is a halo atom such as chloro, bromo or iodo
  • R 4 , R 5 and R 6 are as defined above for Formula (I), with an amine P- NH 2 in which P is a suitable protecting group such as benzyl or fetf-butyloxycarbonyl hydrazide or benzyloxycarbonyl hydrazide (see for example J. Heterocyclic Chem. (1984) 21 , 1355).
  • Compounds of Formula (VIII) may alternatively be prepared by reacting compounds of Formula (X) with ammonia or ammonium hydroxide.
  • P is a suitable protecting group such as benzyl or tert-butyloxycarbonyl hydrazide or benzyloxycarbonyl hydrazide
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 4 , R 5 and R 6 are as defined above for Formula (I).
  • Compounds of Formula (X) may be prepared by reacting compounds of Formula (XI) or Formula (XII), in which R H , R 4 , R 5 and R 6 are as defined above for Formula (I), with a suitable halogenating agent such as N-bromosuccinimide or bromine, in a suitable solvent such as acetic acid, carbon tetrachloride or acetonitrile.
  • a suitable halogenating agent such as N-bromosuccinimide or bromine
  • Y is a halo atom such as chloro, bromo or iodo
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I) when n is 0, using a palladium catalyst such as tris(dibenzylideneacetone)palladium(0) (Pd 2 (dba) 3 ) and a ligand such as 2-(diphenylphosphino)-2'-(N,N-dimethylamino)biphenyl, with a base such as lithium tert-butoxide (see for example J. Org. Chem (2002) 67, 465).
  • a palladium catalyst such as tris(dibenzylideneacetone)palladium(0) (Pd 2 (dba) 3 ) and a lig
  • R H is an alkoxy, benzyloxy or silyloxy group
  • Y is a halo atom such as chloro, bromo or iodo
  • R 2 , R 4 , R 5 and R 6 are as defined above for Formula (I) when n is 0, by reaction with a suitable acylating agent, for example R 3 -C(O)-hal, wherein hal is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 5 and R 6 are hydrogen
  • R 2 is as defined above for Formula (I)
  • Y is a halo atom such as chloro, bromo or iodo
  • R 4 is as defined above for Formula (I) when n is 0, and reduction of the resulting imine using for example sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride.
  • Compounds of Formula (XIV) may also be prepared from compounds of Formula (IX) in which R H is an alkoxy, benzyloxy or silyloxy group, and R 2 is as defined above for Formula (I), and R 5 and R 6 are hydrogen, by reaction with compounds of Formula (XVI) in which Y is a halo atom such as chloro, bromo or iodo and R 4 is as defined above for Formula (I).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 8 represents C ⁇ - ⁇ alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R 4 , R 5 and R 6 are as defined above for Formula (I) by reaction with formaldehyde, and an acid such as hydrochloric acid (see for example Bioorg Med Chem Letters (1998) 8, 2447, Chem. Pharm. Bull. (1988) 36, 190).
  • Y is a halo atom such as chloro, bromo or iodo
  • a base such as sodium hydroxide
  • a suitable solvent such as toluene
  • a phase transfer catalyst such as tetrabutylammonium bromide
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 1 and R 2 independently represent hydrogen, C- ⁇ _ 6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I); may be prepared from a compound of Formula (XXI)
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 1 and R 2 independently represent hydrogen, C ⁇ . 6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 4 , R 5 and R 6 are as defined above for Formula (I)
  • a suitable acylating agent for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine and thereafter removing any protecting group.
  • Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts 'Protective Groups in Organic Synthesis', 3 rd Ed (1999), J Wiley and Sons.
  • R H is an alkoxy or benzyloxy group
  • R 1 represents hydrogen, C ⁇ alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 4 , R 5 and R 6 are as defined above for Formula (I)
  • a suitable reagent such as phosphorous oxychloride
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 1 and R 2 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I)
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 1 and R 2 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I)
  • R H is an alkoxy, benzyloxy or silyloxy group
  • R 1 and R 2 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I)
  • Compounds of Formula (XXIV) may be prepared from a compound of Formula (XXV) in which R H and R 3 are as defined above for Formula (I), by reaction with a compound of Formula (XIX) in the presence of base such as sodium methoxide in a suitable solvent such as methanol (see for example Synthesis (1992) 1157).
  • R H is an alkoxy, benzyloxy or silyloxy group and R 4 , R 5 and R 6 are as defined above for Formula (I), by reaction with formaldehyde, and an acid such as hydrochloric acid (see for example Bioorg Med Chem Letters (1998) 8, 2447).
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl and R 4 , R 5 and R 6 are as defined above for Formula (I) by reaction with a compound of formula R 2 COCOR H in which R H is as defined above for Formula (III) and R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl (see for example J. Org. Chem. (1976) 41 , 443).
  • R 7 and R 8 independently represent hydrogen, C ⁇ -6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, and R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I), by treatment with an aqueous acid such as hydrochloric acid.
  • the acid may then be esterified using an acid such as hydrochloric acid in the presence of a suitable alcohol such as methanol.
  • R 7 represents hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 3 , R 4 and R 5 are as defined above for Formula (I), for example using palladium on carbon and hydrogen in a suitable solvent such as ethanol, or using sodium borohydride in methanol.
  • Compounds of Formula (XXX) may be prepared from a compound of Formula (XXXI) in which R 7 represents hydrogen, C 1-e alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, and R 4 and R 5 are as defined above for Formula (I), using a cyanide source such as sodium cyanide, potassium cyanide or trimethylsilyl cyanide and a suitable acylating agent, for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo and R 3 is as defined above for Formula (I), and optionally with a Lewis acid catalyst such as aluminium trichloride (an example of a Reissert reaction). Examples are given in (but are not restricted to) J. Org. Chem (1992) 57, 750, J. Org. Chem. (1970) 35, 3119.
  • R 1 represents C(O)R H wherein R H is an alkoxy group
  • R 2 represents C 1- ⁇ alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I), may also be prepared from a compou
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I), for example by treatment with an aqueous acid such as hydrochloric acid.
  • the acid may then be esterified using an acid such as hydrochloric acid in the presence of a suitable alcohol such as methanol.
  • Compounds of Formula (XXXII) may be prepared from a compound of Formula (XXIX) in which in which R 7 and R 8 independently represent hydrogen, C ⁇ -6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, and R 3 , R 4 , R 5 and R 6 are as defined above for Formula (I), by treatment with a suitable base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, lithium 2,2,6,6-tetramethylpiperidide (LTMP), sodium hydride, and an alkylating agent R 2 Y where Y is a halo atom such as chloro, bromo or iodo and R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl, in a suitable solvent such as tetrahydrofuran.
  • a suitable base such as lithium bis(trimethylsilyl
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 4 , R 5 and R 6 are as defined above for Formula (I)
  • a cyanide source such as sodium cyanide, potassium cyanide or trimethylsilyl cyanide and a suitable acylating agent, for example R 3 -C(O)-hal, wherein hal is a halo atom, preferably chloro or bromo and R 3 is as defined above for Formula (I), and optionally with a Lewis acid catalyst such as aluminium trichloride (an example of a Reissert reaction). Examples are given in (but are not restricted to) J. Org. Chem. (1992) 57, 750.
  • Compounds of Formula (XXXIII) may be prepared by a Bischler-Napieralski reaction, that is cyclisation of a compound of Formula (XXXIV)
  • R 2 represents C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl
  • R 7 and R 8 independently represent hydrogen, C -6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R 4 , R 5 and R 6 are as defined above for Formula (I), using a suitable reagent such as phosphorous oxychloride or phosphorous pentoxide. Examples are given in, but not restricted to, Org React (1951) 6, 74, J. C. S. Perkin Trans 1 (1981) 2830.
  • R H is an alkoxy group
  • R 7 represents hydrogen, C ⁇ alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl and R 4 and R 5 are as defined above for Formula (I)
  • a suitable acylating agent for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (I).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • R H is an alkoxy group and R 7 represents hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl and R 4 and R 5 are as defined above for Formula (I), by reduction, for example by using hydrogen and a platinum oxide catalyst, see for example Chem. Pharm. Bull. (1997) 45, 1248.
  • R 7 and R 8 independently represent hydrogen, C ⁇ alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl and R 4 , R 5 and R 6 are as defined for Formula (I), using a cyanide source such as sodium cyanide, potassium cyanide or trimethylsilyl cyanide and a suitable acylating agent, for example R 3 -C(O)-Y, wherein Y is a halo atom, preferably chloro or bromo and R 3 is as defined above for Formula (I), and optionally with a Lewis acid catalyst such as aluminium trichloride (an example of a Reissert reaction). Examples are given in (but are not restricted to) J. Org. Chem. (1992) 57, 750.
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is a carboxylic acid may be prepared from a compound of Formula (II) in which R 4 is trifluoromethanesulphonate or a halide such bromide, by treatment with carbon monoxide and water in the presence of a suitable palladium catalyst such as palladium (II) acetate and bis-diphenylphosphinoferrocene or combinations thereof, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a suitable palladium catalyst such as palladium (II) acetate and bis-diphenylphosphinoferrocene or combinations thereof
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is an ester (CO 2 R D ), may be prepared from a compound of Formula (II) in which R 4 is is trifluoromethanesulphonate or a halide such bromide, by treatment with carbon monoxide an alcohol R D OH in the presence of a suitable palladium catalyst such as palladium (II) acetate and bis- diphenylphosphinoferrocene or combinations thereof, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a suitable palladium catalyst such as palladium (II) acetate and bis- diphenylphosphinoferrocene or combinations thereof
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is a 2-substituted ethyl group may be prepared by hydrogenation of an appropriately substituted vinyl derivative using a catalyst such as palladium on carbon, in a suitable solvent such as ethanol.
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is trifluoromethanesulphonate may be prepared from a compound of Formula (II) in which R 4 is OH, by treatment with trifluoromethanesulphonic anhydride in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is an aryl or heteroaryl group may be prepared by reaction between a compound of Formula (II) in which R 4 is trifluoromethanesulphonate or a halide such bromide, and an appropriate aryl or heteroaryl boronic acid derivative (R 4 - B(OH) 2 ), in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base such as potassium phosphate in a suitable solvent such as dimethoxymethane.
  • the aryl or heteroaryl group may be in the form an organozinc reagent (R 4 -Zn-hal) or an organotin reagent (R 4 -Sn(n-alkyl) 3 ).
  • a suitable base such as sodium hydride or potassium carbonate
  • a suitable solvent such as DMF.
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and the compound of Formula (I) contains an amide group may be prepared from the corresponding carboxylic acid using an amine or amine equivalent R B R°NH and a coupling agent such as HATU (O-(7-azabenzotriazol-1yl)- N,N,N',N',-tetramethyluronium hexafluorophosphate) in a suitable solvent such as DMF.
  • HATU O-(7-azabenzotriazol-1yl)- N,N,N',N',-tetramethyluronium hexafluorophosphate
  • Compounds of Formula (I) in which R H is NR B R G may be prepared from compounds of Formula (I) in which R 1 is hydroxy, using an amine or amine equivalent R B R G NH and a coupling agent such as HATU (O-(7-azabenzotriazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate) in a suitable solvent such as DMF.
  • HATU O-(7-azabenzotriazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is NH 2 may be prepared from compounds of Formula (I) in which R 4 is a halogen such as bromo by treatment with lithium bis(trimethylsilyl)amide and catalyst reagents such as tris(dibenzylidenacetone)dipalladium(0) and 2-(dicyclohexylphosphino)biphenyl or combinations therof, in a suitable solvent such as tetrahydrofuran.
  • Compounds of Formula (I) in which R H is esterified to form OR wherein OR is an alkoxy, benzyloxy or silyloxy group, and R 4 is SO 2 R D may be prepared from compounds of Formula (I) in which R 4 is a halogen such as bromo by treatment with a sodium salt of an akylsulfinic acid (eg sodium methylsulfinic acid), in the presence of a copper catalyst (such as copper triflate complexed with toluene) in a suitable solvent such as dimethylsulfoxide, preferably in the temperature range 80-120 °C.
  • a halogen such as bromo by treatment with a sodium salt of an akylsulfinic acid (eg sodium methylsulfinic acid), in the presence of a copper catalyst (such as copper triflate complexed with toluene) in a suitable solvent such as dimethylsulfoxide, preferably in the temperature range 80-120 °C.
  • Phenylalanine fert-butyl ester hydrochloride (2 g) was dissolved in dichloromethane (20 mL) and treated with 4-chlorobenzaldehde (1.09 g). Triethylamine (1.08 mL) was added and the mixture stirred at 50 °C for 4h. The reaction mixture was washed with water (25 mL). The organic phase was collected through a hydrophobic frit and concentrated to give the title compound.
  • the residue was purified by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents to give the title compound.
  • Example 11 was prepared from Intermediate 22 using a similar procedure to that described for Example 3.
  • Example 15 was prepared from Intermediate 25 using a similar procedure to that described for Example 6.
  • Example 17 was prepared from Intermediate 29 using a similar procedure to that described for Example 6.
  • compositions for use in therapy comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.
  • the compounds of the present invention can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound (IC 50 ) potency, (EC 50 ) efficacy, and the biological half-life (of the compound), the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of administration of the present compounds.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(l).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • compositions are in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or thchlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non- aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • Reaction Conditions were 0.5 ⁇ M [ 33 P]-GTP (0.2 Ci/mMol), 1 mM Dithiothreitol, 20 mM MgCI 2 , 5mM MnCI 2, 20 mM Tris-HCI, pH7.5, 1.6 ⁇ g/mL polyC/0.256 ⁇ M biotinylated oligoG13, 10% glycerol, 0.01 % NP-40, 0.2 u/ ⁇ L RNasin and 50 mM NaCl.
  • HCV RNA Polymerase Recombinant full-length NS5B (Lohmann et al, J. Virol. 71 (11), 1997, 8416 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity') expressed in baculovirus and purified to homogeneity) was added to 10 nM final concentration.
  • 5x concentrated assay buffer mix was prepared using 1 M MnCI 2 (0.25 mL), glycerol (4mL), 10% NP-40 (0.025 mL) and Water (7.225 mL), Total 10 mL.
  • 2x concentrated enzyme buffer contained 1M-Tris-HCI, pH7.5 (0.4 mL), 5M NaCl (0.2 mL), 1 M-MgCI 2 (0.4 mL), glycerol (1 mL), 10% NP-40 (10 ⁇ L), 1 M DTT (20 ⁇ L) and water (7.97 mL), Total 10 mL
  • Substrate Mix was prepared using 5x Concentrated assay Buffer mix (4 ⁇ L), [ 33 P]-GTP (10 ⁇ Ci/ ⁇ L, 0.02 ⁇ L), 25 ⁇ M GTP (0.4 ⁇ L), 0.4 u/ ⁇ L RNasin (0.04 ⁇ L), 20 ⁇ g/mL polyrC/biotinylated-oligorG (1.6 ⁇ L), and Water (3.94 ⁇ L), Total 10 ⁇ L.
  • Enzyme Mix was prepared by adding 1 mg/ml full-length NS5B polymerase (1.5 ⁇ L) to 2.811mL 2x-concentrated enzyme buffer.
  • the Assay was set up using compound (1 ⁇ L), Substrate Mix (10 ⁇ L), and Enzyme Mix
  • the reaction was performed in a U-bottomed, white, 96-well plate.
  • the reaction was mixed on a plate-shaker, after addition of the Enzyme, and incubated for 1h at 22 °C.
  • SPA beads in 0.1 M EDTA were incubated with the reaction mixture for 1 h at 22 °C after which 120 ⁇ L 0.1 M EDTA in PBS was added. The plate was sealed, mixed centrifuged and incorporated radioactivity determined by counting in a Trilux (Wallac) or
  • Exemplified compounds have an IC 50 of ⁇ 25 ⁇ M in the above described assay.
  • Preferred compounds have an IC 50 of ⁇ 5 ⁇ M. Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example immune therapies ((eg. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys; Hoffmann-La Roche))
  • immune therapies eg. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent.

Abstract

La présente invention concerne des agents antiviraux représentés par la formule générale (I) dans laquelle : R3 désigne un aryle ou un hétéroaryle ; R4 désigne un ou deux substituants sélectionnés indépendamment dans le groupe comprenant de l'hydrogène, un alkyle en C1-6, un halo, un ORA, un C(O)NRBRC, un C(O)RD, un CO2H, un CO2RD, un NRBRC, un NREC(O)RD, un NRECO2RD, un NREC(O)NRFRG, un NRESO2RD, un SO2NRFRG, un SO2RD, un nitro, un cyano, un hétorocyclyle, un hétéroaryle, un aryle, un arylalkyle, un hétéroarylalkyle ou un CF3 ; R5 et R6 désignent chacun un hydrogène, un alkyle en C1-6, un aryle, un hétéroaryle, un arylalkyle ou un hétéroarylalkyle ; n vaut 0 ou 1 ; lorsque n vaut 0, R1 désigne un C(O)RH et R2 désigne un alkyle en C1-6, un hétérocyclylalkyle, un arylalkyle ou un hétéroarylalkyle ; lorsque n vaut 1, soit i) R1 désigne un C(O)RH ; R2 désigne un alkyle en C1-6, un hétérocyclylalkyle, un arylalkyle ou un hétéroary
PCT/EP2004/004660 2003-05-01 2004-04-29 Derives d'acyle isoindoline et d'acyle isoquinoline utilises comme agents antiviraux WO2004096774A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
KR20160033224A (ko) * 2013-07-23 2016-03-25 르 라보레또레 쎄르비에르 이소인돌린 또는 이소퀴놀린 화합물, 이들의 제조 방법 및 이들을 함유하는 약학적 조성물
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CN110724102A (zh) * 2019-10-25 2020-01-24 华南农业大学 一种含四氢罂粟碱-3-羧酸甲酯的多酚类化合物及其制备方法和应用
WO2021086879A1 (fr) * 2019-10-28 2021-05-06 Tango Therapeutics, Inc. Composés et procédés d'utilisation
US11492350B2 (en) 2020-07-31 2022-11-08 Tango Therapeutics, Inc. Compounds and methods of use

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Publication number Priority date Publication date Assignee Title
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9499531B2 (en) 2004-07-15 2016-11-22 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9173879B2 (en) 2009-05-12 2015-11-03 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US9604960B2 (en) 2009-05-12 2017-03-28 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
KR20160033224A (ko) * 2013-07-23 2016-03-25 르 라보레또레 쎄르비에르 이소인돌린 또는 이소퀴놀린 화합물, 이들의 제조 방법 및 이들을 함유하는 약학적 조성물
KR102008431B1 (ko) 2013-07-23 2019-08-07 르 라보레또레 쎄르비에르 이소인돌린 또는 이소퀴놀린 화합물, 이들의 제조 방법 및 이들을 함유하는 약학적 조성물
WO2017093938A1 (fr) * 2015-12-04 2017-06-08 Viiv Healthcare Uk Limited Dérivés de tétrahydroisoquinoline
CN110724102A (zh) * 2019-10-25 2020-01-24 华南农业大学 一种含四氢罂粟碱-3-羧酸甲酯的多酚类化合物及其制备方法和应用
CN110724102B (zh) * 2019-10-25 2021-06-15 华南农业大学 一种含四氢罂粟碱-3-羧酸甲酯的多酚类化合物及其制备方法和应用
WO2021086879A1 (fr) * 2019-10-28 2021-05-06 Tango Therapeutics, Inc. Composés et procédés d'utilisation
US11492350B2 (en) 2020-07-31 2022-11-08 Tango Therapeutics, Inc. Compounds and methods of use

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