WO2005079799A1 - 4-acyl-piperazines en tant qu'agents antiviraux - Google Patents

4-acyl-piperazines en tant qu'agents antiviraux Download PDF

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Publication number
WO2005079799A1
WO2005079799A1 PCT/EP2005/001451 EP2005001451W WO2005079799A1 WO 2005079799 A1 WO2005079799 A1 WO 2005079799A1 EP 2005001451 W EP2005001451 W EP 2005001451W WO 2005079799 A1 WO2005079799 A1 WO 2005079799A1
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Prior art keywords
carbonyl
methoxy
butylphenyl
piperazine
carboxylic acid
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PCT/EP2005/001451
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English (en)
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John Andrew Corfield
Pritom Shah
Martin John Slater
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Glaxo Group Limited
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Priority claimed from GB0403267A external-priority patent/GB0403267D0/en
Priority claimed from GB0422995A external-priority patent/GB0422995D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2005079799A1 publication Critical patent/WO2005079799A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to novel acyl piperazine derivatives useful as anti-viral agents. Specifically, the present invention involves novel HCV inhibitors.
  • WO99/37304 and WO01/07436 disclose oxoazaheterocyclyl derivatives, especially piperazinone compounds, having Factor Xa and Factor I la inhibitory activity. These derivatives may include certain acyl piperazine derivatives. There is no mention of HCV polymerase inhibitory activity for the disclosed compounds.
  • WO02/08221 discloses diaryl piperazine derivatives having capsaicin antagonistic activity. These derivatives may include certain acyl piperazine derivatives. There is no mention of HCV polymerase inhibitory activity for the disclosed compounds.
  • WO98/20001 discloses thioproline-containing derivatives having farnesyl protein transferase inhibitory activity. These derivatives may include certain acyl piperazine derivatives. There is no mention of HCV polymerase inhibitory activity for the disclosed compounds.
  • WO99/29705 discloses sialyl Lewis X and sialyl Lewis A glycomimetic compounds having utility in the treatment of selectin-mediated disorders. These compounds may include certain acyl piperazine derivatives. There is no mention of HCV polymerase inhibitory activity for the disclosed compounds.
  • 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 1 b 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), p.2046-2051).
  • inhibition of NS5B RdRp activity is predicted to cure HCV infection.
  • the present invention involves acyl piperazine compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • the present invention provides at least one chemical entity chosen from compounds of Formula (I) :
  • A represents hydroxy or -NH 2 ;
  • D represents aryl or heteroaryl
  • E represents hydrogen, straight or branched chain -C ⁇ alkyl, -CO 2 R 1 , -C(O)R 1a , -C(O)NR 2 R 3 , -SO 2 R ⁇ -SO 2 NR 2 R 3 , aryl, arylC ⁇ alkyl, heteroaryl, heteroaryld-salkyl, heterocyclyl or heterocyclyld-salkyl;
  • R 1 is selected from the group consisting of -C h alky!, aryl, aryld-salkyl, heteroaryl, heteroarylCi-salkyl, heterocyclyl or heterocyclylC ⁇ - 3 alkyl;
  • R 1a is selected from the group consisting of -Ci-ealkyl, aryl, aryld-salkyl, heteroaryl, heteroaryld-salkyl, heterocyclyl or heterocyclylC ⁇ - 3 alkyl;
  • R 2 and R 3 are independently selected from hydrogen, -Ci-ealkyl, aryl and heteroaryl; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • G represents -Ci-ealkyl, heterocyclylC ⁇ - 3 alkyl, arylC ⁇ - 3 alkyl or heteroarylCi- 3 alkyl;
  • R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, then R is other than tetf-butyl.
  • 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 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 at least one chemical entity chosen from compounds of Formula (I) and physiologically acceptable salts, solvates or esters thereof.
  • the method involves inhibiting HCV replication.
  • 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.
  • the following substituent groups provide certain aspects of the present invention in respect of Formula I:
  • A represents hydroxy
  • D represents optionally substituted phenyl; more preferably terf-butylphenyl optionally further substituted; in a further aspect, D represents para-tert-butylphenyl optionally further substituted, such as mete-substituted, by halo, -d-3alkyl or -d- 3 alkoxy, especially bromo, chloro, methyl or methoxy; in a further aspect, D is mete-methoxy-para- terf-butylphenyl (3-methoxy-4-tert-butylphenyl).
  • R 1a is selected from the group consisting of straight or branched chain -d-ealkyl, aryl, aryld- 3 alkyl, heteroaryl, heteroarylC ⁇ - 3 alkyl, heterocyclyl or heterocyclylCi- 3 alkyl; in a further aspect, R 1a is selected from the group consisting of straight or branched chain -Ci-ealkyl, aryl, arylC ⁇ - 3 alkyl, heteroaryl, or heteroarylC ⁇ - 3 alkyl.
  • E represents hydrogen, methyl, Ph, -PhC(O)CH 3 , -C(O)Me, -C(O)Ph, -C(O)-cyclopentyl, -C(O)NHPh, -C(O)NH-2-CIPh, -C(O)NH-3-CIPh, -C(O)NH-2-MeOPh, -C(O)NH-4-MeOPh, -C(O)NH-cyclohexyl, -C(O)NHEt, -C(O)CH 2 NHC(O)CH 3 , -C(O)(CH 2 ) 2 CO 2 H, -C(O)CH 2 CO 2 H, -CO 2 Me, -CO 2 .-Bu, -CO 2 Ph, -CH 2 Ph, -SO 2 Me, -SO 2 Ph, -SO 2 CH 2 Ph, -SO 2 CH 2 SO 2 Me, pyrimidin-2-yl
  • E represents hydrogen, methyl, Ph, -PhC(O)CH 3 , -C(O)Me, -C(O)Ph, -C(O)NHPh, -C(O)NH-3-CIPh, -C(O)NH-4-MeOPh, -C(O)NH-cyclohexyl, -C(O)NHEt, -C(O)CH 2 NHC(O)CH 3 , -C(O)(CH 2 ) 2 CO 2 H, -C(O)CH 2 CO 2 H, -CO 2 Me, -CO 2 .-Bu, -CO 2 Ph, -CH 2 Ph, -SO 2 Me, -SO 2 Ph, -SO 2 CH 2 Ph, -SO 2 CH 2 SO 2 Me, pyrimidin-2-yl, 1 ,3-benzoxazol-2- yl, 1H-benzimidazol-2-yl, 1 ,3-thiazol-2-
  • E represents hydrogen, methyl, -C(O)Me, -C(O)Ph, -C(O)NHPh, -C(O)NHEt, -C(O)(CH 2 ) 2 CO 2 H, -C(O)CH 2 CO 2 H, -CO 2 Me, -CO 2 f-Bu, -CH 2 Ph, -SO 2 Me, -SO 2 Ph, -SO 2 CH 2 Ph, -SO 2 CH 2 SO 2 Me, or pyrimidin-2-yl.
  • G represents -C h alky!, arylalkyl or heteroarylalkyl; in a further aspect, G represents isobutyl, prop-2-enyl, benzyl, 1 ,3-thiazol-4-ylmethyl, or pyridylmethyl; in a further aspect, G represents isobutyl, benzyl, 1 ,3-thiazol-4-ylmethyl, especially isobutyl or 1 ,3-thiazol-4-ylmethyl.
  • alkyl refers to an optionally substituted, linear, branched or cyclic, saturated or unsaturated hydrocarbon group. Where the alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group. Where the alkyl hydrocarbon group is unsaturated, it will be understood that there will be a minimum of 2 carbon atoms in the group and that the group may be, for example, an alkenyl or alkynyl group. In one aspect, the group is saturated.
  • alkyl moieties are -Ci-ealkyl, such as -C ⁇ --,alkyl.
  • optional substituents include Ci-ealkyl, halo, -OR 4 , -SR 4 , -C(O)NR 5 R 6 , -C(O)R 7 , -CO 2 H, -CO 2 R 7 , -NR 5 R 6 , -NHC(O)R 7 , -NHCO 2 R 7 , -NHC(O)NR 8 R 9 , -SO 2 NR 8 R 9 , -SO 2 R 7 , nitro, cyano, or oxo.
  • R 4 represents hydrogen, -Ci-ealkyl, arylalkyl, or heteroarylalkyl
  • R 5 and R 6 independently represent hydrogen, -Ci-ealkyl, aryl or heteroaryl; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R 7 represents -Ci-ealkyl, heterocyclyl, heterocyclylCi-ealkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;
  • R 8 and R 9 independently represent hydrogen, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; or R 8 and R 9 together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • alkoxy as used herein include, but are not limited to; methoxy, ethoxy, n-propoxy, i-propoxy and the like.
  • 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, for example phenyl, naphthyl or bi-phenyl. In one aspect, “aryl” contains 6-12 carbon atoms. In one aspect, "aryl” moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • aryl substituents are selected from the group consisting of Ci-ealkyl, halo, -OR 4 , -C(O)NR 5 R 6 , -C(O)R 7 , -CO 2 H, -CO 2 R 7 , - NR 5 R ⁇ , -NHC(O)R 7 , -NHCO 2 R 7 , -NHC(O)NR 8 R 9 , -SO 2 NR 8 R 9 , -SO 2 R 7 , cyano, oxo, heterocyclyl, heteroaryl, -CF 3 , and nitro.
  • heteroaryl refers to an optionally substituted, 5, 6 or 9 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.
  • heteroaryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted pyrimidinyl, pyridyl, pyrazinyl, thiazolyl, benzoxazolyl and benzimidazolyl.
  • heteroaryl substituents are selected from the group consisting of d- ⁇ alkyl, halo, -OR 4 , -C(O)NR 5 R 6 , -C(O)R 7 , -CO 2 H, -CO 2 R 7 , - NR R 6 , -NHC(O)R 7 , -NHCO 2 R 7 , -NHC(O)NR 8 R 9 , -SO 2 NR 8 R 9 , -SO 2 R 7 , cyano, oxo, heterocyclyl, unsubstituted heteroaryl, -CF 3 , and nitro.
  • heterocyclic and “heterocyclyl” refer to an optionally substituted, 5 or 6 membered, saturated or partially saturated, cyclic hydrocarbon group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, d ⁇ alkyl, -C(O)R 7 , - SO 2 R 7 , unsubstituted aryl, unsubstituted heteroaryl or unsubstituted heterocyclyl; O; and S, optionally substituted by one or two oxygen atoms.
  • Ring carbon atoms may be optionally substituted by d- ⁇ alkyl, oxo, OR 4 , -NR 5 R 6 , C(O)R 7 , or SO 2 R 7 .
  • chemical entities useful in the present invention may be chosen from compounds of Formula (I) selected from the group consisting of:
  • the present invention provides compounds of Formula (I) selected from the group consisting of Examples 1 to 47 hereinafter defined, and salts, solvates and esters, and where appropriate, individual enantiomers thereof.
  • the present invention provides compounds of Formula (I) selected from the group consisting of Examples 1 to 27 hereinafter defined, and salts, solvates and esters, and where appropriate, individual enantiomers thereof.
  • 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
  • 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.
  • the present invention relates to at least one chemical entity chosen from compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof.
  • A is a protected hydroxy group, for example an alkoxy, benzyloxy or silyloxy, for example tri-(C . alkyl)-silyloxy group
  • D, E and G are as defined above for Formula (I), by deprotection.
  • 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
  • an appropriate base for example aqueous sodium hydroxide, optionally in a solvent such as methanol, tetrahydrofuran or mixtures thereof.
  • the temperature is in the range 25 to 100°C, more preferably 50 to 100°C.
  • a suitable solvent such as pyridine, lutidine or collidine, preferably in the temperature range 100-170°C.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 0 to 50°C, more preferably 20 to 30°C.
  • a suitable catalyst for example palladium-on- carbon.
  • the reaction is carried out in a solvent, for example ethanol.
  • the temperature is in the range 0 to 50°C.
  • A is allyloxy
  • D, E and G are as defined above for Formula (I)
  • a suitable catalyst for example tetrakis(triphenylphosphine)palladium(0)
  • a suitable proton source for example phenylsilane.
  • the reaction is carried out in a suitable solvent, for example dichloromethane.
  • A is tri(methyl)silyloxy
  • D, E and G 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.
  • Compounds of Formula (I) in which E represents -C(O)NR 2 R 3 may also be prepared by reaction of a compound of Formula (I) in which E represents H with an isocyanate or a p- nitrophenyl carbamate in a suitable solvent such as dichloromethane or dimethylformamide, optionally in the presence of a base, such as triethylamine or DBU.
  • a suitable solvent such as dichloromethane or dimethylformamide
  • Compounds of Formula (I) in which E represents -C(O)R 1a may be prepared by reaction of a compound of Formula (I) in which E represents H, by reaction with a suitable acylating agent, for example E-hal, wherein hal is a halo atom, preferably chloro or bromo, and E is -C(O)R 1a .
  • suitable acylating agents include acyl halides.
  • the reaction is carried out in the presence of a base, such as DBU, in a suitable solvent, such as DMF.
  • Compounds of Formula (I) in which E represents -C(O)R 1a may also be prepared by reaction of a compound of Formula (I) in which E represents H, with a suitable acid, such as R 1a COOH in the presence of a suitable coupling agent, such as HATU.
  • a suitable acid such as R 1a COOH
  • a suitable coupling agent such as HATU
  • the reaction is carried out in the presence of a base, such as DBU, in a suitable solvent, such as DMF.
  • Compounds of Formula (II) in which E represents -C(O)R 1a may be prepared by reaction of a compound of Formula (III) in which A, D, and G are as defined above for Formula (II); by reaction with a suitable acylating agent, for example E-hal, wherein hal is a halo atom, preferably chloro or bromo. Suitable acylating agents include acyl halides.
  • Compounds of Formula (II) in which E represents -C(O)R 1a may also be prepared by reaction of a compound of Formula (III) with a suitable acid, such as R 1a COOH in the presence of a suitable coupling agent, such as HATU.
  • reaction is carried out in the presence of a base, such as DBU in a suitable solvent, such as DMF.
  • a base such as DBU
  • a suitable solvent such as DMF
  • Compounds of Formula (II) in which E represents -SO 2 R 1 may be prepared by reaction with a suitable sulphonyl haiide.
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • Compounds of Formula (II) in which E represents -C(O)NR 2 R 3 may be prepared by reaction of a compound of Formula (III) with an isocyanate or a p-nitrophenyl carbamate.
  • Compounds of Formula (II) in which E represents an aryl, heteroaryl or heterocycle may be prepared by reaction of a compound of Formula (III) with a suitable halo-aryl, halo-heteroaryl or halo-heterocycle, E-hal, in the presence of a base such as potassium carbonate in a suitable solvent such as DMF, or alternatively by using a palladium catalyst such as palladium acetate, a phosphine catalyst and a base.
  • these reactions may be performed at elevated temperature using radiation, for example by carrying out the reaction in an industrial microwave oven.
  • Compounds of Formula (II) in which E represents -CO 2 R 1 may be prepared by reaction of a compound of Formula (III) with a suitable halo-formate derivative, for example R 1 -O-C(O)hal.
  • Compounds of Formula (II) in which E is a substituted alkyl group may be prepared by reaction of a compound of Formula (III) with a suitable alkylating agent, for example E-hal, in the presence of a base such as potassium carbonate in a suitable solvent such as acetone.
  • A, D and G are as defined for Formula (II) above and P is a suitable nitrogen protecting group, by removal of the protecting group P.
  • Optional protecting groups include, but are not restricted to, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (CBZ). Boc groups may be removed by acid reagents such as trifluoroacetic acid or hydrogen chloride in a suitable solvent such as dioxan. CBZ groups may be removed by hydrogenolysis using a catalyst such as palladium on carbon in a suitable solvent, for example ethanol.
  • 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.
  • a and D are as defined for Formula (II) above and P is a nitrogen protecting group, with a base such as potassium bis(trimethylsilyl) amide and a compound of formula
  • G-L wherein G is as defined for Formula (I), and L is a leaving group such as a halo atom, preferably chloro or bromo, or a sulphonate ester such as mesylate or tosylate.
  • a suitable solvent for example tetrahydrofuran, dimethylformamide or mixtures thereof.
  • A is as defined for Formula (II) above and P is a nitrogen protecting group, by reaction with a suitable acylating agent, for example DC(O)-hal, wherein D is as defined for Formula (I) above and hal is a halo atom, preferably chloro or bromo.
  • a suitable acylating agent for example DC(O)-hal
  • D is as defined for Formula (I) above and hal is a halo atom, preferably chloro or bromo.
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine.
  • Compounds of Formula (IV) may also be prepared by reaction of a compound of Formula (VII) wherein A, and G are as defined for Formula (II) above and P is a nitrogen protecting group; by reaction with a suitable acylating agent, for example DC(O)-hal, wherein D is as defined for Formula (I) above and hal is a halo atom, preferably chloro or bromo.
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine.
  • a and G are as defined for Formula (II) above and P and P' are suitable nitrogen protecting groups, by reaction with a suitable reagent to selectively remove the P' group.
  • suitable reagent examples include hydrogenolysis when P' is a CBZ group, with a catalyst such as palladium on carbon, in a suitable solvent such as ethanol.
  • Suitable protecting groups and deprotection conditions 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.
  • A is as defined for Formula (II) above and P and P' are suitable nitrogen protecting groups, with a base such as potassium bis(trimethylsilyl) amide and an alkyl haiide G-hal, wherein hal is a halo atom, preferably chloro or bromo.
  • a base such as potassium bis(trimethylsilyl) amide and an alkyl haiide G-hal, wherein hal is a halo atom, preferably chloro or bromo.
  • hal is a halo atom, preferably chloro or bromo.
  • the reaction is carried out in a suitable solvent, for example tetrahydrofuran, dimethylformamide or mixtures thereof.
  • A, D and E are as defined above for Formula (II), by treatment with a base such as potassium bis(trimethylsilyl) amide and and a compound of formula G-L, wherein G is as defined for Formula (I), and L is a leaving group such as a halo atom, preferably chloro or bromo, or a sulphonate ester such as mesylate or tosylate.
  • a base such as potassium bis(trimethylsilyl) amide
  • G-L wherein G is as defined for Formula (I), and L is a leaving group such as a halo atom, preferably chloro or bromo, or a sulphonate ester such as mesylate or tosylate.
  • a suitable solvent for example tetrahydrofuran, dimethylformamide or mixtures thereof.
  • acylating agent for example E-hal, wherein hal is a halo atom, preferably chloro or bromo.
  • Suitable acylating agents include acyl halides.
  • Compounds of Formula (X) in which E represents -SO 2 R 1 may be prepared by reaction with a suitable sulphonyl haiide. Preferably the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • Compounds of Formula (X) in which E represents -C(O)NR 2 R 3 may be prepared by reaction of a compound of Formula (XI) with an isocyanate or a p-nitrophenyl carbamate.
  • Compounds of Formula (X) in which E is represents an aryl, heteroaryl or heterocycle may be prepared by reaction of a compound of Formula (XI) with a suitable halo-aryl, halo-heteroaryl or halo-heterocycle, E-hal, in the presence of a base such as potassium carbonate in a suitable solvent such as DMF, or alternatively by using a palladium catalyst such as palladium acetate, a phosphine catalyst and a base.
  • Compounds of Formula (X) in which E represents -CO 2 R 1 may be prepared by reaction of a compound of Formula (XI) with a suitable halo-formate derivative (R 1 -O-C(O)hal).
  • Compounds of Formula (X) in which E is a substituted alkyl group may be prepared by reaction of a compound of Formula (XI) with a suitable alkylating agent (E-hal) in the presence of a base such as potassium carbonate, in a suitable solvent such as acetone.
  • Compounds of Formula (XI) may be prepared by reaction of a compound of Formula (V) wherein A and D are as defined for Formula (II) above and P is a suitable nitrogen protecting group, by removal of the protecting group P.
  • Optional protecting groups include, but are not restricted to, terf-butoxycarbonyl (Boc) and benzyloxycarbonyl (CBZ).
  • Boc groups may be removed by acid reagents such as trifluoroacetic acid or hydrogen chloride in a suitable solvent such as dioxan.
  • CBZ groups may be removed by hydrogenolysis using a catalyst such as palladium on carbon in a suitable solvent, for example ethanol.
  • 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.
  • racemic compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) and/or (XI) may be optionally resolved into their individual enantiomers. Such resolutions may conveniently be accomplished by standard methods known in the art. For example, a racemic compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) and/or (XI) may be resolved by chiral preparative HPLC.
  • racemic compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) and/or (XI) may be resolved by standard diastereoisomeric salt formation with a chiral acid or base reagent as appropriate. Such techniques are well established in the art.
  • Esters of compounds of Formula (I) may be prepared by esterification of a compound of Formula (I) using standard literature procedures for esterification.
  • Compounds of Formula (I) in which A is NH 2 may be prepared from a compound of Formula (I) in which A is hydroxy using a coupling agent such as HATU (O-(7- azabenzotriazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate) and an ammonium salt, such as ammonium acetate, in the presence of a base, such as triethylamine.
  • a coupling agent such as HATU (O-(7- azabenzotriazol-1yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate) and an ammonium salt, such as ammonium acetate, in the presence of a base, such as triethylamine.
  • Benzimidazole (3.47 g, 29.4 mmol) was dissolved in anhydrous THF (100 mL) at 0°C under an atmosphere of nitrogen.
  • To the stirred solution was added dropwise n-butyl lithium (18.5 mL of a 1.6 M solution in hexanes, 29.6 mmol) then SEM-CI (5.2 mL, 29.4 mmol).
  • the mixture was warmed to ambient temperature for 3 hours and then cooled to -78°C.
  • To the stirred solution was added dropwise n-butyl lithium (18.5 mL of a 1.6 M solution in hexanes, 29.6 mmol).
  • Example 10 1 -[(3-Methoxy-4-tert-butylphenyl)carbonyl]-2-(phenylmethyl)-4- [(phenylmethyl)sulfonyl]-piperazine-2-carboxylic acid
  • Example 15 1-[(3-Methoxy-4-tert-butyiphenyl)carbonyl]-2-(phenylmethyJ)-4-(carboxyacetyl)- piperazine-2-carboxylic acid H NMR (de-DMSO, mixture of rotamers): ⁇ 7.40-7:23 (6H, m), 6.86-6.73 (2H, m), 4.41 (0.65H, d), 3.97 (0.35H, d), 3.86-3.75 (4.35H, m), 3.60-3.12 (7H, m), 3.03 (0.65H, d), 2.98 (1 H, d), 2.67 (1 H, t), 1.33 (9H, s).
  • Example 48 1 -[(3-Methoxy-4-tert-butylphenyl)carbonyl]-2-(1 ,3-thiazol-4-ylmethyl)-4- (cyclopentylcarbonyl)-piperazine-2-carboxylic acid
  • Example 36 1 -[(3-Methoxy-4-tert-butylphenyl)carbonyl]-2-(1 ,3-thiazol-4-ylmethyl)-4-(1 ,3-thiazol-2- yl)-piperazine-2-carboxylic acid
  • the organic phase was separated, evaporated and purified by reverse phase HPLC on a C 8 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, and analysis of the fractions by electrospray mass spectroscopy.
  • the fractions containing the desired product were combined and evaporated. The residue was freeze dried from dioxan to give the title compound as a solid.
  • 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, including administration via a patch.
  • 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.
  • composition is 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.
  • 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 non-CFC propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • a conventional non-CFC propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • 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 (20 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 NaCI.
  • 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 4 nM final concentration.
  • 5x concentrated assay buffer mix was prepared using 1 M MnCI 2 (0.25 mL), glycerol (2.5mL), 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 NaCI (0.2 mL), 1M-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), PJ-GTP (10 ⁇ Ci/ ⁇ L, 0.02 ⁇ L), 25 ⁇ M GTP (0.4 ⁇ L), 40 u/ ⁇ L RNasin (0.1 ⁇ L), 20 ⁇ g/mL polyrC/biotinylated-oligorG (1.6 ⁇ L), and Water (3.94 ⁇ L), Total 10 ⁇ L.
  • Enzyme Mix was prepared by adding 1mg/ml full-length NS5B polymerase (1.5 ⁇ L) to 2.81 mL 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 1h 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
  • the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV.
  • Preferred compounds had an IC 50 of ⁇ 5 ⁇ M.
  • 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-lntron; Schering-Plough) or peginterferon alpha-2a (Pegasys; Hoffmann-La Roche)), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g.
  • Interferon such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1
  • 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, especially interferon and/or ribavirin.

Abstract

L'invention concerne des agents antiviraux de formule (I) dans laquelle, A représente hydroxy ou -NH2, D représente aryle ou hétéroaryle, E représente hydrogène, alkyleC1-6 à chaîne ramifiée ou linéaire, -CO2R1, -C(O)R1a, -C(O)NR2R3, -SO2R1, aryle, arylalkyleC1-3, hétéroaryle, hétéroarylalkyleC1-3, hétérocyclyle ou hétérocyclylalkyleC1-3, R1 est choisi dans le groupe comprenant alkyleC1-6, aryle, arylealkylC1-3, hétéroaryle, hétéroarylalkyleC1-3, hétérocyclyle ou hétérocyclylalkyleC1-3, R1a est choisi dans le groupe comprenant alkyleC1-6, aryle, arylalkyleC1-3, hétéroaryle, hétéroarylalkyleC1-3, hétérocyclyle ou hétérocyclylalkyleC1-3, R2 et R3 sont choisis indépendamment dans le groupe comprenant hydrogène, alkyleC1-6, aryle et hétéroaryle, ou R2 et R3 avec l'atome d'azote auquel ils sont attachés forment un groupe cyclique saturé à 5 ou 6 chaînons, G représente alkyleC1-6, hétérocyclylalkyleC1-3, arylalkyleC1-3 ou hétéroarylalkyleC1-3, et des sels, solvates et esters de ceux-ci, à condition que lorsque A est estérifié pour former OR, R étant choisi dans le groupe comprenant alkyle, aralkyle, aryloxyalkyle, ou aryle à chaîne ramifiée ou linéaire, alors R est autre que tert-butyl. L'invention concerne également des procédés de préparation de ces agents, des compositions pharmaceutiques comprenant ceux-ci ainsi que des procédés d'utilisation de ces agents dans des traitements du VHC.
PCT/EP2005/001451 2004-02-13 2005-02-10 4-acyl-piperazines en tant qu'agents antiviraux WO2005079799A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098859A1 (fr) * 2007-02-15 2008-08-21 F. Hoffmann-La Roche Ag Inhibiteurs de la vhc polymérase
WO2011079114A1 (fr) 2009-12-23 2011-06-30 Elan Pharmaceuticals, Inc. Ptéridinones en tant qu'inhibiteurs de polo-like kinase
WO2012048129A2 (fr) 2010-10-08 2012-04-12 Elan Pharmaceuticals, Inc. Inhibiteurs de kinase de type polo
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
CN105920004A (zh) * 2016-05-24 2016-09-07 暨南大学 1,2,4-三取代哌嗪化合物在制备抗流感病毒药物中的用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058526A1 (fr) * 1998-05-13 1999-11-18 Dong Wha Pharm. Ind. Co., Ltd. Nouveaux derives d'acide 2,5-pyridinecarboxylique
WO2000001677A1 (fr) * 1998-07-06 2000-01-13 Universite Paris 7 - Denis Diderot Derives de la piperazine pour l'inhibition de la replication du virus de l'immunodeficience humaine
WO2002026720A2 (fr) * 2000-09-29 2002-04-04 Millennium Pharmaceuticals, Inc. INHIBITEURS DE FACTOR Xa A BASE DE PIPERAZINE
WO2002046171A2 (fr) * 2000-12-06 2002-06-13 Signal Pharmaceuticals, Inc. Derives d'anilinopyrimidine utilises comme inhibiteurs de kinase i$g(k)b (ikk), compositions et techniques associees
WO2003084953A1 (fr) * 2002-04-04 2003-10-16 B & C Biopharm Derives de 6-(anilino-4-substitue)pyrimidine, procede de preparation de ces derives et composition pharmaceutique antivirale les contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058526A1 (fr) * 1998-05-13 1999-11-18 Dong Wha Pharm. Ind. Co., Ltd. Nouveaux derives d'acide 2,5-pyridinecarboxylique
WO2000001677A1 (fr) * 1998-07-06 2000-01-13 Universite Paris 7 - Denis Diderot Derives de la piperazine pour l'inhibition de la replication du virus de l'immunodeficience humaine
WO2002026720A2 (fr) * 2000-09-29 2002-04-04 Millennium Pharmaceuticals, Inc. INHIBITEURS DE FACTOR Xa A BASE DE PIPERAZINE
WO2002046171A2 (fr) * 2000-12-06 2002-06-13 Signal Pharmaceuticals, Inc. Derives d'anilinopyrimidine utilises comme inhibiteurs de kinase i$g(k)b (ikk), compositions et techniques associees
WO2003084953A1 (fr) * 2002-04-04 2003-10-16 B & C Biopharm Derives de 6-(anilino-4-substitue)pyrimidine, procede de preparation de ces derives et composition pharmaceutique antivirale les contenant

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098859A1 (fr) * 2007-02-15 2008-08-21 F. Hoffmann-La Roche Ag Inhibiteurs de la vhc polymérase
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
WO2011079114A1 (fr) 2009-12-23 2011-06-30 Elan Pharmaceuticals, Inc. Ptéridinones en tant qu'inhibiteurs de polo-like kinase
WO2011079118A1 (fr) 2009-12-23 2011-06-30 Elan Pharmaceuticals, Inc Ptéridinones en tant qu'inhibiteurs de polo-like kinase
WO2012048129A2 (fr) 2010-10-08 2012-04-12 Elan Pharmaceuticals, Inc. Inhibiteurs de kinase de type polo
CN105920004A (zh) * 2016-05-24 2016-09-07 暨南大学 1,2,4-三取代哌嗪化合物在制备抗流感病毒药物中的用途
CN105920004B (zh) * 2016-05-24 2018-10-09 暨南大学 1，2，4-三取代哌嗪化合物在制备抗流感病毒药物中的用途

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