WO2005103045A1 - Derives acyl-dihydro-pyrrole utilises en tant qu'inhibiteurs du vhc - Google Patents

Derives acyl-dihydro-pyrrole utilises en tant qu'inhibiteurs du vhc Download PDF

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Publication number
WO2005103045A1
WO2005103045A1 PCT/EP2005/004270 EP2005004270W WO2005103045A1 WO 2005103045 A1 WO2005103045 A1 WO 2005103045A1 EP 2005004270 W EP2005004270 W EP 2005004270W WO 2005103045 A1 WO2005103045 A1 WO 2005103045A1
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aryl
heteroaryl
alkyl
heteroarylalkyl
arylalkyl
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PCT/EP2005/004270
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English (en)
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David Haigh
Martin John Slater
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Glaxo Group Limited
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Priority to JP2007508842A priority Critical patent/JP2007533693A/ja
Priority to EP05734941A priority patent/EP1740582A1/fr
Publication of WO2005103045A1 publication Critical patent/WO2005103045A1/fr

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    • 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
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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 dihydro pyrrole derivatives useful as anti-viral agents. Specifically, the present invention involves novel Hepatitis C virus (HCV) inhibitors.
  • HCV Hepatitis C virus
  • WO2002/44168, WO96/33170 and EP505868A2 disclose 4',5'-unsubstituted acyl pyrrolidine compounds useful as intermediates in the synthesis of indolecarboxamide, N- aroylamino acid amide and N-acyl- ⁇ -amino acid derivatives respectively; no medical use was disclosed for the acyl pyrrolidine compounds.
  • De Caprariis et al, (1989) Journal of Heterocyclic Chemistry 26(4): 1023-1027 discloses 3 pyrrolidinedicarboxylic acid derivatives useful as intermediates in the synthesis of pyrrolo[1 ,4]benzodiazepine compounds; no medical use was disclosed for the pyrrolidinedicarboxylic acid derivatives.
  • WO99/37304 discloses oxoazaheterocyclyl derivatives, especially piperazinone compounds, having Factor Xa inhibitory activity. These derivatives may include certain acyl pyrrolidine 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).
  • HCV is now widely accepted as the most common causative agent of post- transfusion non-A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and 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 1 a and 1 b 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 dihydro pyrrole 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
  • D represents aryl or heteroaryl
  • E represents hydrogen, C ⁇ - 6 alkyl, aryl, heteroaryl or heterocyclyl
  • G represents hydrogen or C ⁇ - 6 alkyl optionally substituted by one or more substituents selected from halo, OR 1 , SR 1 , C(O)NR 2 R 3 , CO 2 H, C(O)R 4 , CO 2 R 4 , NR 2 R 3 , NHC(O)R 4 , NHCO 2 R 4 , NHC(O)NR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , nitro, cyano, aryl, heteroaryl and heterocyclyl;
  • R represents hydrogen, C ⁇ - 6 alkyl, arylalkyl, or heteroarylalkyl
  • R 2 and R 3 are independently selected from hydrogen, C- ⁇ - 6 alkyl, 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;
  • R 4 is selected from the group consisting of C ⁇ - 6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C ⁇ - 6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; 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; and
  • J represents C ⁇ - 6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
  • 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.
  • D represents optionally substituted phenyl; in another aspect terf-butylphenyl optionally further substituted; in a further aspect D represents para-tert-butylphenyl optionally further substituted, in one aspect mef ⁇ -substituted, by halo, C ⁇ - 3 alkyl or C ⁇ alkoxy, for example bromo, chloro, methyl or methoxy; in another aspect D represents mefa-methoxy-para-terf-butylphenyl (3-methoxy-4-te/f-butylphenyl).
  • E represents optionally substituted heteroaryl; in a further aspect E represents thiazolyl or isoxazolyl, each of which may be optionally substituted. In one aspect, E represents optionally substituted thiazolyl. In another aspect, E represents optionally substituted isoxazolyl. In another aspect, E represents 1 ,3-thiazol-2-yl or 5- methyl-isoxazol-3-yl .
  • G represents C ⁇ - 6 alkyl optionally substituted by OR 1 , SR 1 or SO 2 R 4 ; in another aspect, G represents methyl optionally substituted by OR 1 , SR 1 or SO 2 R 4 .
  • R 1 represents C ⁇ alkyl; in another aspect, R 1 represents methyl, ethyl, or propyl; in a further aspect methyl or ethyl.
  • R 4 represents C ⁇ alkyl; in another aspect, R 4 represents methyl, ethyl, or propyl, especially methyl.
  • J represents C h alky!, arylalkyl or heteroarylalkyl. In another aspect, J represents C h alky! or heteroarylmethyl. In a further aspect, J represents isobutyl or 1 ,3- thiazol-4-ylmethyl. In one aspect, J represents isobutyl. In another aspect, J represents 1 ,3-thiazol-4-ylmethyl.
  • alkyl refers to an optionally substituted hydrocarbon group.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Where the alkyl group is linear or branched, examples of such groups include methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like. In one aspect, alkyl moieties are C ⁇ - 4 alkyl.
  • alkyl hydrocarbon group is unsaturated, it will be understood that there will be a minimum of 2 carbon atoms in the group, for example an alkenyl or alkynyl group.
  • alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group.
  • the cyclic alkyl group may be saturated or unsaturated, monocyclic or bridged bicyclic. Where the cyclic alkyl group is saturated, examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cyclic alkyl group is unsaturated
  • examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • the cyclic alkyl group has from 3 to 6 carbon atoms.
  • optional substituents include C ⁇ alkyl, halo, OR 1 , SR 1 , C(O)NR 2 R 3 , C(O)R 4 , CO 2 H, CO 2 R 4 , NR 2 R 3 , NHC(O)R 4 , NHCO 2 R 4 , NHC(O)NR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , nitro, cyano, oxo, and heterocyclyl.
  • alkenyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds. In one aspect the alkenyl group has from 2 to 6 carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.
  • alkynyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds. In one aspect the alkynyl group has from 2 to 6 carbon atoms. Examples of such groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.
  • alkoxy refers to an alkyl ether radical, in which 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.
  • aryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • aryl substituents are selected from the group consisting of C h alky!, halo, OR 1 , C(O)NR 2 R 3 , C(O)R 4 , CO 2 H, CO 2 R 4 , NR 2 R 3 , NHC(O)R 4 , NHCO 2 R 4 , NHC(O)NR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , nitro, cyano, oxo, heterocyclyl, CF 3 , and NO 2 .
  • arylalkyl refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • 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.
  • heteroaryl moieties are unsubstituted, monosubstituted or disubstituted thiazolyl.
  • heteroaryl moieties are unsubstituted, monosubstituted or disubstituted isoxazolyl.
  • heteroaryl substituents are selected from the group consisting of C h alky!, halo, OR 1 , C(O)NR 2 R 3 , C(O)R 4 , CO 2 H, CO 2 R 4 , NR 2 R 3 , NHC(O)R 4 , NHCO 2 R 4 , NHC(O)NR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , nitro, cyano, oxo, heterocyclyl, CF 3 , and NO 2 .
  • heteroarylalkyl refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.
  • 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 ⁇ - 6 alkyl, C(O)R 4 , SO 2 R 4 , aryl or heteroaryl; O; and S, optionally substituted by one or two oxygen atoms.
  • heterocyclylalkyl refers to a heterocyclyl group attached to the parent molecular moiety through an alkyl group
  • salts and solvates of compounds of the invention which are suitable for use in medicine are those in which the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
  • chemical entities useful in the present invention may be at least one chemical entity selected from the group consisting of: re/-(2S,5R)-2-Isobutyl-1-(3-methoxy-4-te/ -butylbenzoyl)-4-ethoxymethyl-5-(1 ,3-thiazol-2- yl)-2,5-dihydro-1 H-pyrrole-2-carboxylic acid; re/-(2S,5R)-2-lsobutyl-1-(3-methoxy-4-te/ ⁇ f-butylbenzoyl)-4-methoxymethyl-5-(1 ,3-thiazol-
  • 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.
  • 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 s
  • 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 h alky! or C ⁇ alkoxy or amino).
  • any alkyl moiety present in such esters contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms.
  • Any aryl moiety present in such esters comprises in one aspect a phenyl group.
  • the present invention relates to compounds of Formula (I) and salts and solvates thereof.
  • the present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof.
  • the present invention relates to solvates of the compounds of Formula (I), for example hydrates.
  • A is a protected hydroxy group, for example an alkoxy or silyloxy, for example tri-
  • reaction when A is fe/if-butoxy, and D, E, G and J are as defined above for Formula (I), by treatment with 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, in another aspect 20 to 30°C.
  • a suitable catalyst for example tetrakis(triphenylphosphine)palladium(0) and 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, G and J 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 THF.
  • acylating agent for example D-C(O)-hal, in which hal is a halo atom, for example chloro or bromo, and D is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine
  • 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 is hydroxy or an alkoxy or tri-(C 1 - 4 alkyl)-silyloxy group
  • D, E and J are as defined above for Formula (I)
  • L represents CO 2 Y or COY in which Y represents hydrogen or alkyl.
  • a compound of Formula (II) in which G represents hydroxyalkyl may be prepared by reduction of a compound of Formula (I la) in which L represents CO 2 Y or COY and Y represents hydrogen or alkyl, using a suitable reducing agent, for example lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, borane/dimethyl sulfide complex or lithium aluminium hydride, or suitable combinations thereof, in a suitable solvent or mixture thereof for example THF or methanol.
  • a suitable reducing agent for example lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, borane/dimethyl sulfide complex or lithium aluminium hydride, or suitable combinations thereof.
  • a compound of Formula (II) in which G represents hydroxyalkyl may also be prepared by reaction of a compound of formula (I la) in which L represents CO 2 Y or COY and Y represents hydrogen or alkyl, with a suitable organometallic reagent, for example methylmagnesium bromide or methyl lithium, in a suitable solvent, for example THF.
  • a suitable organometallic reagent for example methylmagnesium bromide or methyl lithium
  • a compound of formula (II) in which G represents difluoroalkyl may be prepared by reaction of a compound of formula (lla) in which L represents COY and Y represents alkyl, with a suitable fluorinating agent, for example diethylaminosulfur trifluoride, in a suitable solvent, for example dichloromethane.
  • a suitable fluorinating agent for example diethylaminosulfur trifluoride
  • a compound of formula (II) in which G represents alkenyl may be prepared by treatment of a compound of formula (lla) in which L represents COY and Y represents hydrogen or alkyl, with a phosphonium salt, for example phosphonium halide salts such as methyltriphenylphosphonium bromide, methyltriphenylphosphonium chloride, methoxymethyltriphenylphosphonium bromide or methoxymethyltriphenylphosphonium chloride, in the presence of a base, for example lithium bis(trimethylsilyl)amide, and in a suitable solvent, for example THF.
  • a base for example lithium bis(trimethylsilyl)amide
  • a compound of Formula (II) may be prepared by appropriate manipulation of another compound of Formula (II).
  • a compound of Formula (II) in which G represents hydroxyalkyl may be converted into a compound of Formula (II) in which G represents optionally substituted alkyl, for example alkyl, haloalkyl or alkoxyalkyl.
  • a compound of Formula (II) in which G represents alkoxyalkyl may be prepared by alkylation of a compound of formula (II) in which G represents hydroxyalkyl using a suitable base for example sodium hydride and a suitable alkylating agent such as an alkyl iodide, for example methylating using methyl iodide or ethylating using ethyl iodide.
  • a suitable solvent for example DMF.
  • a compound of Formula (II) in which G represents haloalkyl may be prepared by halogenation of a compound of Formula (II) in which G represents hydroxyalkyl using a suitable halogenating agent, for example hydroxymethyl may be converted into fluoromethyl using a suitable fluorinating agent, for example diethylaminosulfur trifluoride, in a suitable solvent, for example dichloromethane.
  • a suitable fluorinating agent for example diethylaminosulfur trifluoride
  • a compound of Formula (II) in which G represents cyanomethyl may be prepared by reacting a compound of Formula (II) in which G represents hydroxymethyl with, for example trifluoromethanesulfonic anhydride, and subsequently treating the product with a nucleophile, for example a cyanide salt such as tetrabutylammonium cyanide.
  • a nucleophile for example a cyanide salt such as tetrabutylammonium cyanide.
  • a compound of Formula (II) in which G represents C ⁇ alkylthiomethyl can similarly be prepared using C ⁇ alkylthiolate as the nucleophile.
  • a compound of Formula (II) in which G represents may be prepared by oxidising a compound of Formula (II) in which G represents Ci- 4 alkylthiomethyl, using for example 3-chloroperbenzoic acid, in a suitable solvent, for example dichloromethane.
  • a compound of Formula (II) in which G represents alkyl may be prepared by deoxygenation of a compound of Formula (II) in which G represents hydroxyalkyl.
  • the deoxygenation is carried out in a two step process in which: Step(i) A compound of formula (II) in which G represents hydroxyalkyl is converted into a thionocarbonate by treatment with a suitable chloroformate for example 4-fluorophenyl thionochloroformate.
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base catalyst, for example 4-(N,N- dimethylamino)pyridine.
  • Step(ii) The thionocarbonate from step(i) is treated with a suitable radical initiator, for example AIBN, and a suitable proton source, such as tris(trimethylsilyl)silane, in a suitable solvent, for example dioxan.
  • a suitable radical initiator for example AIBN
  • a suitable proton source such as tris(trimethylsilyl)silane
  • the temperature is in the range 80 to 120°C.
  • a compound of Formula (II) in which G represents an unsaturated alkyl group, for example 1-methylethenyl or 2-methoxyethenyl may be converted into a compound of Formula (II) in which G represents a saturated alkyl group, for example isopropyl or 2-methoxyethyl, by hydrogenation in the presence of a suitable catalyst, for example palladium-on-carbon, and in a suitable solvent, for example ethanol.
  • a suitable catalyst for example palladium-on-carbon
  • a compound of Formula (II) in which G represents alkenyloxyalkyl or substituted alkenyloxyalkyl may be converted into a compound of Formula (II) in which G represents alkyloxyalkyl or substituted alkyloxyalkyl by hydrogenation in the presence of a suitable catalyst, for example palladium-on-carbon, and in a suitable solvent, for example ethanol.
  • a suitable catalyst for example palladium-on-carbon
  • a suitable solvent for example ethanol.
  • allyloxyalkyl or substituted allyloxyalkyl may be converted into propyloxyalkyl or substituted. propyloxyalkyl.
  • a compound of Formula (lla) in which L represents CO 2 Y in which Y represents hydrogen may be prepared from a compound of Formula (lla) in which L represents CO 2 Y in which Y represents alkyl.
  • a compound of Formula (lla) in which L represents CO 2 Me may be converted into a compound of Formula (lla) in which L represents CO 2 H by hydrolysis, for example base catalysed hydrolysis using a suitable base such as sodium hydroxide in a suitable solvent such as methanol.
  • a compound of Formula (lla) in which L represents CO 2 Y or COY in which Y represents hydrogen or alkyl may be prepared from a compound of Formula (Ilia) in which L represents CO 2 Y or COY in which Y represents hydrogen or alkyl, and A, E, and J are as defined above for Formula (I); with a suitable acylating agent, for example D- C(O)-hal, in which hal is a halo atom, for example chloro or bromo, and D is as defined above for Formula (1).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • a compound of Formula (lla) in which L represents COY and Y represents hydrogen may be prepared in a two-stage process from a compound of Formula (lla) in which L represents CO 2 Y and Y represents hydrogen or alkyl.
  • the compound of Formula (lla) in which L represents CO 2 Y and Y represents hydrogen or alkyl is treated with a suitable reducing agent, for example, lithium aluminium hydride or sodium borohydride.
  • the resultant hydroxy group is oxidised with a suitable oxidising agent which may be selected from conventional oxidising reagents known in the art, for example an appropriate mixture of oxalyl chloride, dimethyl sulfoxide and triethylamine.
  • a suitable oxidising agent which may be selected from conventional oxidising reagents known in the art, for example an appropriate mixture of oxalyl chloride, dimethyl sulfoxide and triethylamine.
  • a compound of Formula (lla) in which A is hydroxy may be converted to a compound of Formula (lla) in which A is an alkoxy or silyloxy group by standard hydroxy protecting techniques.
  • a compound of Formula (lla) in which A is an alkoxy or silyloxy group may be converted to a compound of Formula (lla) in which A is hydroxy by standard deprotecting techniques.
  • 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 compound of Formula la) may be prepared by reaction of a compound of Formula (IV)
  • reaction in which L represents CO 2 Y or COY in which Y represents hydrogen or alkyl.
  • a suitable solvent for example THF or acetonitrile
  • a Lewis acid catalyst such as lithium bromide or silver acetate
  • a base such as triethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or tetramethyl guanidine.
  • reaction is carried out in a suitable solvent, for example THF or acetonitrile, in the presence of an acid, such as acetic acid, or the reaction may be carried out by heating compounds of Formula (IV) and Formula (V) in a suitable solvent, for example toluene, xylene or acetonitrile in the absence of a catalyst.
  • a suitable solvent for example THF or acetonitrile
  • an acid such as acetic acid
  • Compounds of Formula (III) in which G represents optionally substituted alkyl may be prepared by appropriate manipulation of a compound of Formula (Ilia) after first optionally protecting the N-atom of the dihydropyrrole ring with a suitable N-protecting group, for example benzyloxycarbonyl (CBZ) or fe/t-butoxycarbonyl.
  • a compound of Formula (III) in which G represents hydroxyalkyl may be prepared by reduction of a compound of Formula (Ilia) in which L represents CO 2 Y and Y represents alkyl, using a suitable reducing agent, for example lithium borohydride or sodium borohydride, in a suitable solvent for example THF.
  • deprotection of the N-atom results in the compound of Formula (III).
  • deprotection may be achieved by treatment with a suitable acid, for example trifluoroacetic acid.
  • a compound of Formula (III) in which G represents hydroxyalkyl and the N-atom is protected, may be converted into a compound of Formula (III) in which G represents optionally substituted alkyl, for example alkyl, haloalkyl or alkoxyalkyl and the N-atom is protected. Deprotection of the N-atom by standard procedures results in the new compound of Formula (III).
  • Compounds of Formula (IV) may be prepared by reaction of a compound of Formula (VI) in which J is as defined above for Formula (I) and A is as defined above for Formula (II) with a compound of Formula E-CHO in the presence of an optional drying agent, for example magnesium sulfate, in a suitable solvent, for example dichloromethane.
  • an optional drying agent for example magnesium sulfate
  • a suitable solvent for example dichloromethane.
  • an acid addition salt such as a hydrochloride salt
  • the reaction may be performed in the presence of a suitable base, for example triethylamine.
  • Compounds of Formula (VI) in which J is other than heteroarylalkyl, acid addition salts of compounds of Formula (VI) and E-CHO are known in the art or may be prepared by standard literature procedures.
  • Compounds of Formula (VI) in which J is heteroarylalkyl, such as 1 ,3-thiazol-4-ylmethyl, and A is an alkoxy, benzyloxy or tri-(C 1 - 4 alkyl)-silyloxy group may be prepared by treatment of a compound of Formula (VII) in which J is heteroarylalkyl, such as 1 ,3-thiazol-4-ylmethyl, and A is an alkoxy, benzyloxy or tri-(C ⁇ - 4 alkyl)-silyloxy group with an acid, for example 15% citric acid.
  • the reaction is carried out in a suitable solvent, for example THF.
  • reaction is carried out in the presence of a suitable base such as potassium ferf-butoxide.
  • reaction is carried out in a suitable solvent, for example THF.
  • suitable solvent for example THF.
  • reaction is carried out at a temperature in the range -10 to 10°C, more preferably 0°C.
  • Compounds of Formula (I) in which A is an ester may be prepared by esterification of a compound of Formula (I) in which A is hydroxy by standard literature procedures for esterification.
  • racemic compounds of Formula (I), (II), (lla), (III) and/or (Ilia) 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), (lla), (III) and/or (Ilia) may be resolved by chiral preparative HPLC. Alternatively, racemic compounds of Formula (I), (II), (lla), (III) and/or (Ilia) which contain an appropriate acidic or basic group, such as a carboxylic acid group or amine group may be resolved by standard diastereoisomeric salt formation with a chiral base or acid reagent respectively as appropriate.
  • an appropriate acidic or basic group such as a carboxylic acid group or amine group
  • individual enantiomeric compounds of Formula (III) and/or (Ilia) may be prepared by general methods of asymmetric synthesis using, where appropriate, chiral auxiliaries or chiral catalytic reagents and additionally performing any suitable functional group interconversion step as hereinbefore described, including the addition or removal of any such chiral auxiliary.
  • Such general methods of asymmetric synthesis are well known in the art and include, but are not restricted to, those described in "Asymmetric Synthesis," Academic Press, 1984 and/or “Chiral Auxiliaries and Ligands in Asymmetric Synthesis", Wiley, 1995.
  • suitable general chiral auxiliaries include chiral alcohols such as menthol or 1-phenylethanol; chiral oxazolidinones such as 4-benzyloxazolidin-2-one or 4-isopropyloxazolidin-2-one; chiral sultams such as camphor sultam; or chiral amines such as 1-phenylethylamine or 2-amino-2-phenylethanol.
  • Suitable general chiral catalytic reagents include chiral basic amines and chiral ligands such as N-methylephedrine, 1-phenyl-2-(1-pyrrolidinyl)-1-propanol, 3-(dimethylamino)- 1 ,7,7-trimethylbicyclo[2.2.1]-heptan-2-ol, 3,4-bis(diphenylphosphanyl)-1-(phenylmethyl)- pyrrolidine, chinchonine, chinchonidine, sparteine, hydroquinine or quinine, BINAP or chiral bis(oxazoline) (BOX) ligands and derivatives, optionally in the presence of a metal salt, for example M m X x where M is silver, cobalt, zinc, titanium, magnesium, or manganese, and X is halide (for example chloride or bromide), acetate, trifluoroacetate, p- toluene
  • Methanesulfonyl chloride (0.044 mL, 0.57 mmol) was diluted in dry dichloromethane (3 mL). To this solution was added triethylamine (0.08 mL, 0.57 mmol) followed by Intermediate 4 (0.3 g, 0.57 mmol) as a solution in dry dichloromethane (3 mL) and the mixture was stirred overnight at room temperature. Another equivalent each of methanesulfonyl chloride and triethylamine were added and after 1 hour the reaction was quenched with water (5 mL). The phases were separated using a hydrophobic frit and the solvent was evaporated to give the title compound. MS calcd for (C 30 H 42 N 2 O 7 S 2 + H) + : 607. MS (electrospray): Found (M+H) + 607.
  • the resulting oil was purified by reverse phase HPLC on a C 18 column using a two-solvent gradient elution comprising (A) water containing 0.1% v/v formic acid and (B) acetonitrile-water (95:5 v/v) containing 0.05% v/v formic acid, with analysis of the fractions by electrospray mass spectroscopy. Further purification by analytical HPLC using a Thermo-Fluophase column (100 x 20 mm, particle size 5 ⁇ ), eluting with aqueous acetonitrile (1 :1 v/v) and collecting the fraction with retention time 29 minutes gave the title compound as a solid.
  • the resulting oil was purified by reverse phase HPLC on a Ci ⁇ column using a two-solvent gradient elution comprising (A) water containing 0.1% v/v formic acid and (B) acetonitrile- water (95:5 v/v) containing 0.05% v/v formic acid, with analysis of the fractions by electrospray mass spectroscopy. Further purification by column chromatography over silica gel, eluting with cyclohexane/ethyl acetate (8:2, v/v), gave the title compound. MS calcd for (C 3 o ⁇ 42 ⁇ 2 ⁇ 6 S 2 + H) + : 591. MS (electrospray): Found (M+H) + 591.
  • 4-(chloromethyl)-1,3-thiazole hydrochloride (59.84 g, 352 mmol) was freshly converted to the free base as follows: The hydrochloride was mixed with dichloromethane (750 mL) and water (300 mL) and the pH of the aqueous layer was adjusted to pH 9 with solid sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and carefully evaporated at 80 torr to give the free base. Part C The 4-(chloromethyl)-1 ,3-thiazole (formed in Part B) was dissolved in THF (400 mL) and added dropwise (dropping funnel) over 45 min to the reaction mixture from Part A, keeping the reaction at ice-bath temperature.
  • 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; for example, 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, in one aspect, from 0.01 to 500 mg/Kg, in another aspect, 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 in one aspect from 0.01 mg to 100 mg/Kg, of a compound of Formula (I).
  • a topical formulation contains 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 propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • 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.
  • 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 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 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 1 M-Tris-HCI, pH7.5 (0.4 mL), 5M NaCI (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 (added last to start reaction) (10 ⁇ L), Total 21 ⁇ L.
  • 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 1 h at 22°C. After this time, the reaction was stopped by addition of 40 ⁇ L 1.875 mg/ml streptavidin SPA beads in 0.1 M EDTA.
  • the beads 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 Topcount (Packard) Scintillation Counter.
  • the exemplified compounds all had an IC 50 of ⁇ 50 ⁇ M in the above-described assay. Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV. Preferred compounds had an IC 50 of ⁇ 10 ⁇ 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- 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, especially interferon and/or ribavirin.
  • Another therapeutically active agent especially interferon and/or ribavirin.

Abstract

L'invention concerne des nouveaux agents antiviraux représentés par la formule (I) dans laquelle : A représente hydroxy; D représente aryle ou hetéroaryle; E représente hydrogène, alkyle C1-6, aryle, hétéroaryle ou hétérocyclyle; G représente hydrogène ou alkyle C1-6 éventuellement substitué par un ou plusieurs substituants choisis parmi halo, OR1, SR1, C(O)NR2R3, CO2H, C(O)R4, CO2R4, NR2R3, NHC(O)R4, NHCO2R4, NHC(O)NR5R6, SO2NR5R6, SO2R4, nitro, cyano, aryle, hetéroaryle et hétérocyclyle; R1 représente hydrogène, alkyle C1-6, arylalkyle, ou hétéroarylalkyle; R2 et R3 sont choisis indépendamment parmi hydrogène, alkyle C1-6, aryle et hétéroaryle; ou R2 et R3 conjointement avec l'atome d'azote auquel ils sont fixés forment un groupe cyclique saturé à 5 ou 6 éléments ; R4 est choisi dans le groupe formé d'alkyle C1-6, aryle, hétéroaryle, arylalkyle, et hétéroarylalkyle; R5 et R6 sont sélectionnés indépendamment dans le groupe formé d'hydrogène, alkyle C1-6, aryle, hétéroaryle, arylalkyle, et hétéroarylalkyle; ou R5 et R6 conjointement avec l'atome d'azote auquel ils sont fixés forment un groupe cyclique saturé à 5 ou 6 éléments ; et J représente alkyle C1-6, hétérocyclylalkyle, arylalkyle ou hétéroarylalkyle ; et des sels, solvates et esters de ceux-ci ; à condition que lorsque A est estérifié pour former OR, R étant choisi parmi aralkyle, aryloxyalkyle, aryle ou alkyle à chaîne ramifiée ou linéaire, alors R est différent de tertbutyle. L'invention concerne également des procédés de préparation desdits agents, des compositions pharmaceutiques les comprenant ainsi que des méthodes d'utilisation de ceux-ci dans un traitement contre le VHC.
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US9549941B2 (en) 2011-11-29 2017-01-24 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
US11707479B2 (en) 2013-08-27 2023-07-25 Gilead Sciences, Inc. Combination formulation of two antiviral compounds

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