WO2005034941A1 - Indoles and azaindoles as antiviral agents - Google Patents
Indoles and azaindoles as antiviral agents Download PDFInfo
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- WO2005034941A1 WO2005034941A1 PCT/GB2004/004306 GB2004004306W WO2005034941A1 WO 2005034941 A1 WO2005034941 A1 WO 2005034941A1 GB 2004004306 W GB2004004306 W GB 2004004306W WO 2005034941 A1 WO2005034941 A1 WO 2005034941A1
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- Prior art keywords
- indole
- cyclohexyl
- phenyl
- carboxylic acid
- alkyl
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- 0 CC(C1=CC(*)[C@](*=**=*)N1)=O Chemical compound CC(C1=CC(*)[C@](*=**=*)N1)=O 0.000 description 2
- AJKDUJRRWLQXHM-UHFFFAOYSA-N BrC1C=CCCC1 Chemical compound BrC1C=CCCC1 AJKDUJRRWLQXHM-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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
- C07D417/06—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
Definitions
- the present invention relates to indole and azaindole compounds, to pharmaceutical compositions containing them, to their use in the prevention and treatment of hepatitis C infections and to methods of preparation of such compounds and compositions.
- Hepatitis C HCV
- HCV Hepatitis C
- International patent applications WO 01/47883, WO 02/04425 and WO 03/000254 suggest fused ring compounds as possible inhibitors of HCV polymerase and illustrate thousands of possible benzimidazole derivatives that possess HCV polymerase inhibitory properties.
- Ar is a moiety containing at least one aromatic ring and possesses 5-, 6-, 9- or 10-ring atoms 0 to 3 of which may be N, O or S heteroatoms of which at most 1 will be O or S; which moiety may be optionally substituted by groups Q 1 , Q 2 or Q 3 wherein Q 1 is a hydroxy group, fluorine, chlorine, bromine or iodine atom or a C ⁇ -6 alkyl, C ⁇ _ 6 alkyl substituted by not more than 5 fluorine atoms, C ]-6 alkoxyl, C ⁇ .
- a 1 is C ⁇ -6 alkyl, C 2 .6alkenyl, or Cu ⁇ alkyl or C 2-6 alkenyl substituted by C 1-4 alkoxy or up to 5 fluorine atoms or a non-aromatic ring of 3 to 8 ring atoms which may contain a double bond and which may contain a O, S, SO, SO 2 or NH moiety and which may be optionally substituted by one or two alkyl groups of up to 2 carbon atoms or by 1 to 8 fluorine atoms; one of R 1 and R 2 is a Het or is hydrogen, fluorine, chlorine or bromine atom or a C ⁇ -4 alkyl, C 2- alkenyl, C ]-4 alkoxy, Ci ⁇ alkyl or alkoxy substituted by up to 5 fluorine atoms, nitrile, carboxy, C ⁇ .
- R 1 and R 2 alkoxycarbonyl, C ⁇ . alkyl or C 2 . alkenyl substituted by a carboxy or C ⁇ -4 alkoxycarbonyl group, or a NR 3 R 4 , SO 2 NR 3 R 4 or CONR 3 R 4 group where R 3 is hydrogen, C ]-4 alkyl, SO 2 R 5 or COR 5 and R 4 is hydrogen, hydroxyl or C ⁇ - alkyl or R 3 and R 4 are alkylene linked to form a 5- or 6-membered ring, and R 5 is C ⁇ -4 alkyl optionally substituted by up to 5 fluorine atoms; Het is a 5 or 6-membered aromatic ring of which 1, 2, 3 or 4 ring atoms may be selected from N, O, S with at most 1 being O or S which ring may be substituted by 1 or 2 groups selected C 1-4 alkyl or hydroxy or tautomers thereof, or is 2-hydroxy-cyclobutene-3,4-dione: the other of R 1
- the group C n H 2n may be straight or branched such as a -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -CH(CH 3 )-, -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 - or the like straight or branched butyl, pentyl or hexyl group.
- the C n H 2n group is a -CH 2 - group.
- -ealkyl means methyl, ethyl, 1-propyl, 2-propyl or a straight or branched butyl, pentyl or hexyl group.
- Particularly apt C 1-6 alkyl groups are methyl, ethyl, propyl and butyl groups.
- Favoured alkyl groups are ethyl and methyl groups.
- the methyl group is the preferred alkyl group.
- Most suitably a C 1-6 alkyl group substituted by up to 5 fluorine atoms will include a CF 3 , CHF 2 and/or CF 2 moiety.
- Favoured fluoroalkyl groups are the CF 3 , CH F and CF 2 CF 3 groups.
- the CF 3 group is the preferred fluoroalkyl group.
- C 1-6 alkoxy and fluorinated C ⁇ - 6 alkoxy are analogous to the alkyl and fluoroalkyl groups described above so that, for example, preferred groups include OCH 3 , OCF 3 and OCHF 2 groups.
- Favoured values for R a and R b independently include hydrogen, fluorine, methyl, methoxy and trifluoromethyl.
- R a and R b include hydrogen or fluorine.
- a preferred value for R a is hydrogen.
- a preferred value for R b is hydrogen.
- the Ar moiety may contain a single aromatic ring or one aromatic ring to which a further aromatic or non-aromatic ring is fused.
- Favoured values for Ar include optionally substituted 6-membered heteroaromatic groups with 1, 2 or 3 nitrogen ring atoms; unsubstituted or substituted 5-membered heteroaromatic groups with 1, 2, 3 or 4 nitrogen ring atoms; unsubstituted or substituted 5-membered heteroaromatic groups with one nitrogen ring atom and one oxygen or sulfur ring atoms; unsubstituted or substituted 5-membered heteroaromatic groups with two nitrogen atoms and one oxygen or sulfur atom.
- the optional substituents on such rings include one or two fluorine, chlorine, bromine, hydroxyl, C ⁇ -4 alkoxy or CF 3 groups of which methyl and hydroxyl are preferred.
- Particularly apt values for Ar also include phenyl and substituted phenyl or the formula C 6 H 2 Q ! Q 2 Q 3 of which phenyl, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, dibromophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl, carboxyphenyl, cyanophenyl, trifluoromethylphenyl and the like are preferred.
- Ar is aptly an optionally substituted phenyl, pyridyl, imidazolyl, thiazolyl or oxadiazolyl group.
- the optional substituents on such groups include one or two fluorine, chlorine, bromine, C ⁇ -6 alkyl, hydroxyl, CF 3 , cyano, carboxyl, methylsulfonyl or (CH 2 ) 0 . 3 N(C 1- alkyl) 2 groups, of which methyl, fluoro, chloro, bromo, cyano, carboxyl, methylsulfonyl and CH 2 N(CH 3 ) 2 are preferred.
- Ar is a group selected from phenyl, methylphenyl, mono- or difluorophenyl, mono- or dichlorophenyl, mono- or dibromophenyl, cyanophenyl, carboxyphenyl, methylsulfonylphenyl, pyridyl, imidazolyl or methylthiazolyl.
- Ar is phenyl, 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3- methylphenyl, 4-methylphenyl, 3,5-dibromophenyl, 4-methylsulfonylphenyl, 3- carboxyphenyl, pyrid-2-yl, pyrid-3-yl, 2-methyl-l,3-thiazol-4-yl, lH-imidazol-4-yl or 5-[(dimethylamino)methyl]-l,2,4-oxadiazol-3-yl.
- Ar 1 may contain a single aromatic ring or one aromatic ring to which a further aromatic or non-aromatic ring is fused.
- Ar 1 is aptly phenyl, naphthyl, indolyl, tetrahydronaphthyl, pyridyl, imidazolyl, furyl, thienyl, pyrolidyl, oxazolyl, thiazolyl, pyrazolyl, pyridazolyl, triazolyl, oxadiazolyl, thiodiazolyl or quinonyl, any of which may be optionally substituted by group Q 4 , Q 5 or Q 6 as hereinbefore defined.
- Ar 1 is a pyridyl, furyl or thienyl group or a group of the formula C 6 H 2 Q 4 Q 5 Q 6 .
- One particularly favoured group Ar 1 is the pyridyl group.
- Other particularly favoured Ar 1 groups are optionally substituted phenyl groups of the formula C O H S Q'Q 2 of which phenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, trifluoromethylphenyl, methoxyphenyl, difluorophenyl, dichlorophenyl, ⁇ [isopropyl(methyl)amino]-methyl ⁇ phenyl and the like are preferred.
- Ar 1 is phenyl, methoxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, pyridyl or ⁇ [isopropyl(methyl)amino]-methyl ⁇ . More particularly Ar 1 is phenyl, 4-methoxyphenyl, 2-fluorophenyl, 4-hydroxyphenyl, pyrid-2-yl or 2-(3- ⁇ [isopropyl(methyl)amino]-methyl ⁇ phenyl). Particularly suitable groups A 1 include those groups of the formula:
- Favoured groups A 1 include cycloalkyl and cycloalkenyl groups of 5 or 6 ring members.
- a preferred group A 1 is the cyclohexyl group.
- a preferred group R 1 is the CO 2 H group or a pharmaceutically acceptable salt thereof.
- R 1 and R 2 are a hydrogen atom.
- a favoured value for i is CH.
- a favoured value for X4 is CH.
- Favoured values for A 1 include non-aromatic rings. Such rings are aptly of 5 or 6 carbon atoms and which are saturated or monounsaturated.
- Preferred groups A 1 include cyclopentyl, cyclohexyl and cyclohexenyl groups.
- n, X , Ar, Q , Q and Q are as defined in relation to formula (I) or a pharmaceutically acceptable salt thereof.
- a favoured value for Q is H
- a favoured value for n is 1
- a favoured value for X 1 is CH so that particularly apt compounds of the invention include those of formula (III):
- Ar, Q 1 and Q 2 are defined in relation to formula (I), or a pharmaceutically acceptable salt thereof.
- Q 2 is hydrogen, fluorine chlorine, methyl, hydroxy, methoxy or trifluoromethyl.
- Q 1 is hydrogen or fluorine.
- Q 1 is hydrogen and Q 2 is hydrogen, fluorine, methoxy or hydroxy.
- the compounds of the formula (I) may be in the form of a pharmaceutically acceptable salt such as a sodium, potassium, calcium, magnesium or ammonium salt or a salt with a pharmaceutically acceptable organic base.
- the compound of the formula (I) also contain a group, the compound may be zwitterionic or in the form of a salt with a pharmaceutically acceptable acid such as hydrochloric, sulphuric, phosphoric, methane sulfonic and the like acid.
- a pharmaceutically acceptable acid such as hydrochloric, sulphuric, phosphoric, methane sulfonic and the like acid.
- X , X , X , X , A , Ar , Ar, n, p and q are as defined in relation to formula I and L is a good leaving group such as chlorine, bromine, iodine, methanesulfonate, tolyenesulfonate, triflate or the like.
- L is a good leaving group such as chlorine, bromine, iodine, methanesulfonate, tolyenesulfonate, triflate or the like.
- the compound of the formula (TV) may contain a CO 2 CH 3 group and the resulting compound of the formula (I) may be hydrolysed in conventional manner, for example with sodium hydroxide in aqueous methanol or BBr 3 in DCM to yield the compound containing the carboxylate or its sodium salt.
- the substituents on the core bicycle may be elaborated after the amidation reaction, for example if the desired compound of formula (I) contains a tetrazole group then the compound of formula (IV) may contain CN group and the resulting compound of formula (I) may be reacted with an azide.
- the compounds of formula (I) may be prepared from the corresponding compound of the formula (VI):
- T is a C n H 2n (SO 2 ) p (CO)qAr group by reaction with Ar'f3(OH) 2 in the presence of a Pd[0] catalyst under conditions conventional for the Suzuki reaction, wherein n, p, q, Ar and Ar 1 are as defined in relation to formula (I).
- the compound of formula (VI) wherein T is a C n H 2n (SO ) p (CO) q Ar group can be prepared from the compound of formula (VI) wherein T is a hydrogen atom by reaction with a compound of formula (V).
- the compound of formula (VI) may be prepared by the reaction of NBS and the compound of the formula (VII):
- a further process for the preparation of the compounds of formula (VII) wherein T is hydrogen comprises the reaction of the compounds of the formulae:
- This invention also provides compounds per se of formula (I) (II) or (III) except where Ar is phenyl and X is an acidic function or salts and esters thereof.
- the compounds of formulae (I)-(III) may be used for the inhibition of HCV polymerase and so may be used for the manufacture of medicaments which may be used to treat HCV infection.
- this invention provides a pharmaceutical composition comprising a compound of the formula (I) as hereinbefore described as a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
- the invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
- compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
- a pharmaceutical carrier e.g.
- a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- liquid forms in which the novel compositions of the present invention may be inco ⁇ orated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin.
- a suitable dosage level is about 0.01 to 250 mg kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day.
- the compounds may be administered on a regimen of 1 to 4 times per day. Most suitably the administration is orally using a unit done as previously indicated.
- this invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of infection by hepatitis C virus.
- the medicament is in unit dose form adapted for oral administration as indicated hereinbefore.
- this invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of infection by hepatitis C virus in a mammal and preferably in a human. Most suitably the treatment is effected by oral administration of a unit dose form as indicated hereinbefore.
- a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of infection by hepatitis C virus in a mammal and preferably in a human. Most suitably the treatment is effected by oral administration of a unit dose form as indicated hereinbefore.
- the following Examples are illustrative of this invention.
- the compounds of the invention were tested for inhibitory activity against the HCV RNA dependent RNA polymerase (NS5B) in an enzyme inhibition assay
- example i an enzyme assay and an cell based sub-genomic replication assay (described in example ii)).
- the compounds generally have IC50's below 0.5 ⁇ M in the enzyme assay and EC50's typically below 20 ⁇ M in the cell based assay.
- WO 96/37619 describes the production of recombinant HCV RdRp from insect cells infected with recombinant baculovirus encoding the enzyme.
- the purified enzyme was shown to possess in vitro RNA polymerase activity using RNA as template.
- the reference describes a polymerisation assay using poly(A) and oligo(U) as a primer or an heteropolymeric template.
- Incorporation of tritiated UTP or NTPs is quantified by measuring acid-insoluble radioactivity.
- the present inventors have employed this assay to screen the various compounds described above as inhibitors of HCV RdRp. Incorporation of radioactive UMP was measured as follows.
- the standard reaction (50 ⁇ l) was carried out in a buffer containing 20 mM tris/HCl pH 7.5, 5 mM MgCl 2 , 1 mM DTT, 50 mM NaCl, 0.03 % N-octylglucoside, 1 ⁇ Ci [ 3 H]-UTP (40 Ci/mmol, NEN), 10 ⁇ M UTP and 10 ⁇ g/ml poly(A) or 5 ⁇ M NTPs and 5 ⁇ g/ml heteropolymeric template. Oligo(U) ⁇ 2 (1 ⁇ g/ml, Genset) was added as a primer in the assay working on Poly(A) template. The final NS5B enzyme concentration was 5 nM.
- the order of assembly was: 1) compound, 2) enzyme, 3) template/primer, 4) NTP. After 1 h incubation at 22 °C the reaction was stopped by adding 50 ⁇ l of 20 % TCA and applying samples to DE81 filters. The filters were washed thoroughly with 5 % TCA containing 1M Na 2 HPO 4 /NaH 2 PO 4 , pH 7.0, rinsed with water and then ethanol, air dried, and the filter-bound radioactivity was measured in the scintillation counter. Carrying out this reaction in the presence of various concentrations of each compound set out above allowed determination of IC 50 values by utilising the formula:
- Cell clones that stably maintain subgenomic HCV replicon were obtained by transfecting Huh-7 cells with an RNA replicon identical to I 377 neo/NS3-37wt described by Lohmann et al. (1999) (EMBL-genbank No. AJ242652), followed by selection with neomycin sulfate (G418). Viral replication was monitored by measuring the expression of the NS3 protein by an ELISA assay performed directly on cells grown in 96 wells microtiter plates (Cell-ELISA) using the anti-NS3 monoclonal antibody 10E5/24 (we have first described the assay in our replicon patent WO 0259321 A2).
- Cells were seeded into 96 well plates at a density of 10 4 cells per well in a final volume of 0.1 ml of DMEM/10 % FCS. Two hours after plating, 50 ⁇ l of DMEM/10 % FCS containing a 3x concentration of inhibitor were added, cells were incubated for 96 hours and then fixed for 10' with ice-cold isopropanol. Each condition was tested in duplicate and average absorbance values were used for calculations.
- the cells were washed twice with PBS, blocked with 5 % non-fat dry milk in PBS + 0.1 % Triton X100 + 0.02 % SDS (PBSTS) and then incubated o/n at 4° C with the 10E5/24 mab diluted in Milk/PBSTS. After washing 5 times with PBSTS, the cells were incubated for 3 hours at room temperature with Fc specific anti-mouse IgG conjugated to alkaline phosphatase (Sigma), diluted in Milk/PBSTS. After washing again as above, the reaction was developed with p-Nitrophenyl phosphate disodium substrate (Sigma) and the absorbance at 405/620 nm read at intervals.
- PBSTS Triton X100 + 0.02 % SDS
- ⁇ nmr spectra were recorded on Bruker AM series spectrometers operating at (reported) frequencies between 300 and 600 MHz and unless otherwise stated were recorded at 300K. Chemical shifts ( ⁇ ) for signals corresponding to non-exchangeable protons (and exchangeable protons where visible) are recorded in parts per million (ppm) relative to tetramethylsilane and are measured using the residual solvent peak as reference.
- Step 2 methyl 3-(phenylethvnyl)-4-r(trifluoroacetyl)amino1benzoate
- Step 3 methyl 3-cvclohex-l-en-l-yl-2-phenyl-lH-indole-5-carboxylate
- a solution (0.2 M) of methyl 3-(phenylethynyl)-4-[(trifluoroacetyl)amino]benzoate in MeCN was treated with cyclohex-1-en-l-yl trifluoromethanesulfonate (1.0 eq) and K 2 CO 3 (5.0 eq). Pd(PPh 3 ) (0.05 eq) was added and the mixture was stirred at room temperature for 2 h.
- Step 4 methyl 3-cvclohexyl-2-phenyl-lH-indole-5-carboxylate
- a solution (0.05 M) of methyl 3-cyclohex-l-en-l-yl-2-phenyl-lH-indole-5- carboxylate in MeO ⁇ was treated with 50 wt % Pd/C (10 % by weight) and ammonium formate (4.0 eq). The mixture was stirred under reflux for 5 h then cooled and filtered. The filtrate was treated with fresh catalyst and and ammonium formate as above and heated under reflux for 10 h. The cooled solution was filtered and concentrated to give the title compound as an oil.
- Step 5 l-benzyl-3-cvclohexyl-2-phenyl-lH-indole-5-carboxylic acid
- a solution (0.06 M) of methyl 3-cyclohexyl-2-phenyl-lH-indole-5-carboxylate in dry T ⁇ F was treated with Na ⁇ (1.4 eq) then stirred at room temperature for 0.5h.
- Benzyl bromide (1.15 eq) was added and the mixture was stirred for 5 h.
- the solvent was removed, and the residue was diluted to 0.05 M with C ⁇ 2 C1 2 .
- BBr 3 (3.0eq) was added and the mixture was stirred for 0.5 h then concentrated in vacuo.
- Step 3 methyl 3-r(trifluoroacetyl)amino1-4- ⁇ r(trifluoromethyl)sulfonyl1oxy)benzoate
- a solution (0.8 M) of methyl 4-hydroxy-3-[(trifluoroacetyl)amino]benzoate in dry pyridine was cooled to 0 °C and treated dropwise with trifluoromethanesulfonyl anhydride (1.15 eq). The mixture stirred for 1 h at 20 °C then diluted with H 2 O and
- Step 4 methyl 2-pyridin-2-yl-lH-indole-6-carboxylate A solution (0.2 M) of methyl 3-[(trifluoroacetyl)amino]-4-
- Step 1 methyl 2-( -methoxyphenyl)-lH-indole-6-carboxylate Using the procedure described in example 2 step 4, treatment of 3- [(trifluoroacetyl)amino]-4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ benzoate with 4- ethynylanisole (2.0 eq) gave a residue that was purified by flash chromatography on silica gel (3:7 AcOEt:petroleum ether) to afford the title compound (51 %) as a solid.
- Step 4 l-benzyl-3-cyclohexyl-2-(4-methoxyphenyl)-lH-indole-6-carboxylic acid
- a solution (0.04 M) of 3-cyclohexyl-2-(4-methoxyphenyl)-lH-indole-6-carboxylic acid in DMF was treated with Na ⁇ (1.5 eq) and the mixture was stirred for 1 h at room temperature.
- Benzylbromide (1.8 eq) was added and the mixture was stirred at room temperature for 1 h. After dilution with AcOEt the organic layer was washed with ⁇ C1 (I N) and brine then dried.
- Step 2 methyl 3-cyclohex-2-en-l-yl-2-phenyl-lH-indole-6-carboxylate
- a solution (0.06 M) of methyl 2-phenyl-lH-indole-6-carboxylate in dry DMF with Na ⁇ (1.1 eq) and 3- bromocyclohexene (1.3 eq) afforded a residue that was purified by flash chromatography on silica gel (1:9 AcOEt: petroleum ether) to afford the title compound (79 %) as a solid.
- Step 3 methyl 3-cyclohexyl-2-phenyl-lH-indole-6-carboxylate
- MeO ⁇ methyl 3-cyclohex-2-en-l-yl-2-phenyl-lH-indole-6- carboxylate in MeO ⁇
- 10 % Pd/C 10 % wt.
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Abstract
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Priority Applications (5)
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EP04768837A EP1673081A1 (en) | 2003-10-10 | 2004-10-08 | Indoles and azaindoles as antiviral agents |
AU2004280120A AU2004280120A1 (en) | 2003-10-10 | 2004-10-08 | Indoles and azaindoles as antiviral agents |
US10/575,633 US20070072911A1 (en) | 2003-10-10 | 2004-10-08 | Indoles and azaindoles as antiviral agents |
JP2006530604A JP2007508286A (en) | 2003-10-10 | 2004-10-08 | Indole and azaindole as antiviral agents |
CA002541582A CA2541582A1 (en) | 2003-10-10 | 2004-10-08 | Indoles and azaindoles as antiviral agents |
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GBGB0323845.8A GB0323845D0 (en) | 2003-10-10 | 2003-10-10 | Chemical compounds,compositions and uses |
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US (1) | US20070072911A1 (en) |
EP (1) | EP1673081A1 (en) |
JP (1) | JP2007508286A (en) |
CN (1) | CN1863528A (en) |
AU (1) | AU2004280120A1 (en) |
CA (1) | CA2541582A1 (en) |
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Also Published As
Publication number | Publication date |
---|---|
GB0323845D0 (en) | 2003-11-12 |
EP1673081A1 (en) | 2006-06-28 |
CN1863528A (en) | 2006-11-15 |
US20070072911A1 (en) | 2007-03-29 |
JP2007508286A (en) | 2007-04-05 |
AU2004280120A1 (en) | 2005-04-21 |
CA2541582A1 (en) | 2005-04-21 |
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