WO2009102876A1 - Inhibiteurs macrocycliques de protéase de l'hépatite c - Google Patents

Inhibiteurs macrocycliques de protéase de l'hépatite c Download PDF

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Publication number
WO2009102876A1
WO2009102876A1 PCT/US2009/033934 US2009033934W WO2009102876A1 WO 2009102876 A1 WO2009102876 A1 WO 2009102876A1 US 2009033934 W US2009033934 W US 2009033934W WO 2009102876 A1 WO2009102876 A1 WO 2009102876A1
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compound
groups
substituted
cycloalkyl
alkyl
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PCT/US2009/033934
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English (en)
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Michael E. Hepperle
David Alan Campbell
David T. Winn
Juan Manuel Betancort
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Phenomix Corporation
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Priority to CA2705300A priority Critical patent/CA2705300A1/fr
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Publication of WO2009102876A1 publication Critical patent/WO2009102876A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom

Definitions

  • Hepatitis C virus is the causative agent for hepatitis C, a chronic infection characterized by jaundice, fatigue, abdominal pain, loss of appetite, nausea, and darkening of the urine.
  • HCV belonging to the hepacivirus genus of the Flaviviriae family, is an enveloped, single-stranded positive-sense RNA-containing virus.
  • the long-term effects of hepatitis C infection as a percentage of infected subjects include chronic infection (55-85%), chronic liver disease (70%), and death (1-5%).
  • HCV is the leading indication for liver transplant. In chronic infection, there usually presents progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma.
  • the HCV genome (Choo et al., Science 1989, 244, 359-362; Simmonds et al., Hepatology 1995, 21, 570-583) is a highly variable sequence exemplified by GenBank accession NC_004102 as a 9646 base single-stranded RNA comprising the following constituents at the parenthetically indicated positions: 5' NTR (i.e., non-transcribed region) (1-341); core protein (i.e., viral capsid protein involved in diverse processes including viral morphogenesis or regulation of host gene expression) (342-914); El protein (i.e., viral envelope) (915-1490); E2 protein (i.e., viral envelope) (1491-2579); p7 protein (2580- 2768); NS2 protein (i.e., non-structural protein 2) (2769-3419); NS3 protease (3420-5312); NS4a protein (5313-5474); NS4b protein (5475-6257);
  • a 17-kDalton -2/+1 frameshift protein, "protein F”, comprising the joining of positions (342-369) with (371-828) may provide functionality originally ascribed to the core protein.
  • the NS3 (i.e., non-structural protein 3) protein of HCV exhibits serine protease activity, the N-terminus of which is produced by the action of a NS2- NS3 metal-dependent protease, and the C-terminus of which is produced by auto-proteolysis.
  • the HCV NS3 serine protease and its associated cofactor, NS4a process all of the other non-structural viral proteins of HCV. Accordingly, the HCV NS3 protease is essential for viral replication.
  • the present invention is directed to compounds of Formula I, the compounds being adapted to inhibit the viral protease NS3 of the Hepatitis C Virus (HCV); to the use of compounds of compounds of Formula I in the treatment of malconditions for which inhibition of HCV protease is medically indicated, such as in the treatment of HCV infections; and to pharmaceutical compositions and combinations including a compound of Formula I as defined herein.
  • the compounds of Formula I are adapted to bind to, and thus block the action of, an HCV-encoded protease enzyme that is required by the virus for the production of intact, mature, functional viral proteins from the viral polyprotein as translated from the viral RNA, and therefore for the formation of infectious particles, and ultimately for viral replication.
  • the compounds of the invention are mimics or analogs of the peptide domain immediately N-terminal of the substrate site where the viral protease cleaves its native substrate viral polyprotein, and are believed to bind to and inhibit the protease by virtue of this mimicry or analogy.
  • An embodiment of the present invention provides a compound of Formula I:
  • R c at each occurrence is independently H, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl; wherein any carbon atom can be substituted with a J group; or two R c groups together with a nitrogen atom to which they are bound form together with the nitrogen atom a 5-11 membered mono- or bicyclic heterocyclic ring system that is unsubstituted or is substituted with 1-3 J groups;
  • R 1 , R la , R 2 and R 2a are independently H or alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any carbon atom can be unsubstituted or can be substituted with J;
  • D is CH, N, or O, provided that when D is O, R 1 is absent;
  • W is CH, N, or O; provided that when W is O, then D is N, and Q, R l a , V, K and T are absent;
  • L is O, S, C 2 , C 2 H 2 or C 2 H 4 ;
  • V is a bond, CH 2 , C( R 10 ) 2 , C(O), S(O), or S(0) 2:
  • K is a bond, O, S, C(O), S(O), S(O) 2 , or S(O)(NR 1 1 ), N(R 1 1 ); provided that when Q and V or V and K are both bonds, the two bonds taken together are a single bond, or when Q, V and K are all bonds, the three bonds taken together are a single bond;
  • T is R 1 1 , alkyl-R 11 , alkenyl-R 1 1 , alkynyl-R 1 1 , OR 1 1 , or N(R U ) 2 ;
  • R 6 is independently at each occurrence hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, and is substituted with 0-3 J groups; or wherein two R 6 groups together with a carbon atom to which they are bond form a 3-8 membered cycloalkyl, which can be unsubstituted or substituted with 1 -3 J, wherein the 3-8 membered cycloalkyl can contain 0-3 heteroatoms selected from the group consisting of O, NH, NR' and S, wherein the 3-8 membered cycloalkyl can be fused with a cyclo
  • R 7 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aralkanoyl, heteroaralkanoyl, C(O)R 8 , SO 2 R or carboxamido, and is substituted with 0-3 J groups;
  • R 8 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl and is substituted with 0-3 J groups; J is halogen, OR', OC(O)N(R') 2 , CN, CF 3 , OCF 3 , R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R') 2 , SR', SOR', SO 2 R', SO 2 N(R') 2 , SO 3 R', C(O)R', C(O)C(O)R', C(O)CH 2 C(O)R', C(S)R', C(O)OR', OC(O)R', C(0)N(R') 2 , OC(O)N(RO 2 , C(S)N(R') 2 , (CH
  • X is a bond, O, S, CH( R 6 ) or N(R 7 );
  • Y is a bond, CH 2 , C(O), C(O)C(O), S(O), S(O) 2 , or S(O)(NR 7 ); and,
  • Z is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, OR 9 , or N(R 9 ) 2 , wherein a heterocyclyl or heteroaryl group can be bonded by a carbon atom or by a heteroatom, wherein any carbon atom is unsubstituted or is substituted with
  • R 9 is independently at each occurrence hydrogen, or substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl, or two R 9 groups which are bound to a nitrogen atom can form together with the nitrogen atom a 5-11 membered mono- or bicyclic heterocyclic ring system wherein the heterocyclic ring system is substituted with 0-3 J groups and can contain 0-3 additional heteroatoms selected from the group consisting of O, NH, NR' and S.
  • Various embodiments of the invention are directed to methods for synthesis of compounds of Formula I.
  • Various embodiments of the invention are directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I and a suitable excipient.
  • Various embodiments of the invention are further directed to a pharmaceutical combination comprising a compound of Formula I in a therapeutically effective amount and a second medicament in a therapeutically effective amount.
  • the pharmaceutical combination of the invention may be formulated as a pharmaceutical composition of the invention.
  • Various embodiments of the invention are further directed to methods of treatment of a HCV infection in a patient in need thereof, or in a patient when inhibition of an HCV viral protease is medically indicated, comprising administering a therapeutically effective amount of a compound of Formula I to the patient.
  • Various embodiments of the invention are further directed to a method of treatment of a HCV infection in a patient in need thereof, or in a patient when inhibition of an HCV viral protease is medically indicated, comprising administering a therapeutically effective amount of a compound of Formula I to the patient in conjunction with administering an effective amount of a second medicament to the patient.
  • the second medicament can include another antiviral agent, an antibiotic, or a medicament for alleviating symptoms of a Hepatitis C infection.
  • Various embodiments of the invention are directed to use of an inventive compound in preparation of a medicament for the treatment of an HCV infection in a patient.
  • an effective amount of a second bioactive agent can be used in preparation of a medicament for treatment of an HCV infection in a patient.
  • Various embodiments of the invention provide an inventive compound for use in combination with an effective amount of a second medicament in treatment of an HCV infection in a patient.
  • references in the specification to "one embodiment” or “an embodiment” indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.
  • the term “various embodiments” refers to one or a plurality of embodiments, but not necessarily to all embodiments, according to the present invention.
  • other type(s) of therapeutic agents refers to one or more antiviral agents, other than HCV NS3 serine protease inhibitors of the invention.
  • Subject as used herein, includes mammals such as humans, non-human primates, rats, mice, dogs, cats, horses, cows and pigs.
  • treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes administering a compound of the present invention to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • Treating within the context of the instant invention means an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
  • treating a hepatitis C viral infection includes slowing, halting or reversing the growth of the virus and/or the control, alleviation or prevention of symptoms of the infection.
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result by inhibition of HCV NS3 serine protease activity.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount of a HCV NS3 serine protease inhibitor of the invention is an amount sufficient to control HCV viral infection.
  • chiral, diastereomeric, racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • Compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.
  • amino protecting group or “N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine.
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxy acetyl, ⁇ - chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the
  • Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
  • amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbon
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboyxlate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines
  • a substituent When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as O, S, C(O), S(O), or S(O) 2 can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • the O can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]- oxabicyclo system.
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 ) n or (CR' 2 ) n wherein n is 1 , 2, 3, or more, and each R' is independently selected.
  • Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carbocyclic and “carbocycle” denote a ring structure wherein the atoms of the ring are carbon.
  • the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N-I substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • (Cycloalkyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
  • (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C ⁇ CH, -C ⁇ C(CH 3 ), -
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non- carbon groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyl groups include aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, A-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N- hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1- anthracenyl, 2-anthracenyl, 3 -anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3 -pyrazolyl), imidazolyl (1-imidazolyl,
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3- yl methyl, tetrahydro furan-2-yl ethyl, and indol-2-yl propyl.
  • Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • Halo as the term is used herein includes fluoro, chloro, bromo, and iodo.
  • a "haloalkyl” group includes mono-halo alkyl groups, and poly-halo alkyl groups wherein all halo atoms can be the same or different. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1 ,2-dichloroethyl, 1,3- dibromo-3,3-difluoropropyl and the like.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moeity. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • the group is a "formyl” group, an acyl group as the term is defined herein.
  • haloacyl an example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • the term "amine” also includes ammonium ions as used herein.
  • amino group is a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • ammonium ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethyl ammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • urethane (or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR 2 groups, respectively.
  • sulfonamide (or “sulfonamido”) includes S- and N- sulfonamide groups, i.e., -SO 2 NR 2 and -NRSO 2 R groups, respectively.
  • Sulfonamide groups therefore include but are not limited to sulfamoyl groups (- SO 2 NH 2 ).
  • An organosulfur structure represented by the formula -S(O)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • the term "amidine” or “amidino" includes groups of the formula -C(NR)NR 2 . Typically, an amidino group is -C(NH)NH 2 .
  • guanidine or "guanidino” includes groups of the formula -NRC(NR)NR 2 .
  • a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • a "pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other.
  • amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • a “hydrate” is a compound that exists in a composition with water molecules. The composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non-stoichiometric.
  • Tautomers are two forms of a substance differing only by the position of a hydrogen atom in the molecular structures.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals.
  • R 1 , R la , R 2 and R 2a are independently H or alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any carbon atom can be unsubstituted or can be substituted with J; D is CH, N, or O, provided that when D is O, R 1 is absent;
  • W is CH, N, or O; provided that when W is O, then D is N, and Q, R la , V, K and T are absent; Q is a bond, CH, O or N; provided that when Q is a bond or O, R l a is absent; when D is CH, then W is N; when D is O, then W is N, R 1 is absent and Q is a bond; when D is N, then W is CH, and Q is N; or when D is N, then W is N, and Q is a bond; and, m is 1, 2, 3 or 4; n is 0, 1 , 2, 3 or 4; p is 0, 1, 2, 3, or 4, wherein when p is 0 a single bond is present between a carbon atom labeled "a" and a carbon atom labeled "b”; q is 1, 2, 3, or 4; M is O, S, C( R 6 ) 2 or N(R 7 ); L is O, S, C 2 , C 2 H 2 or C 2 H 4 ; V is
  • R 6 is independently at each occurrence hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, and is substituted with 0-3 J groups; or wherein two R 6 groups together with a carbon atom to which they are bond form a 3-8 membered cycloalkyl, which can be unsubstituted or substituted with 1 -3 J, wherein the 3-8 membered cycloalkyl can contain 0-3 heteroatoms selected from the group consisting of O, NH, NR' and S, wherein the 3-8 membered cycloalkyl can be fused with a cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring, or any combination thereof; R 7 is hydrogen, alkyl, cycloalkyl, cycloal
  • R is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryl alkyl and is substituted with 0-3 J groups;
  • J is halogen, OR 1 , OC(O)N(R') 2 , CN, CF 3 , OCF 3 , R, O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R') 2 , SR', SOR', SO 2 R', SO 2 N(R') 2 , SO 3 R 1 , C(O)R', C(O)C(O)R 1 , C(O)CH 2 C(O)R', C(S)R 1 , C(O)OR', OC(O)R', C(0)N(R') 2 , 0C(0)N(R') 2 , C(S)N(R') 2 , (CH 2 ) O-2 NHC(O)R', N(R')N(R')C(0)R', N(R)N(R')C(0)0R', N(R 1 )N(R')C0N(R') 2 ,
  • R 1 ' is independently hydrogen, alkyl, aryl, aralkyl, alkoxy, cycloalkyl, cycloalkylidenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylidenyl, heteroaryl, or heteroarylalkyl, wherein any R 1 1 except hydrogen is substituted with 0-3 J groups, or a first R 1 ' and a second R 1 ' together with a nitrogen atom to which they are bound form a mono- or bicyclic ring system substituted with 0-3 J groups; and X is a bond, O, S, CH( R 6 ) or N(R 7 );
  • Y is a bond, CH 2 , C(O), C(O)C(O), S(O), S(O) 2 , or S(O)(NR 7 ); and, Z is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, OR 9 , or N(R 9 ) 2 , wherein a heterocyclyl or heteroaryl group can be bonded by a carbon atom or by a heteroatom, wherein any carbon atom is unsubstituted or is substituted with
  • R 2 and R 2a are both H.
  • D is NH and W is O, and accordingly V, K and
  • L is C 2 H 2 or C 2 H 4 .
  • Z is aryl or heteroaryl.
  • X is O.
  • Y is a bond.
  • V and K comprise a bond and T is alkyl, for example, T can be methyl.
  • Z is biphenyl or a substituted quinolyl.
  • the substituted quinolyl moiety can be
  • the compound or set of compounds can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • the compound of formula I can be any of the structures shown in the list of exemplary compounds, Table 1 , shown below, or any stereoisomer, hydrate, solvate, tautomer, prodrug, salt, or pharmaceutically acceptable salt, or any mixture thereof.
  • a method of synthesis of a compound of formula I comprising contacting a compound of formula II
  • the olefin metathesis catalyst can be dichloro(o- isopropoxyphenylmethylene) (tricyclohexylphosphine)ruthenium II.
  • the invention further provides a method of synthesis of a compound of formula I wherein L is C 2 H 4 , the method comprising contacting the compound of formula I wherein L is C 2 H 2 and hydrogen in the presence of a catalyst.
  • the catalyst for the hydrogenation step can be platinum or palladium metal.
  • the invention provides methods of inhibiting HCV NS3 protease.
  • the methods include contacting the hepatitis C viral serine protease with a compound as described herein.
  • the methods of inhibiting HCV NS3 protease include administering a compound as described herein to a subject infected with hepatitis C virus.
  • the invention provides methods for treating hepatitis C viral infection.
  • the methods include administering to a subject in need of such treatment an effective amount of a compound of the invention as described herein.
  • a compound can refer to a single compound or a plurality of compounds.
  • the methods for treating hepatitis C viral infection include administering to a subject in need of such treatment an effective amount of a composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the invention provides methods for treating hepatitis C viral infection comprising administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with another medicament, such as another anti-viral agent.
  • anti-viral agent denotes a compound which interferes with any stage of the viral life cycle to slow or prevent HCV reproduction.
  • Representative anti-viral agents include, without limitation, INTRON-A, (interferon alfa-2b available from Schering Corporation, Kenilworth, N.
  • PEG-FNTRON peginteferon alfa-2b, available from Schering Corporation, Kenilworth, N.J.
  • ROFERON-A recombinant interferon alfa-2a available Hoffmann-La Roche, Nutley, N.J.
  • PEGASYS peginterferon alfa-2a available Hoffmann-La Roche, Nutley, N.J.
  • INFERGEN A Schering Plough, inteferon-alpha 2B+Ribavirin
  • WELLFERON interferon alpha-nl
  • cyclophilin inhibitors nucleoside analogues, IRES inhibitors, El inhibitors, E2 inhibitors, IMPDH inhibitors, NS5B polymerase inhibitors such as R-1626, R-7128, MK-0608, A837093, GS9190 and PF-
  • the methods of treating HCV infection include administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with another NS3/4A inhibitor.
  • NS3/4A inhibitors which can be administered in combination with compounds of the present invention include, without limitation, telaprevir (VX950), boceprevir (SCH503034), ITMN191, TMC 435350, MK7009, and PHXl 766.
  • Still other antiviral agents that may be used in conjunction with inventive compounds for the treatment of HCV infection include, but are not limited to, ribavirin (l-beta-D-ribofuranosyl-lH-l,2,- 4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; described in the Merck Index, entry 8365, Twelfth Edition); REBETROL.RTM. (Schering Corporation, Kenilworth, N. J.), COPEGASUS.RTM. (Hoffmann-La Roche, Nutley, N. J.); BEREFOR.RTM.
  • interleukin 2 (Davis, G. L. et al., "Future Options for the Management of Hepatitis C.” Seminars in Liver Disease, 19, pp. 103-112 (1999); Interleukin 6 (Davis et al. "Future Options for the Management of Hepatitis C.” Seminars in Liver Disease 19, pp. 103-1 12 (1999); interleukin 12 (Davis, G.
  • the invention provides a method for treating hepatitis C viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with an anti-proliferative agent.
  • antiproliferative agent denotes a compound which inhibits cellular proliferation. Cellular proliferation can occur, for example without limitation, during carcinogenesis, metastasis, and immune responses.
  • Representative anti-proliferative agents include, without limitation, 5-fluorouracil, daunomycin, mitomycin, bleomycin, dexamethasone, methotrexate, cytarabine, and mercaptopurine.
  • the invention provides a method for treating hepatitis C viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with an immune modulator.
  • immune modulator denotes a compound or composition comprising a plurality of compounds which changes any aspect of the functioning of the immune system.
  • immune modulator includes without limitation anti-inflammatory agents and immune suppressants.
  • Representative immune modulator include without limitation steroids, non-steroidal antiinflammatories, COX2 inhibitors, anti-
  • the invention provides a method for treating hepatitis C viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with an antibiotic.
  • an antibiotic includes an anti-bacterial or anti-fungal agent. Agents of this type are useful in combating, for example, secondary bacterial or fungal infections that may accompany a hepatitis C infection. Examples include beta-lactam antibiotics, macrocyclic antibiotics, triazole anti-fungal agents, and the like.
  • a variety of uses of the invention compounds are possible along the lines of the various methods of treating a subject as described above.
  • Exemplary uses of the invention methods include, without limitation, use of a compound of the invention in a medicament or for the manufacture of a medicament for treating a condition that is regulated or normalized via inhibition of the HCV NS3 serine protease.
  • An embodiment of the invention is directed to use of an inventive compound in preparation of a medicament for the treatment of an HCV infection in a patient.
  • an effective amount of a second bioactive agent such as described above, can be used in preparation of a medicament for treatment of an HCV infection in a patient.
  • An embodiment of the invention provides an inventive compound for use in combination with an effective amount of a second medicament, such as described above, in treatment of an HCV infection in a patient.
  • Fluorescence resonance energy transfer (FRET; see e.g., Heim et al., (1996) Curr. Biol. 6:178-182; Mitra et al., (1996) Gene 173:13-17; and Selvin et al., (1995) Meth. Enzymol. 246:300-345) is an extremely sensitive method for detecting energy transfer between two fluorophoric probes.
  • probes are given the designations "donor” and "acceptor” depending on the relative positions of the maxima in the absorption and emission spectra characterizing the probes. If the emission spectrum of the acceptor overlaps the absorption spectrum of the donor, energy transfer can occur.
  • the degree of hydrolysis of the peptide substrate, and the level of activity of the protease catalyzing hydrolysis of the peptide substrate can be quantitated. Accordingly, using methods known in the arts of chemical and biochemical kinetics and equilibria, the effect of inhibitor on protease activity can be quantitated.
  • compositions include a compound of the invention which inhibits the enzymatic activity of the HCV NS3 protease, and a pharmaceutically acceptable excipient which may be a carrier or a diluent.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the active compound When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration may be any route which effectively transports the active compound of the invention which inhibits the enzymatic activity of the HCV NS3 protease to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
  • Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • sterile oils may be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the formulation may also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection may be in ampoules or in multi-dose containers.
  • the formulations of the invention may be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations may also be formulated for controlled release or for slow release.
  • compositions contemplated by the present invention may comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • HCV NS3 protease inhibitor activity of the compounds of the invention may be determined by use of an in vitro assay system which measures the potentiation of inhibition of the HCV NS3 protease.
  • Inhibition constants i.e., K, or IC 50 values as known in the art
  • K K, or IC 50 values as known in the art
  • the invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic or other physiological processes before becoming active pharmacological substances. Conversion by metabolic or other physiological processes includes without limitation enzymatic (e.g, specific enzymatically catalyzed) and non- enzymatic (e.g., general or specific acid or base induced) chemical transformation of the prodrug into the active pharmacological substance.
  • prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • compositions of a compound described herein comprising formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
  • the methods may further comprise the step of formulating the composition into a tablet or capsule.
  • the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
  • the methods further comprise the step of lyophilizing the composition to form a lyophilized preparation.
  • Combinations of the invention include mixtures of compounds from (a) and (b) in a single formulation and compounds from (a) and (b) as separate formulations. Some combinations of the invention may be packaged as separate formulations in a kit. In some embodiments, two or more compounds from (b) are formulated together while a compound of the invention is formulated separately. Combinations of the invention can further comprise a pharmaceutically acceptable carrier. In some embodiments, the compound of the invention is 90 wt % or more of a single diastereomer or single enantiomer. Alternatively, the compound of the invention can be 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt % or more of a single diastereomer or single enantiomer.
  • reaction solution was diluted with DCM (40 mL), washed with saturated NaHCO 3 (15 mL) and brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum. After purification by silica gel column chromatography, 0.7 g of compound 16 were obtained with (61% yield).
  • the crude solid was purified by column chromatography (4 g silica gel, ISCO) by eluting with: (i) 20% ethyl acetate in dichloromethane (30 mL), (ii) 0% to 2% methanol gradient in dichloromethane (85 mL), (iii) 2% methanol in dichloromethane (50 mL), and (iv) 2% to 4% methanol gradient in dichloromethane (50 mL). The clean fractions were combined and concentrated under reduced pressure to afford compound 42 (128 mg, 90%) as a white solid.

Abstract

L'invention concerne des composés inhibiteurs de la protéase virale de l'hépatite C, des compositions et des combinaisons comprenant les composés, des procédés de traitement d'états dans lesquels une inhibition de la protéase virale de l'hépatite C est indiquée médicalement, et des procédés de traitement d'une infection virale par l'hépatite C chez un patient humain.
PCT/US2009/033934 2008-02-15 2009-02-12 Inhibiteurs macrocycliques de protéase de l'hépatite c WO2009102876A1 (fr)

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Cited By (1)

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CN105712901A (zh) * 2016-01-22 2016-06-29 成都柏睿泰生物科技有限公司 一种光学活性中间体n-叔丁氧羰基-2-氨基-8-壬烯酸二环己胺盐的合成方法

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US6914122B2 (en) * 2000-04-19 2005-07-05 Schering Corporation Macrocyclic NS-3 serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties
WO2007016476A2 (fr) * 2005-08-01 2007-02-08 Phenomix Corporation Inhibiteurs de la sérine protéase de l'hépatite c et emploi desdits inhibiteurs
US20080008681A1 (en) * 2006-06-26 2008-01-10 Deqiang Niu Macrocyclic hepatitis c virus serine protease inhibitors

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US6914122B2 (en) * 2000-04-19 2005-07-05 Schering Corporation Macrocyclic NS-3 serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties
WO2007016476A2 (fr) * 2005-08-01 2007-02-08 Phenomix Corporation Inhibiteurs de la sérine protéase de l'hépatite c et emploi desdits inhibiteurs
US20080008681A1 (en) * 2006-06-26 2008-01-10 Deqiang Niu Macrocyclic hepatitis c virus serine protease inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105712901A (zh) * 2016-01-22 2016-06-29 成都柏睿泰生物科技有限公司 一种光学活性中间体n-叔丁氧羰基-2-氨基-8-壬烯酸二环己胺盐的合成方法

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