US20050222198A1 - Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment - Google Patents

Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment Download PDF

Info

Publication number
US20050222198A1
US20050222198A1 US11/019,830 US1983004A US2005222198A1 US 20050222198 A1 US20050222198 A1 US 20050222198A1 US 1983004 A US1983004 A US 1983004A US 2005222198 A1 US2005222198 A1 US 2005222198A1
Authority
US
United States
Prior art keywords
alkyl
aryl
cycloalkyl
compound
cycloalkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/019,830
Other languages
English (en)
Inventor
Steven Bondy
Eric Dowdy
Choung Kim
Johan Neyts
David Oare
Gerhard Puerstinger
Vahid Zia
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Katholieke Universiteit Leuven
Original Assignee
Katholieke Universiteit Leuven
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Katholieke Universiteit Leuven filed Critical Katholieke Universiteit Leuven
Priority to US11/019,830 priority Critical patent/US20050222198A1/en
Publication of US20050222198A1 publication Critical patent/US20050222198A1/en
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BONDY, STEVEN S., DOWDY, ERIC DAVIS, KIM, CHOUNG U., OARE, DAVID A., ZIA, VAHID
Assigned to K.U. LEUVEN RESEARCH & DEVELOPMENT reassignment K.U. LEUVEN RESEARCH & DEVELOPMENT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NEYTS, JOHAN
Assigned to K.U. LEUVEN RESEARCH & DEVELOPMENT, GILEAD SCIENCES, INC., PUERSTINGER, GERHARD reassignment K.U. LEUVEN RESEARCH & DEVELOPMENT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PUERSTINGER, GERHARD
Assigned to K.U. LEUVEN RESEARCH & DEVELOPMENT, GILEAD SCIENCES, INC., PUERSTINGER, GERHARD reassignment K.U. LEUVEN RESEARCH & DEVELOPMENT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GILEAD SCIENCES, INC., K.U. LEUVEN RESEARCH & DEVELOPMENT
Assigned to K.U. LEUVEN RESEARCH & DEVELOPMENT reassignment K.U. LEUVEN RESEARCH & DEVELOPMENT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GILEAD SCIENCES, INC.
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • 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
    • 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

Definitions

  • the present invention relates to a series of novel imidazo[4,5-c]pyridine compounds, processes for their preparation, their use to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with viruses belonging to the family of the Flaviviridae and Picornaviridae and more preferably infections with hepatitis-C-virus (HCV).
  • HCV hepatitis-C-virus
  • the family of the Flaviviridae consists of 3 genera, the pestiviruses, the flaviviruses and the hepaciviruses and also contains the hepatitis G virus (HGV/GBV-C) that has not yet been assigned to a genus.
  • Pestiviruses such as the Classical Swine Fever Virus (CSFV), the Bovine Viral Diarrhea Virus (BVDV) and the Border Disease Virus (BDV) cause infections of domestic livestock (respectively pigs, cattle and sheep) and are responsible for significant economic losses world-wide.
  • CSFV Classical Swine Fever Virus
  • BVDV Bovine Viral Diarrhea Virus
  • BDV Border Disease Virus
  • BVDV the prototypic representative of the pestivirus genus is ubiquitous and causes a range of clinical manifestations, including abortion, teratogenesis, respiratory problems, chronic wasting disease, immune system dysfunction, and predisposition to secondary viral and bacterial infections and may also cause acute fatal disease. Fetuses of cattle can be infected persistently with BVDV, these animals remain viremic throughout life and serve as a continuous source for virus spread in herds.
  • Vaccines are used in some countries with varying degrees of success to control pestivirus disease. In other countries, animal culling and slaughter are used to contain pestivirus disease outbreaks.
  • HCV hepatitis C virus
  • Coxsackie viruses belong to the group of the enteroviruses, family of the Picornaviridae. They cause a heterogeneous group of infections including herpangina, aseptic meningitis, a common-cold-like syndrome, a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot-mouth syndrome, pediatric and adult pancreatitis and serious myocarditis.
  • WO 00/20416 WO 00/39127, WO 00/40583, WO 03/007945 A1, WO 03/010140 A2, WO 03/010141 A2, WO 93/02080, WO 93/14072, WO 96/11192, WO 96/12703, WO 99/27929, Akamatsu, et al., New Efficient Route for Solid-Phase Synthesis of Benzimidazole Derivatives”, 4:475-483 , J. COMB.
  • An embodiment of the present invention provides compounds having the general formula (A), wherein:
  • Another embodiment of the present invention provides compounds having the general formula (A), wherein:
  • An embodiment of the present invention provides compounds having the general formula (A), wherein:
  • An embodiment of the present invention provides compounds of the formula (B) wherein Y is a single bond, and R 1 is aryl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein X is C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is heterocylic.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is heterocyclic substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein Y is a single bond, and R 1 is phenyl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is phenyl.
  • Yet another embodiment of the present invention provides compounds having the formula (C),
  • An embodiment of the present invention provides compounds of the formula (C) wherein Y is a single bond, and R 1 is aryl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein X is C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is heterocylic.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is heterocyclic substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein Y is a single bond, and R 1 is phenyl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is phenyl.
  • the compounds of formula (A) are optionally combined with pharmacologically acceptable excipients.
  • the compounds of formula (A) are administered in therapeutically effective amounts to subjects (humans or animals) in need of antiviral therapy, in particular for inhibiting the infection, growth or replication of Flaviviridae and Picornaviridae, especially BVDV, HCV and Coxsackie virus.
  • the invention further relates to a method of screening antiviral compounds which comprises providing a compound of formula (A) and determining the anti-viral activity of said compound.
  • a metabolite of the compounds of formula (A) made by the process of administering a compound of formula (A) to a subject and recovering the metabolite from the subject.
  • the invention also comprises a method for structure-activity determination of analogues of formula (A) compounds wherein the substituents are defined in WO 2004/005286, comprising
  • Alkyl means saturated hydrocarbon moiety where the moiety may be cyclic, cyclic or a combination of acyclic and cyclic portions.
  • the acyclic portion may contain 1 to 3 carbon atoms, and each ring may contain 3 to 6 carbon atoms (for example, 3-methylcyclohexyl).
  • cycloalkyl refers to the saturated hydrocarbon moieties that are cyclic.
  • alkyl examples include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu) 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cyclopropyl, cyclobutyl, cyclopenty
  • Alkenyl means a hydrocarbon moiety with at least one site of double bond unsaturation where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions.
  • the acyclic portion may contain 1 to 3 carbon atoms, and each cyclic portion may contain 3 to 6 carbon atoms.
  • a site of double bond unsaturation may be in a acyclic portion, a cyclic portion.
  • cycloalkenyl refers to the double bond unsaturated hydrocarbon moieties that are cyclic.
  • alkenyl include, but are not limited to, ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ), 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
  • the double bond optionally is in the cis or trans configuration.
  • Alkynyl means a hydrocarbon moiety with a least one site of triple bond unsaturation where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions.
  • the acyclic portion may contain contain 1 to 3 carbon atoms, and each cyclic portion may contain 7 or more carbon atoms.
  • cycloalkynl refers to triple bond unsaturated hydrocarbon moieties that are cyclic. Examples of the term “alkynyl” include, but are not limited to, —C ⁇ CH, —CH 2 C ⁇ CH, —CH 2 C—C-cyclohexyl, or —CH 2 -cycloheptynyl.
  • alkyl, alkenyl and alkynyl groups refers to such groups with at least 2 sites of substitution.
  • polyvalent hydrocarbon radicals include, but are not limited to, methylene (—CH 2 —) 1,2-ethylene (—CH 2 CH 2 —), 1,3-propylene (—CH 2 CH 2 CH 2 —), 1,4-butylene (—CH 2 CH 2 CH 2 CH 2 —), 1,2-ethylene (—CH ⁇ CH—), —C ⁇ C—, propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH—).
  • Aryl means an aromatic hydrocarbon containing 1 or more rings, generally 1, 2 or 3, with 4 to 6 carbon atoms in each, ordinarily 5 or 6 carbon atoms.
  • Arylalkyl means an alkyl, alkenyl or alkynyl radical, respectively, in which one of the hydrogen atoms, typically a terminal or sp3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • carbocycles optionally are found as single rings or multiple ring systems. Ordinarily the hydrocarbons of the compounds of formula (A) are single rings. Monocyclic carbocycles generally have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • the number of carbon atoms is unspecified for a hydrocarbon, typically the number of carbon atoms will range from 1 to 18, except that the number of carbons typically will range from 2 to 18 for unsaturated hydrocarbons and from 6 to 10 for aryl.
  • Heterocyclic or “heterocycle” means any 4, 5, 6, 7, 8 or 9 membered single or fused ring system containing one or more heteroatoms selected from the group consisting of O, N or S. Heterocycles optionally are entirely aromatic, entirely saturated, or contain 1 or more intra-ring sites of unsaturation, typically double bonds. Multiple heterocyclic rings (one or more of which contains a heteroatom) are bridged or spiro. Generally, the heterocyclic rings will be aromatic, and usually they are single rings.
  • heterocycles include oxazacyloalkyl, morpholinyl, dioxacycloalkyl, thiacycloalkenyl, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyranyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydro
  • Carbon bonded heterocycles typically are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • Nitrogen containing heterocycles are bonded at nitrogen or a carbon, typically a carbon atom. These include, for example, position 1 of aziridine, 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-piperidinyl, 2-pyrroline, 3-pyrroline, 2-imidazoline, 3-imidazoline, 9-carbazole, 4-morpholine, 9-alpha or 13-carboline, 2-isoindole, 2-pyrazoline and 3-pyrazoline, and by analogy, azetidine, pyrrole, pyrrolidine piperidine, piperazine, indole, pyrazoline, indoline, imidazole, imidazolidine, 1H-indazole and isoindoline. These and other N-containing heterocycles are well-known to those skilled in the art, and their linkage sites are a matter of discretion.
  • Sulfur containing heterocycles are bonded through carbon or sulfur. They include oxidized states such as —S( ⁇ O)( ⁇ O). In general, they are linked in the compounds of formula (A) analogous to N-containing heterocycles.
  • Alkoxy”, “cycloalkoxy”, “aryloxy”, “arylalkyloxy”, “oxy heterocycle”, “thioalkyl”, “thiocycloalkyl”, “arylthio”, and “arylalkylthio” means substituents wherein an alkyl, cycloalkyl, aryl, or arylalkyl, respectively, are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
  • the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state—any and all protonated forms of the compounds are intended to fall within the scope of the invention.
  • Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included.
  • any site in the parental molecule is substituted with an amino acid, although it is within the scope of this invention to introduce amino acids at more than one permitted site.
  • the ⁇ -amino or ⁇ -carboxyl group of the amino acid are bonded to the remainder of the molecule, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates).
  • amino acid esters optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH >10) conditions.
  • they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
  • R 28 usually is C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with amino, carboxyl, amide, carboxyl (as well as esters, as noted above), hydroxyl, C 6 -C 7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate.
  • R 1 is generally aryl or aromatic heterocyle substituted with 1, 2 or 3 R 6 wherein R 6 is halogen, C 1-18 alkoxy; or C 1-18 haloalkyl. Typically, R 1 is phenyl substituted with 1, 2 or 3 halogens, usually fluoro.
  • Y generally is a single bond, O, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene or one of said groups containing 1 to 3, usually 1, heteroatoms selected from O, S or NR 11 .
  • Examples include —O(CH 2 ) 1-5 —, —(CH 2 ) 1-4 —O—(CH 2 ) 1-4 —, —S—(CH 2 ) 1-5 —, —(CH 2 ) 1-4 —S—(CH 2 ) 1-4 —, —NR 11 —(CH 2 ) 1-5 —, —(CH 2 ) 1-4 —NR 11 —(CH 2 ) 1-4 or C 3-10 cycloalkylidene.
  • Y is —OCH 2 —, —CH 2 O—, C 1-2 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, 0 or a bond, but usually a bond.
  • YR 1 is not any one of H, an unsubstituted C 3-10 cycloalkyl or C1-C6 alkyl.
  • YR 1 is halo or halomethyl-substituted (typically trihalomethyl) phenyl (and usually 1 to 2 substituents in ortho or meta).
  • R 17 is M-Q in some embodiments of the invention.
  • M is a ring. This means any cyclic organic structure, whether carbocyclic or heterocyclic, and whether saturated, unsaturated or aromatic or single or fused ring systems. M is chosen from rings that are structurally stable in biological systems. In general, M is a aryl or aromatic heterocycle where heterocycle is defined above.
  • Q is a spacer group, and is not critical. Typically it is not cyclic and contains from no to 3 atoms, generally C, O or S, usually C or 0.
  • R 17 typically is selected from the group consisting of C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy (optionally an benzyloxy); arylalkylthio (optionally a benzylthio); a heterocycle; C 1-18 hydroxyalkyl, but typically is an aryl or a heterocycle, and where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, or heterocycle is optionally substituted with 1 or more R 19 .
  • R 17 generally is positioned dist
  • R 9 and R 18 typically are H, OH or alkyl.
  • R 18 optionally is not NR 15 R 16 .
  • R 6 generally is halogen. Optionally, R 6 is not C(O)R 18 .
  • R 7 , R 8 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 20 , R 21 , R 23 and R 24 typically are independently H or C 1-18 alkyl.
  • R 12 and R 22 typically are independently OH or alkyl.
  • R 19 usually is H; C 1-18 alkyl; C 2-18 alkenyl; C 2-18 alkynyl; C 1-18 alkoxy; alkenyloxy; alkynyloxy; C 1-18 alkylthio; C 3-10 cycloalkyl; C 4-10 cycloalkenyl; C 4-10 cycloalkynyl; halogen; OH; CN; cyanoalkyl; NO 2 ; NR 20 R 21 ; haloalkyl; haloalkyloxy; C( ⁇ O)R 18 ; C( ⁇ O)OR 18 ; OalkenylC(—O)OR 18 ; —OalkylC(—O)NR 20 R 21 ; aryl; heterocycle; —OalkylOC( ⁇ O)R 18 ; C( ⁇ O)N(C 1-6 alkyl), N(H)S(O)(O)(C 1-6 alkyl); arylalkyloxy; aryloxy; ary
  • R 25 and R 26 usually are not present but if they are then typically they are cyclopentyl or cyclohexyl. If the compound is substituted at R 25 or R 26 , either R 2 or R 4 is selected from ( ⁇ O), (—S), and ( ⁇ NR 27 ), usually ⁇ O.
  • M typically is an aromatic ring, usually single or two fused rings, and containing 4 to 10 atoms. Usually, M is hydrocarbon, but also optionally comprises 1 to 3 N, O and/or S heteroatoms.
  • Q usually is a hydrocarbon chain, typically a normal or secondary alkylene, which optionally comprises at least one oxy or thio ester. Generally Q is 1 to 6 atoms, usually 1 to 3. Q typically is not substituted with R 19 , but if it is then typically it is substituted with one R 19 . R 19 as substituted on Q usually is halogen, nitro or cyano. Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
  • Haloalkyl or haloalkyloxy typically are —CF3 or —OCF3.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound.
  • prodrugs are capable of acting as prodrugs.
  • prodrugs are labile functional groups which separate from an active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process.
  • prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a “prodrug” is thus a covalently modified analog of a therapeutically-active compound.
  • a prodrug moiety of course can be therapeutically active in its own right.
  • Exemplary prodrug moieties include the hydrolytically sensitive or labile esters (—CO 2 R′) of carboxylic acids (—CO 2 H) or other functional groups with an acidic proton which is bound to the imidazo[4,5-c]pyridine compounds of the invention.
  • the R′ group of such hydrolytically sensitive or labile esters may include: (i) acyloxymethyl esters —CH 2 C( ⁇ O)R 9a ; and (ii) acyloxymethyl carbonates —CH 2 C( ⁇ O)OR 9a where R 9a is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the invention.
  • An exemplary acyloxymethyl ester R group is pivaloyloxymethoxy, (POM) —CH 2 C( ⁇ O)C(CH 3 ) 3 .
  • An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH 2 C( ⁇ O)OC(CH 3 ) 3 .
  • Cleavable moieties capable of acting as prodrug functionalities are optionally linked at any tolerant site on the compound of this invention, for example R 3 and any of its substituents.
  • the present invention excludes all compounds expressly disclosed in any prior art reference (to the extent the reference is effective as novelty- or inventive step/obviousness-defeating as the case may be) set forth in this application (as well as any compounds disclosed in any reference patent family member) and and any other compounds over which the claims of this application are not novel or do not posses an inventive step or are obvious under applicable law.
  • the present invention excludes, as required, compounds according to the general formula (A) where
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein (a) Y R 1 is not phenyl para substituted with OH, or (b) is H, an unsubstituted C 3-10 cycloalkyl, or C 1-6 alkyl.
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R 1 is not H, Y is not NR 11 with R 11 C 1-6 alkyl or methyl, and/or YR 1 is not monomethylamino.
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R 1 is a phenyl substituted with 1R 6 , R 6 is C( ⁇ O)R 18 and R 18 is t-butoxy.
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R 1 is not piperidinyl and is not piperazinyl substituted with methyl.
  • the compounds of this invention exclude those compounds disclosed by WO 2004/005286, in particular the compounds in table 8 thereof.
  • the compounds of this invention optionally exclude those in which XR 3 is the definitional equivalent to the substructure —CH2)n—Y—C(O)—N(R1)(R2) set forth on column 1, line 49 to column 2 line 38 of U.S. Pat. No. 5,302,601 and the comparable disclosure in any member of the patent family of U.S. Pat. No. 5,302,601, which disclosure is herewith expressly incorporated by reference.
  • the compounds of this invention optionally exclude those in which R 5 contains any of the substituents designated as ⁇ Ar>> in WO 00/39127, in particular aryl, aryl phenoxy, or benzyl.
  • the compounds of this invention optionally do not include the compounds of Example 35 of U.S. Pat. No. 5,302,601, Example 6 of U.S. Pat. No. 4,990,518, Examples 1 to 5 of U.S. Pat. No. 4,988,707, Examples 1-5 of U.S. Pat. No. 5,208,241, Example 39 of U.S. Pat. No. 5,137,896, the azabenzimidazole compound of WO 99/27929, Examples 1-20 and 45 of U.S. Pat. No. 5,227,384, Examples 3 and/or 11 of WO 96/12703 and/or compounds 340A, 347C, 349C, 351C, 355C and/or 356 C of WO 96/11192.
  • the compounds of this invention optionally exclude those in which XR 3 is equivalent to the substructure —(CH 2 )n-Het-C(O)—N(R 1 )(R 2 ) set forth on column 1, line 41 to column 2 line 24 of U.S. Pat. No. 4,990,518.
  • the compounds of this invention do not include the compounds expressly disclosed in the patents listed in the Background of the Invention above, in Chemical Abstracts acc no. 1987:18435 and in Chemical Abstracts acc no. 1983:594812.
  • the compounds of this invention do not include the compounds expressly disclosed in Justus Liebigs Annalen der Chemie (1971), 747, 158-171 or in the Journal of the Chemical Society [section B]: Physical Organic (1966), 4, 285-291.
  • the compounds of this invention exclude the compounds found in any patent family member of any published or issued patent specifically recited in this application.
  • the compounds of this invention optionally also exclude the methylene homologues of the foregoing known compounds excluded from the scope of this invention. It is understood that a compound optionally excluded also includes the salts thereof.
  • the compounds of this invention or the metabolites produced from these compounds in vivo, have a large number of uses. They are useful in immunology, chromatography, diagnostics and therapeutics, among other fields.
  • the compounds of formula (A) are conjugated to immunogenic polypeptides as a reagent for eliciting antibodies capable of binding specifically to the polypeptide, to the compounds or to their metabolic products which retain immunologically recognized epitopes (sites of antibody binding).
  • immunogenic compositions therefore are useful as intermediates in the preparation of antibodies for use in diagnostics, quality control, or the like, or in assays for the compounds of formula (A) or their novel metabolic products.
  • the compounds are useful for raising antibodies against otherwise non-immunogenic polypeptides, in that the compounds serve as haptenic sites stimulating an immune response which cross-reacts with the unmodified conjugated protein.
  • Conjugates of the compounds of formula (A) with immunogenic polypeptides such as albumin or keyhole limpet hemocyanin generally are useful as immunogens.
  • the polypeptides are conjugated at the same sites denoted for amino acids.
  • the metabolic products described above may retain a substantial degree of immunological cross reactivity with the compounds of the invention.
  • the antibodies of this invention will be capable of binding to the unprotected compounds of the invention without binding to the protected compounds.
  • the metabolic products will be capable of binding to the protected compounds and/or the metabolitic products without binding to the protected compounds of the invention, or will be capable of binding specifically to any one or all three.
  • the antibodies desirably will not substantially cross-react with naturally-occurring materials.
  • Substantial cross-reactivity is reactivity under specific assay conditions for specific analytes sufficient to interfere with the assay results.
  • the immunogens of this invention contain the compound of this invention presenting the desired epitope in association with an immunogenic substance.
  • association means covalent bonding to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bonded materials, or a combination of the above.
  • Immunogenic substances include adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, and immunogenic polysaccharides.
  • the compound having the structure of the desired epitope is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) cross-linking agent.
  • a polyfunctional (ordinarily bifunctional) cross-linking agent for the manufacture of hapten immunogens are conventional per se, and any of the methods used heretofore for conjugating haptens to immunogenic polypeptides or the like are suitably employed here as well, taking into account the functional groups on the precursors or hydrolytic products which are available for cross-linking and the likelihood of producing antibodies specific to the epitope in question as opposed to the immunogenic substance.
  • polypeptide is conjugated to a site on the compound of the invention distant from the epitope to be recognized.
  • the conjugates are prepared in conventional fashion.
  • the conjugates comprise a compound of the invention attached by a bond or a linking group of 1-100, typically, 1-25, more typically 1-10 carbon atoms to the immunogenic substance.
  • the conjugates are separated from starting materials and by products using chromatography or the like, and then are sterile filtered and vialed for storage.
  • Animals are typically immunized against the immunogenic conjugates or derivatives and antisera or monoclonal antibodies prepared in conventional fashion.
  • the compounds of this invention are useful as linkers, spacers or affinity (typically hydrophobic) moieties in preparing affinity absorption matrices.
  • the compounds of the invention optionally are bound covalently to an insoluble matrix and used for affinity chromatography separations, depending on the nature of the groups of the compounds, for example compounds with pendant aryl groups are useful in making hydrophobic affinity columns.
  • the compounds herein contain functional groups that are suitable as sites for cross-linking desired substances.
  • affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates.
  • affinity reagents such as hormones, peptides, antibodies, drugs, and the like
  • immobilized enzymes are used to perform catalytic conversions with facile recovery of enzyme.
  • Bifunctional compounds are commonly used to link analytes to detectable groups in preparing diagnostic reagents.
  • the compounds of this invention are labeled with detectable moieties such biotin, radioisotopes, enzymes and the like for diagnostic purposes.
  • detectable moieties such biotin, radioisotopes, enzymes and the like for diagnostic purposes.
  • Suitable techniques for accomplishing the labeling of the compounds of formula (A) are well known and will be apparent to the artisan from consideration of this specification as a whole.
  • one suitable site for labeling is R17 or R19.
  • the compounds of the invention are employed for the treatment or prophylaxis of viral infections such as yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus, but more particularly flaviviral or picornaviral infections, in particular, HCV and BVDV.
  • viral infections such as yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus, but more particularly flaviviral or picornaviral infections, in particular, HCV and BVDV.
  • the therapeutic compound(s) of this invention are administered to a subject mammal (including a human) by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the compound(s) is a flaviviral or picornaviral growth inhibiting amount. More preferably, it is a flaviviral or picornaviral replication inhibiting amount or a flaviviral or picoruaviral enzyme inhibiting amount of the compounds of formula (A).
  • the actual amount will depend upon many factors known to the artisan, including bioavailability of the compound, whether it contains a prodrug functionality, its metabolism and distribution in the subject and its potency, among others. It typically is necessary to determine the proper dosing in the clinical setting, and this is well within the skill of the ordinary artisan.
  • the therapeutically effective amount of the compound(s) of this invention optionally are divided into several sub-units per day or are administered at daily or more than one day intervals, depending upon the pathologic condition to be treated, the patient's condition and the nature of the compound of this invention.
  • the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg . (1984) 22:27 or tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC 50 for calculating the fractional inhibitory concentration.
  • Suitable anti-viral agents for inclusion in combination antiviral compositions or for coadministration in a course of therapy include, for instance, interferon alpha, ribavirin, a compound falling within the scope of disclosure of EP 1162196, WO 03/010141, WO 03/007945 and WO 03/010140, a compound falling within the scope of disclosure of WO 00/204425, and other patents or patent applications within their patent families, in amounts of 1 to 99.9% by weight compound of this invention, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight as can be readily determined by one skilled in the art.
  • Such co-administered agents need not be formulated in the same dosage form as the compound of the invention. They optionally are simply administered to the subject in the course of treatment along with a course of treatment with a compound of formula (A).
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore, for example in the treatment of BVDV.
  • Veterinary carriers are materials useful for the purpose of administering the composition and are excipients which are otherwise inert or acceptable in the veterinary art and are compatible with the compound of this invention. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • salts as used herein means the therapeutically active non-toxic salt forms formed by the compounds of formula (A). Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges.
  • the net charge of the compounds of the invention may be either positive or negative.
  • Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion.
  • the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
  • counter ions e.g., dry salts
  • counter ions e.g., aqueous or organic solutions
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li+, Na+, Ca+2 and Mg+2 and K+.
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, benzoic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, fumaric, tartaric, pyruvic, maleic, malonic, malic, salicylic (i.e.
  • 2-hydroxybenzoic 2-hydroxybenzoic
  • p-aminosalicylic isethionic, lactobionic, succinic oxalic and citric acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids, C1-C6 alkylsulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, and the like.
  • Preferred salts include mesylate and HCl.
  • the compounds of this invention include the solvates formed with the compounds of formula (A) and their salts, such as for example hydrates, alcoholates and the like.
  • the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • a basic or acidic group e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • Salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a compound of formula (A). All salts, whether or not derived form; a physiologically acceptable acid or base, are within the scope of the present invention.
  • isomers as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formula (A) may possess, but not including position isomers.
  • the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomets and enantiomers (since the compounds of formula (A) may have one or more chiral centers), as well as the stereochemically pure or enriched isomers. More particularly, stereogenic centers may have either the R- or S-configuration, and double or triple bonds optionally are in either the cis- or trans-configuration.
  • Enriched isomeric forms of a compound of this invention are defined as a single isomer substantially free of the compound's other enantiomers or diastereomers.
  • the term “stereoisomerically enriched” or “chirally enriched” relates to compounds having a single stereoisomeric proportion of at least about 80% (i.e. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%.
  • the terms “enantiomerically pure” and “diastereomerically pure” contain undetectable levels of any other isomer.
  • stereoisomers Separation of stereoisomers is accomplished by standard methods known to those in the art.
  • One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing an acidic functionality, such as carboxylic acid and sulfonic acid.
  • enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like
  • an acidic functionality such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts optionally are induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to-be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994). Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase.
  • Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives.
  • Commercially available polysaccharide based chiral stationary phases are ChiralCeITM CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP(+) and OT(+).
  • eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.
  • an alcohol such as ethanol, isopropanol and the like.
  • the present invention also provides the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. C14 or H3) compound of the invention, administering it parenterally in a detectable dose (e.g.
  • a radiolabelled e.g. C14 or H3
  • metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no antiviral activity of their own.
  • the compounds of the invention optionally are formulated with conventional pharmaceutical carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the term “pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
  • Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antiftungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antiftungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
  • Suitable surface-active agents also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties.
  • Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents.
  • Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C 10 -C 22 ), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil.
  • Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates.
  • Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g.
  • Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
  • alkylarylsulphonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product.
  • corresponding phosphates e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids.
  • Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g.
  • phosphatidylethanolamine phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalritoylphoshatidyl-choline and their mixtures.
  • Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol.
  • non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups.
  • Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
  • non-ionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol.
  • Fatty acid esters of polyethylene sorbitan such as polyoxyethylene sorbitan trioleate
  • glycerol glycerol
  • sorbitan sucrose and pentaerythritol are also suitable non-ionic surfactants.
  • Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl radicals.
  • C8C22 alkyl radical e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like
  • Compounds of the invention and their physiologically acceptable salts may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration may vary with for example the condition of the recipient.
  • the formulations both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients.
  • the carrier(s) optimally are “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • For infections of the eye or other external tissues e.g.
  • the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
  • Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like.
  • the rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers.
  • Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on.
  • the pharmaceutical composition may require protective coatings.
  • Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
  • each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
  • the compounds of formula (A) are prepared using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further.
  • the processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.
  • the invention also relates to methods of making the compositions of the invention.
  • the compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in “Compendium of Organic Synthetic Methods” (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
  • reaction conditions such as temperature, reaction time solvents, workup procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • the temperatures will be ⁇ 100° C. to 200° C.
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Workup typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to ⁇ 100° C.
  • solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to ⁇ 100° C.) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
  • treated means contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • treating compound one with compound two is synonymous with “allowing compound one to react with compound two”, “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
  • “Treating” indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures ( ⁇ 100° C. to 250° C., typically ⁇ 78° C. to 150° C., more typically ⁇ 78° C. to 100° C., still more typically 0° C. to 100° C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated.
  • the knowledge of similar reactions known in the art of organic synthesis is used in selecting the conditions and apparatus for “treating” in a given process. In particular, one of ordinary skill in the art of organic sysnthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example, size exclusion or ion exchange chromatography, high, medium, or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • alkylating reagents which may be employed in the pyridyl alkylation reaction of Scheme 1.
  • the residue of the alkylating agent is located at the X R 3 site of the compound of this invention.
  • the remainder of the compound will be as found in any of the compounds of examples 2-7.
  • Alkylating reagent MW 195.475 203.053 168.666 223.471 154.639 253.109 154.639 203.053 145.588 203.053 190.672 273.478 338.832 269.059 205.039 223.471 325.225 289.478 262.579 269.059 228.721 253.06 207.016 253.06 307.03 253.06 199.09 221.043 175.057 285.567 154.639 344.203 216.663 261.569 218.682 212.078 275.144 195.57 198.648 299.113 294.907 228.077 244.144 193.632 222.084 223.471 152.623 255.961 118.523 252.11 255.138 190.039 328.828 176.012 202.611 237.099 281.123 238.087 170.638 239.623 257.023 198.648 257.023 350.235 257.023 252.11 257.023 236.111 257.023 320.206 257.023 2
  • Scheme 2 shows a synthetic route to 5-biarylmethyl-2-phenyl-5H-imidazo[4,5-c]pyridines and 5-benzyl-2-biaryl-5H-imidazo[4,5-c]pyridines.
  • Scheme 3 shows a synthetic route to 5-(alkoxybenzyl)-2-phenyl-5H-imidazo[4,5-c]pyridines and 5-benzyl-2-alkoxybenzyl-5H-imidazo[4,5-c]pyridines.
  • R, R′, and R′′ can be any alkyl, benzylic or heterobenzylic groups.
  • Analogous compounds may be synthesized in the same fashion as in the foregoing schemes by varying the starting materials, intermediates, solvents and conditions as will be known by those skilled in the art.
  • Phosphorous pentoxide 24.56 g was dissolved in methanesulfonic acid (165.8 mL) at 50° C. with stirring.
  • methanesulfonic acid 165.8 mL
  • 3,4-diaminopyridine (12.3 g, 0.1 mmoles) and 2,3-difluorobenzoic acid (19.4 g, 0.12 moles) were added.
  • the reaction mixture was heated to 190° C. for 3 hours. The reaction was done three times.
  • the reaction mixtures was cooled to 50° C. and poured into ice with stirring. At this stage, all three batches were combined.
  • the reaction mixture was neutralized by the addition of NaOH with stirring until the pH is 8. Solid material precipitated out of solution, was collected by filtration and air-dried.
  • the material was crystallized by dissolving the material in MeOH with heat, followed by precipitation with water. This crystallization process was then repeated yielding 5((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (15.385 g, 38 mmole) as white crystal at a yield of 74%.
  • 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine (20 g, 86.6 mmole) was added to 430 mL of DMF; Some of the solid material did not dissolve.
  • To this solution was added 43 mL of a 10% NaOH (w/v) solution. With vigorous stirring, the un-dissolved material went into solution.
  • the resulting solution was divided into 30 equal portions of 16.3 mL, 3 mmole of 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine so as to fit into a microwave reaction vessel.
  • reaction vessel To each reaction vessel was added of 11-(chloromethyl)-4-(trifluoromethoxy)benzene (693 mg, 3 mmole). Each reaction mixture was microwaved for 1 minute at 110° C. Following the completion of all the microwave reactions, all of the reaction vessels were combined (one was lost due to breakage of the vessel) into three batches for workup. For each batch, DMF was removed by vacuum, and the resulting material was washed three times with deionized water.
  • 2,4-difluorophenylboronic acid (196 mg, 1.24 mmole) was added to a solution of 5-(4-iodobenzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (460 mg, 1.03 mmole) in DMF (10 mL).
  • Na 2 CO 3 was dissolved in H 2 O, added to the DMF solution and stirred.
  • Pd(PPh3) 4 was then added to the DMF reaction mixture. The reaction mixture was heated in a microwave at 200° C. for 2 minutes.
  • 2,4-(bis-trifluoromethyl)benzaldoxime (9.75 g, 0.038 mol) was suspended in CH 2 Cl 2 (45 mL, 0.85 M) and cooled to 4° C.
  • Propargyl chloride (2.72 mL, 0.038 mol) was added to the reaction solution followed by dropwise addition of NaOCl (10-13. % free chlorine, 37.6 mL, 0.061 mol).
  • the reaction mixture was stirred at 4° C. for 15 min then heated to reflux for 3 h. After cooling to room temperature, the reaction was partitioned between CH 2 Cl 2 and H 2 O. The organic layer was separated, washed with saturated aqueous NaCl, and dried over sodium sulfate. After removal of solvent, the crude product chloromethylisoxazole was purified by column chromatography on silica (10% CH 2 Cl 2 /hexanes)(6.5 g, 0.020 mol).
  • the solid material was recrystallized from EtoAc/hexanes to obtain 5-((3-(2-trifluoromethy-4-fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine in 69% yield.
  • Example 7B Either salt of Example 7B was mixed 1:1 by weight in dry pregelatinized starch. 100 mg of the mixture was loaded into a hard gel capsule.
  • the scaffold in this case 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine
  • the total amount of 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine was dissolved in enough DMF to give 500 ul/reaction.
  • To each solution was added 60 ⁇ L of 10% (w/v)NaOH/H 2 O.
  • the alkylating agents were dissolved in DMF at a concentration 480 ⁇ mole/mL and 250 ⁇ L of these solutions were added to the respective reaction.
  • Each reaction was then heated to 110° C. for 1 min using microwave irradiation.
  • the aryl boronic acid (1.2 eq.) was added to a solution of 5-(4-iodobenzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (1 eq.) in DMF.
  • Na 2 CO 3 (2eq) was dissolved in H 2 O, added to the DMF solution and stirred.
  • Pd(PPh3)4 was then added to the DMF reaction mixture.
  • the reaction mixture was heated in a microwave at 200° C. for 2 minutes.
  • the reaction mixture was applied to a 1 g solid phase extraction cartridge (C-18) and the column was washed with 3 ⁇ 2 mL of methanol.
  • the eluents were filtered through a 0.45 um filter and then concentrated to dryness.
  • the resulting material was redissolved in DMF, and purified by reverse phase HPLC/MS.
  • Oxime was suspended in CH 2 Cl 2 and cooled to 4° C. Propargyl chloride (1 equiv.) was added to the reaction solution followed by dropwise addition of NaOCl (10-13% free chlorine, 1 equiv.). The reaction mixture was stirred at 4° C. for 15 min then heated to reflux for 3 h. After cooling to room temperature, the reaction was partitioned between CH 2 Cl 2 and H 2 O. The organic layer was separated, washed with saturated aqueous NaCl, and dried over sodium sulfate. After removal of solvent, the crude product was purified by trituration (hexanes) or by column chromatography on silica (10% CH 2 Cl 2 /hexanes).
  • the aryl bromide (1.2 eq.) was added to a solution of 4-((2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridin-5-yl)methyl)phenylboronic acid (1 eq.) in DMF.
  • Na 2 CO 3 (2eq) was dissolved in H 2 O, added to the DMF solution and stirred.
  • Pd(PPh 3 ) 4 (5 mole %) was then added to the DMF reaction mixture.
  • the reaction mixture was heated in a microwave at 200° C. for 2 minutes.
  • the reaction mixture was applied to a 1 g solid phase extraction cartridge (C-18) and the column was washed with 3 ⁇ 2 mL of methanol.
  • the eluents were filtered through a 0.45 um filter and then concentrated to dryness.
  • the resulting material was redissolved in DMF, and purified by reverse phase HPLC/MS.
  • the appropriately substituted 4′-[2-(2,3-Difluoro-phenyl)-imidazo[4,5-c]pyridin-5-ylmethyl]-biphenyl-4-ol (5) scaffold was prepared by first treating 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine) (1) with 1-bromomethyl-4-iodobenzene (2) in DMF using aqueous sodium hydroxide as base.
  • Example 9 95 387.340 388.340 A
  • Example 10 90 395.440 396.440 A
  • Example 11 90 413.431 414.431 A
  • Example 12 92 404.451 405.451 A
  • Example 13 95 407.451 408.451 A
  • Example 14 85 405.479 406.479 A
  • Example 15 90 389.331 390.331 A
  • Example 16 90 431.418 432.418 A
  • Example 17 93 404.834 405.834
  • Example 18 90 370.389 371.389 A
  • Example 19 95 389.331 390.331 A
  • Example 20 95 389.331 390.331 A
  • Example 21 95 389.331 390.331 A
  • Example 22 97 355.777 356.777 A
  • Example 23 90 407.451 408.451
  • Example 24 90 461.134 462.134 A
  • Example 25 90 401.404 402.404 A
  • Example 26 95 371.377 372.377 A
  • Example 27 95 439.375 440.375
  • the final step was performed as described above. Recrystallized from ethyl acetate.
  • MDBK Madin-Darbey Bovine Kidney cells were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with BVDV-free 5% fetal calf serum (DMEME-FCS) at 37° C. in a humidified, 5% CO 2 atmosphere.
  • BVDV-1 strain PE5175 was used to assess the antiviral activity in MDBK cells.
  • the 50% effective concentration (EC 50 ) value was defined as the concentration of compound that protects 50% of the cell monolayer from virus-induced cytopathic effect.
  • Huh-5-2 cells [a cell line with a persistent HCV replicon 1389luc-ubi-neo/NS3-3′/5.1; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B HCV polyprotein] was cultured in RPMI medium (Gibco) supplemented with 10% fetal calf serum, 2 mM L-glutamine (Life Technologies), 1 ⁇ non-essential amino acids (Life Technologies); 100 IU/mL penicillin and 100 ug/ml streptomycin and 250 ug/mL G418 (Geneticin, Life Technologies).
  • Cells were seeded at a density of 7000 cells per well in 96 well View PlateTM (Packard) in medium containing the same components as described above, except for G418. Cells were allowed to adhere and proliferate for 24 hr. At that time, culture medium was removed and serial dilutions of the test compounds were added in culture medium lacking G418. Interferon alfa 2a (500 IU) was included as a positive control. Plates were further incubated at 37° C. and 5% CO 2 for 72 hours. Replication of the HCV replicon in Huh-5 cells results in luciferase activity in the cells.
  • Luciferase activity is measured by adding 50 ⁇ L of 1 ⁇ Glo-lysis buffer (Promega) for 15 minutes followed by 50 ⁇ L of the Steady-Glo Luciferase assay reagent (Promega). Luciferase activity is measured with a luminometer and the signal in each individual well is expressed as a percentage of the untreated cultures. Parallel cultures of Huh-5-2 cells, seeded at a density of 7000 cells/well of classical 96-well cell culture plates (Becton-Dickinson) are treated in a similar fashion except that no Glo-lysis buffer or Steady-Glo Luciferase reagent is added. Instead the density of the culture is measured by means of the MTS method (Promega).
  • Replicon cells were plated at 7.5 ⁇ 10 3 cells per well in a 96-well plate plates at 37° C. and 5% CO 2 in Dulbecco's modified essential medium containing 10% fetal calf serum, 1% nonessential amino acids and 1 mg/ml Geneticin. After allowing 24 h for cell attachment, different dilutions of compound were added to the cultures. Plates were incubated for 5 days, at which time RNA was extracted using the Qiamp Rneazyi Kit (Qiagen, Hilden, Germany).
  • a 50 ⁇ L PCR reaction contained TaqMan EZ buffer (50 mmol/L Bicine, 115 mmol/L potassium acetate, 0.01 mmol/L EDTA, 60 nmol/L 6-carboxy-X-rhodamine, and 8% glycerol, pH 8.2; Perkin Elmer Corp./Applied Biosystems), 300 mmol/L deoxyadenosine triphosphate, 300 ⁇ mol/L deoxyguanosine triphosphate, 300 mmol/L deoxycytidine triphosphate, 600 ⁇ mol/L deoxyuridine triphosphate, 200 ⁇ mol/L forward primer [5′-ccg gcT Acc Tgc ccA TTc], 200 ⁇ mol/L reverse primer [ccA GaT cAT ccT gAT cgA cAA G], 100 ⁇ mol/L TaqMan probe [6-FAM-AcA Tcg cAT cgA g Agc
  • Ct-value is defined as the number of PCR cycles for which the signal exceeds the baseline, which defines a positive value. The sample was considered to be positive if the Ct-value was ⁇ 50. Results are expressed as genomic equivalents (GE).
  • the effect of the drugs on exponentially growing MDBK cells was assessed as follows. Cells were seeded at a density of 5000 cell/well in 96 well plates in MEM medium (Gibco) supplemented with 10% fetal calf serum, 2 mM L-glutamine (Life Technologies) and bicarbonate (Life Technologies). Cells were cultured for 24 hr after which serial dilutions of the test compounds were added. Cultures were then again further incubated for 3 days after which the effect on cell growth was quantified by means of the MTS method (Promega). The concentration that results in 50% inhibition of cell growth is defined as the 50% cytostatic concentration (CC 50 ).
  • the compounds of Examples 2, 3A, 4 and 5 were found to have an EC50 in Replicon assay 2 of, respectively in micromoles, 0.01, 0.02, 0.01 and 0.0039, and to have a CC50 in the CC50 assay protocol of, respectively in micromoles, 26, 34, 19 and 10.8 (replicate 13.4).
  • Substantially all of the compounds in Table 1 demonstrated activity of at least 1 micromolar in an anti-HCV/Replicon assay system. In addition, a number of the compounds also exhibited anti-BVDV activity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
US11/019,830 2003-12-22 2004-12-21 Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment Abandoned US20050222198A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/019,830 US20050222198A1 (en) 2003-12-22 2004-12-21 Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US53229203P 2003-12-22 2003-12-22
US53396304P 2004-01-02 2004-01-02
US59102404P 2004-07-26 2004-07-26
US59106904P 2004-07-26 2004-07-26
US59099004P 2004-07-26 2004-07-26
US59098904P 2004-07-26 2004-07-26
US11/019,830 US20050222198A1 (en) 2003-12-22 2004-12-21 Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment

Publications (1)

Publication Number Publication Date
US20050222198A1 true US20050222198A1 (en) 2005-10-06

Family

ID=34744004

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/583,814 Active 2025-12-27 US7648998B2 (en) 2003-12-22 2004-12-21 Imidazo 4,5-c pyridine compounds and methods of antiviral treatment
US11/019,830 Abandoned US20050222198A1 (en) 2003-12-22 2004-12-21 Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment
US12/577,865 Active 2026-03-25 US8329727B2 (en) 2003-12-22 2009-10-13 Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/583,814 Active 2025-12-27 US7648998B2 (en) 2003-12-22 2004-12-21 Imidazo 4,5-c pyridine compounds and methods of antiviral treatment

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/577,865 Active 2026-03-25 US8329727B2 (en) 2003-12-22 2009-10-13 Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment

Country Status (18)

Country Link
US (3) US7648998B2 (fr)
EP (3) EP2161273B1 (fr)
JP (3) JP4970048B2 (fr)
KR (1) KR101131589B1 (fr)
AT (1) ATE544765T1 (fr)
AU (2) AU2004309390B2 (fr)
CA (1) CA2549606C (fr)
CY (1) CY1112733T1 (fr)
DK (2) DK2161273T3 (fr)
ES (1) ES2381890T3 (fr)
HK (1) HK1092793A1 (fr)
IL (1) IL176298A (fr)
NZ (2) NZ548074A (fr)
PL (1) PL1706403T3 (fr)
PT (1) PT1706403E (fr)
SG (1) SG149067A1 (fr)
SI (1) SI2161273T1 (fr)
WO (1) WO2005063744A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050239821A1 (en) * 2002-07-03 2005-10-27 Johan Neyts Viral inhibitors
US20060052602A1 (en) * 2004-07-27 2006-03-09 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, their uses and methods of preparation
US20060252791A1 (en) * 2004-12-21 2006-11-09 Gilead Sciences, Inc. Imidazo[4,5-c]pyridine compound and method of antiviral treatment
US20070244148A1 (en) * 2003-12-22 2007-10-18 Bondy Steven S Imidazo 4,5-C Pyridine Compounds and Methods of Antiviral Treatment
US20080199427A1 (en) * 2006-07-07 2008-08-21 Bondy Steven S Novel pyridazine compound and use thereof
US20090036460A1 (en) * 2007-07-06 2009-02-05 Gilead Sciences, Inc. Crystalline pyridazine compound
CN102427731A (zh) * 2009-02-27 2012-04-25 英安塔制药有限公司 丙型肝炎病毒抑制剂
US8673954B2 (en) 2009-02-27 2014-03-18 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
US8927739B2 (en) 2011-05-18 2015-01-06 Enanta Pharmaceuticals, Inc. Processes for the preparation of 5-azaspiro[2.4]heptane-6-carboxylic acid and its derivatives
US9765087B2 (en) 2009-02-27 2017-09-19 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69932323T2 (de) 1998-03-02 2006-11-23 Anthony S. Ramona Ellsworth Fahrradaufhängungsvorrichtung und entsprechendes verfahren
US20070128625A1 (en) * 2005-07-25 2007-06-07 Gilead Sciences, Llc Drug-resistant mutants of hepatitis C virus
UA96296C2 (en) * 2006-07-07 2011-10-25 Гилиад Сайенсиз, Инк. Pyridazine compounds and use thereof
AU2011253901B2 (en) * 2006-07-07 2013-08-29 Gilead Sciences, Inc. Novel pyridazine compound and use thereof
CA2672298C (fr) 2006-12-14 2015-02-03 K.U.Leuven Research & Development Composes fusionnes de pyridine utiles dans la prevention ou le traitement des infections virales
TW200920372A (en) * 2007-07-13 2009-05-16 Genelabs Tech Inc Anti-viral compounds, compositions, and methods of use
US20090197880A1 (en) * 2007-07-13 2009-08-06 Genelabs Technologies, Inc. Anti-viral compounds, compositions, and methods of use
UY31685A (es) * 2008-03-04 2009-11-10 Smithkline Beecham Corp Compuestos antivirales, composiciones y metodos para usarlos
KR101220182B1 (ko) * 2009-02-25 2013-01-11 에스케이바이오팜 주식회사 치환된 아졸 유도체 화합물, 이를 포함하는 약제학적 조성물 및 이를 이용한 파킨슨씨 병 치료방법
US10752611B2 (en) 2009-02-27 2020-08-25 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
US8101643B2 (en) * 2009-02-27 2012-01-24 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
CA2784646A1 (fr) 2009-12-18 2011-06-23 Boehringer Ingelheim International Gmbh Polytherapie du vhc
US8933110B2 (en) 2010-01-25 2015-01-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8785487B2 (en) 2010-01-25 2014-07-22 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
EP2555622A4 (fr) 2010-04-09 2013-09-18 Enanta Pharm Inc Inhibiteurs du virus de l'hépatite c
KR101799429B1 (ko) * 2010-05-03 2017-11-21 에스케이바이오팜 주식회사 신경 세포 사멸 또는 신경 퇴화를 억제하기 위한 약학적 조성물
JP2013526581A (ja) * 2010-05-21 2013-06-24 ギリアード サイエンシーズ， インコーポレイテッド ヘテロ環式フラビウイルス科ウイルス阻害剤
US8778938B2 (en) 2010-06-04 2014-07-15 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2012021704A1 (fr) 2010-08-12 2012-02-16 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
ES2527544T1 (es) 2011-10-21 2015-01-26 Abbvie Inc. Tratamiento mono (PSI-7977) o de combinación con AAD para su uso en el tratamiento del VHC
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
AR088463A1 (es) 2011-10-21 2014-06-11 Abbvie Inc Metodos para el tratamiento de hcv
RS62434B1 (sr) 2014-12-26 2021-11-30 Univ Emory Antivirusni n4-hidroksicitidin derivati
WO2017189978A1 (fr) 2016-04-28 2017-11-02 Emory University Compositions thérapeutiques à base de nucléotides et nucléosides contenant un alcyne et utilisations associées
EP3455218A4 (fr) 2016-05-10 2019-12-18 C4 Therapeutics, Inc. Dégronimères de type glutarimide liés au carbone c3 pour la dégradation de protéines cibles
EP3454856B1 (fr) 2016-05-10 2024-09-11 C4 Therapeutics, Inc. Dégronimères hétérocycliques pour la dégradation de protéines cibles
WO2017197036A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères spirocycliques pour la dégradation de protéines cibles
CN111372592A (zh) 2017-12-07 2020-07-03 埃默里大学 N4-羟基胞苷及衍生物和与其相关的抗病毒用途
AU2021225333A1 (en) * 2020-02-24 2022-08-11 Katholieke Universiteit Leuven Pyrrolopyridine and imidazopyridine antiviral compounds

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040171626A1 (en) * 2003-01-22 2004-09-02 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US20040186125A1 (en) * 2003-01-22 2004-09-23 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US6803374B2 (en) * 2001-09-26 2004-10-12 Bristol-Myers Squibb Company Compounds useful for treating hepatitis C virus
US20060229336A1 (en) * 2002-12-13 2006-10-12 Kazmierski Wieslaw M Ccr5 antagonists as therapeutic agents
US20070032497A1 (en) * 1999-12-27 2007-02-08 Japan Tobacco Inc. Fused-ring compounds and use thereof as drugs
US7285551B2 (en) * 1999-12-27 2007-10-23 Japan Tobacco Inc. Fused-ring compounds and use thereof as drugs
US7294457B2 (en) * 2001-08-07 2007-11-13 Boehringer Ingelheim (Canada) Ltd. Direct binding assay for identifying inhibitors of HCV polymerase
US20080188516A1 (en) * 2004-12-21 2008-08-07 Bondy Steven S Imiadazo[4,5-c] pyridine compound and method of antiviral treatment

Family Cites Families (105)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US462009A (en) * 1891-10-27 Four-hundred-day clock
US232937A (en) * 1880-10-05 Pipe cutter and wrench
US605836A (en) * 1898-06-21 George ashley
US89588A (en) * 1869-05-04 Improved apparatus for making illuminating-gas from gasoline
US510260A (en) * 1893-12-05 Electric-arc-lighting system
US78019A (en) * 1868-05-19 Albert b
US300726A (en) * 1884-06-17 Benjamin franklin opp
US637615A (en) * 1899-07-31 1899-11-21 Dluarej Norwood Jerauld Fire-escape.
US658625A (en) * 1899-08-16 1900-09-25 John Eicher Cream-ripening apparatus.
US706795A (en) * 1902-03-24 1902-08-12 Internat Silver Co Tilting vessel.
US1048742A (en) * 1912-04-17 1912-12-31 Theodore Scherba Trolley.
US1162196A (en) * 1913-07-05 1915-11-30 Safety Car Heating & Lighting Dynamo-mounting.
US1400241A (en) * 1919-04-09 1921-12-13 Sholdebrand Henry Oliver Stovepipe-cleaner
US1386923A (en) * 1920-01-02 1921-08-09 Edward C Capper Automatic fire-alarm device
US2191978A (en) * 1935-10-10 1940-02-27 Ig Farbenindustrie Ag Quaternary nitrogen compounds and process of preparing them
US2264115A (en) * 1939-01-14 1941-11-25 T & T Vicars Ltd Method and apparatus for treating dough
US2411662A (en) * 1943-05-13 1946-11-26 Geigy Ag J R Imino-di-fatty acid amide
US2548863A (en) * 1946-05-29 1951-04-17 Wyeth Corp Substituted glycinamides
US2516674A (en) * 1948-10-29 1950-07-25 Wyeth Corp Substituted glycinamide
US3035207A (en) * 1959-01-14 1962-05-15 A E I Lamp And Lighting Compan Circuit arrangement for operating electric discharge lamp
US3985891A (en) * 1973-02-03 1976-10-12 Boehringer Ingelheim Gmbh 2-Phenyl-imidazo (4,5-b)pyridines and salts thereof
SU813921A1 (ru) 1979-10-26 1986-12-23 Институт физико-органической химии и углехимии АН УССР Стирильные производные имидазо(4,5- @ )пиридиний иодида,обладающие фунгицидной активностью
SU851940A1 (ru) 1980-03-20 1988-04-30 Институт физико-органической химии и углехимии АН УССР Четвертичные соли имидазо @ 4,5-с @ пиридини ,обладающие антимикробной и фунгистатической активностью
SU860463A1 (ru) 1980-04-09 1998-05-27 Институт физико-органической химии и углехимии АН Украинской ССР Производные 4-амино-1,3-диметилимидазо [4,5-с] пиридин-2-она, обладающие акарицидным действием
SU1048742A1 (ru) 1981-03-30 1986-12-23 Институт физико-органической химии и углехимии АН УССР 2,4-Дистирилпроизводные имидазо-(4,5- @ )пиридини ,обладающие бактериостатической и фунгистатической активностью
US4358387A (en) * 1981-08-10 1982-11-09 Texaco Inc. Cylinder lubricating oil composition
CA1183847A (fr) * 1981-10-01 1985-03-12 Georges Van Daele N-(3-hydroxy-4-piperidinyl)benzamide; derives
US5137896A (en) * 1981-10-01 1992-08-11 Janssen Pharmaceutica N.V. N-(3-hydroxy-4-piperidinyl)benzamide derivatives
FR2527608B1 (fr) * 1982-05-28 1986-10-10 Sandoz Sa Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments
GB2148289B (en) 1983-10-17 1987-09-23 Lilly Co Eli 3-bicyclicpyridinium-methyl cephalosporins
US4692443A (en) * 1983-10-17 1987-09-08 Eli Lilly And Company 3-bicyclicpyridinium-methyl cephalosporins
GB8501542D0 (en) * 1985-01-22 1985-02-20 Erba Farmitalia 4 5 6 7-tetrahydro-imidazo(4 5-clpyridine derivatives
GB8530602D0 (en) 1985-12-12 1986-01-22 Fujisawa Pharmaceutical Co Heterocyclic compounds
ES2052544T3 (es) 1986-02-03 1994-07-16 Janssen Pharmaceutica Nv Composiciones anti-histaminicas que contienen n-heterociclil-4-piperidinaminas.
US4804658A (en) * 1986-09-15 1989-02-14 G. D. Searle & Co. Imidazopyridine derivatives and pharmaceutical compositions
NZ225447A (en) 1987-07-20 1991-12-23 Merck & Co Inc Piperazinyl derivatives of purine and purine isosteres and pharmaceutical compositions
US5057517A (en) * 1987-07-20 1991-10-15 Merck & Co., Inc. Piperazinyl derivatives of purines and isosteres thereof as hypoglycemic agents
US5227384A (en) * 1988-03-14 1993-07-13 G. D. Searle & Co. 5-substituted [4,5-c] imidazopyridines and pharmaceutical use thereof
US4914108A (en) * 1988-03-14 1990-04-03 G. D. Searle & Co. 5-substituted(4,5-c)imidazopyridine compounds which have useful platelet activating factor antagonistic activity
US5019581A (en) * 1988-03-14 1991-05-28 G. D. Searle & Co. 5-substituted (4,5-c) imidazopyridine compounds which have useful platelet activating factor antagonistic activity
US5302601A (en) * 1988-03-14 1994-04-12 G. D. Searle & Co. 5-substituted imidazo[4,5-c]pyridines
US5332744A (en) * 1989-05-30 1994-07-26 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US4988707A (en) 1989-09-13 1991-01-29 G. D. Searle & Co. Pharmacologically active phenylalkanoyl substituted imidazo (4,5-C) pyridines
US4990518A (en) * 1989-09-13 1991-02-05 G. D. Searle & Co. Pharmacologically active heteroaryl substituted imidazo (4,5-c) pyridines
US5095873A (en) 1989-09-13 1992-03-17 Yamaha Hatsudoki Kabushiki Kaisha Fuel injection system and method for engine
FR2663332B1 (fr) 1990-06-15 1997-11-07 Roussel Uclaf Nouvelles cephalosporines comportant en position 3 un radical propenyle substitue par un ammonium quaternaire, leur procede de preparation, leur application comme medicaments, les compositions les renfermant et les nouveaux intermediaires obtenus.
US5011832A (en) * 1990-06-26 1991-04-30 Merck & Co., Inc. 2-biphenyl-carbapenem antibacterial agents
US5372808A (en) * 1990-10-17 1994-12-13 Amgen Inc. Methods and compositions for the treatment of diseases with consensus interferon while reducing side effect
JPH04327587A (ja) 1991-04-26 1992-11-17 Asahi Chem Ind Co Ltd ６’−ｃ−アルキル−３−デアザネプラノシンａ誘導体、その製造法およびその用途
GB9116056D0 (en) * 1991-07-24 1991-09-11 British Bio Technology Compounds
US5587372A (en) * 1991-12-12 1996-12-24 Roussel Uclaf Cephalosporins
GB9200245D0 (en) 1992-01-07 1992-02-26 British Bio Technology Compounds
GB9202792D0 (en) 1992-02-11 1992-03-25 British Bio Technology Compounds
DE4211474A1 (de) 1992-04-06 1993-10-07 Merck Patent Gmbh Imidazopyridine
US5208242A (en) 1992-08-26 1993-05-04 G. D. Searle & Co. 5-substituted-4-phenyl-5H-imidazo[4,5-c]pyridine derivatives
DE4230464A1 (de) 1992-09-11 1994-03-17 Merck Patent Gmbh Imidazolderivate
DE4236026A1 (de) * 1992-10-24 1994-04-28 Merck Patent Gmbh Imidazopyridine
JP3115455B2 (ja) 1992-12-18 2000-12-04 明治製菓株式会社 新規セファロスポリン誘導体
US5374638A (en) 1993-03-19 1994-12-20 Merck & Co., Inc. Six membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives used to treat asthma
DE4309969A1 (de) 1993-03-26 1994-09-29 Bayer Ag Substituierte heteroanellierte Imidazole
DE4318813A1 (de) 1993-06-07 1994-12-08 Merck Patent Gmbh Imidazopyridine
DE4324580A1 (de) * 1993-07-22 1995-01-26 Thomae Gmbh Dr K Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
US5486525A (en) * 1993-12-16 1996-01-23 Abbott Laboratories Platelet activating factor antagonists: imidazopyridine indoles
US5563143A (en) 1994-09-21 1996-10-08 Pfizer Inc. Catechol diether compounds as inhibitors of TNF release
US6506876B1 (en) * 1994-10-11 2003-01-14 G.D. Searle & Co. LTA4 hydrolase inhibitor pharmaceutical compositions and methods of use
US5585492A (en) * 1994-10-11 1996-12-17 G. D. Searle & Co. LTA4 Hydrolase inhibitors
US5635514A (en) * 1994-10-25 1997-06-03 G. D. Searle & Company Heteroaralkyl and heteroarylthioalkyl thiophenolic compounds as 5-lipoxgenase inhibitors
US5880140A (en) * 1996-04-03 1999-03-09 Merck & Co., Inc. Biheteroaryl inhibitors of farnesyl-protein transferase
US5854265A (en) * 1996-04-03 1998-12-29 Merck & Co., Inc. Biheteroaryl inhibitors of farnesyl-protein transferase
US5874452A (en) * 1996-04-03 1999-02-23 Merck & Co., Inc. Biheteroaryl inhibitors of farnesyl-protein transferase
US6080870A (en) * 1996-04-03 2000-06-27 Merck & Co., Inc. Biaryl substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
US5872136A (en) * 1996-04-03 1999-02-16 Merck & Co., Inc. Arylheteroaryl inhibitors of farnesyl-protein transferase
US5883105A (en) * 1996-04-03 1999-03-16 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6063930A (en) * 1996-04-03 2000-05-16 Merck & Co., Inc. Substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
US5859035A (en) * 1996-04-03 1999-01-12 Merck & Co., Inc. Arylheteroaryl inhibitors of farnesyl-protein transferase
US5939557A (en) * 1996-04-03 1999-08-17 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6015817A (en) * 1996-12-05 2000-01-18 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
NZ504800A (en) * 1997-11-28 2001-10-26 Sumitomo Pharma 6-Amino-9-benzyl-8-hydroxy-purine derivatives and interferon inducers, antiviral agents, anticancer agents and therapeutic agents for immunologic diseases thereof
DE19845153A1 (de) 1998-10-01 2000-04-06 Merck Patent Gmbh Imidazo[4,5]-pyridin-4-on-derivate
US6271380B1 (en) 1998-12-30 2001-08-07 Dupont Pharmaceuticals Company 1H-imidazo[4,5-d]pyridazin-7-ones, 3H-imidazo-[4,5-c]pyridin-4-ones and corresponding thiones as corticotropin releasing factor (CRF) receptor ligands
DE69932263T2 (de) * 1999-01-08 2007-06-06 Chisso Corp. Borderivate und organische elektrolumineszierende verbindungen
DE19900471A1 (de) 1999-01-08 2000-07-13 Merck Patent Gmbh Imidazo[4,5c]-pyridin-4-on-derivate
EP1182195A4 (fr) * 1999-05-07 2003-03-26 Takeda Chemical Industries Ltd Composes cycliques et leurs utilisations
US6844367B1 (en) * 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
EP1259485B1 (fr) * 2000-02-29 2005-11-30 Millennium Pharmaceuticals, Inc. Benzamides et inhibiteurs associes du facteur xa
EP1132381A1 (fr) 2000-03-08 2001-09-12 Cermol S.A. Derivés d'esters d'acide propionique et compositions pharmaceutiques les contenant
US6448281B1 (en) * 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
KR100892614B1 (ko) 2001-04-17 2009-04-09 다이닛본 스미토모 세이야꾸 가부시끼가이샤 신규 아데닌 유도체
AR035543A1 (es) * 2001-06-26 2004-06-16 Japan Tobacco Inc Agente terapeutico para la hepatitis c que comprende un compuesto de anillo condensado, compuesto de anillo condensado, composicion farmaceutica que lo comprende, compuestos de benzimidazol, tiazol y bifenilo utiles como intermediarios para producir dichos compuestos, uso del compuesto de anillo con
US20030073836A1 (en) * 2001-07-05 2003-04-17 Boehringer Ingelheim Pharma Kg Heteroarylcarboxylic acid amides, the preparation thereof and their use as pharmaceutical compositions
US6841566B2 (en) 2001-07-20 2005-01-11 Boehringer Ingelheim, Ltd. Viral polymerase inhibitors
EP2335700A1 (fr) 2001-07-25 2011-06-22 Boehringer Ingelheim (Canada) Ltd. Inhibiteurs de la polymerase du virus hepatitis C avec une structure heterobicylic
DE10140246A1 (de) * 2001-08-09 2003-03-06 Forsch Pigmente Und Lacke E V Verfahren zur Behandlung von Oberflächen von Substraten
AU2003205570A1 (en) 2002-01-10 2003-07-24 Boehringer Ingelheim Pharma Gmbh And Co. Kg Combination of mtp inhibitors or apob secretion inhibitors with fibrates for use as drugs
GB0215293D0 (en) * 2002-07-03 2002-08-14 Rega Foundation Viral inhibitors
SI1532149T1 (sl) 2002-08-21 2010-05-31 Boehringer Ingelheim Pharma amino piperidin il ksantini njihova priprava in njihova uporaba kot zdravila
US20040097574A1 (en) 2002-08-29 2004-05-20 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
DE602004022633D1 (de) * 2003-01-30 2009-10-01 Boehringer Ingelheim Pharma 2,4-diaminopyrimidinderivate, die sich als inhibitoren von pkc-theta eignen
US7566707B2 (en) * 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
AU2004291262C1 (en) * 2003-11-05 2011-08-11 F. Hoffmann-La Roche Ag Phenyl derivatives as PPAR agonists
US7648998B2 (en) * 2003-12-22 2010-01-19 K.U. Leuven Research & Development Imidazo 4,5-c pyridine compounds and methods of antiviral treatment
CA2574220C (fr) * 2004-07-27 2014-09-16 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, procedes d'utilisation et de preparation correspondants
CN101018843B (zh) 2004-09-13 2011-05-11 西巴特殊化学品控股有限公司 烷基氨基乙酰胺润滑添加剂
WO2008005519A2 (fr) * 2006-07-07 2008-01-10 Gilead Sciences, Inc. Nouveau composé à base de pyrizadine et son utilisation
UA99466C2 (en) 2007-07-06 2012-08-27 Гилиад Сайенсиз, Инк. Crystalline pyridazine compound

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070032497A1 (en) * 1999-12-27 2007-02-08 Japan Tobacco Inc. Fused-ring compounds and use thereof as drugs
US7285551B2 (en) * 1999-12-27 2007-10-23 Japan Tobacco Inc. Fused-ring compounds and use thereof as drugs
US7294457B2 (en) * 2001-08-07 2007-11-13 Boehringer Ingelheim (Canada) Ltd. Direct binding assay for identifying inhibitors of HCV polymerase
US6803374B2 (en) * 2001-09-26 2004-10-12 Bristol-Myers Squibb Company Compounds useful for treating hepatitis C virus
US20060229336A1 (en) * 2002-12-13 2006-10-12 Kazmierski Wieslaw M Ccr5 antagonists as therapeutic agents
US20040171626A1 (en) * 2003-01-22 2004-09-02 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US20040186125A1 (en) * 2003-01-22 2004-09-23 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7098231B2 (en) * 2003-01-22 2006-08-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7223785B2 (en) * 2003-01-22 2007-05-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US20080188516A1 (en) * 2004-12-21 2008-08-07 Bondy Steven S Imiadazo[4,5-c] pyridine compound and method of antiviral treatment

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7737162B2 (en) 2002-07-03 2010-06-15 Gilead Sciences, Inc. Viral inhibitors
US8779141B2 (en) 2002-07-03 2014-07-15 Gilead Sciences, Inc. Viral inhibitors
US20050239821A1 (en) * 2002-07-03 2005-10-27 Johan Neyts Viral inhibitors
US20070244148A1 (en) * 2003-12-22 2007-10-18 Bondy Steven S Imidazo 4,5-C Pyridine Compounds and Methods of Antiviral Treatment
US8329727B2 (en) 2003-12-22 2012-12-11 Gilead Sciences, Inc. Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment
US7648998B2 (en) 2003-12-22 2010-01-19 K.U. Leuven Research & Development Imidazo 4,5-c pyridine compounds and methods of antiviral treatment
US20100028301A1 (en) * 2003-12-22 2010-02-04 Bondy Steven S IMIDAZO[4,5-c]PYRIDINE COMPOUNDS AND METHODS OF ANTIVIRAL TREATMENT
US20060052602A1 (en) * 2004-07-27 2006-03-09 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, their uses and methods of preparation
US7790730B2 (en) * 2004-07-27 2010-09-07 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, their uses and methods of preparation
US20090208456A1 (en) * 2004-07-27 2009-08-20 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, their uses and methods of preparation
US20080188516A1 (en) * 2004-12-21 2008-08-07 Bondy Steven S Imiadazo[4,5-c] pyridine compound and method of antiviral treatment
US7795276B2 (en) * 2004-12-21 2010-09-14 Gilead Sciences, Inc. Imiadazo[4,5-c] pyridine compound and method of antiviral treatment
US20060252791A1 (en) * 2004-12-21 2006-11-09 Gilead Sciences, Inc. Imidazo[4,5-c]pyridine compound and method of antiviral treatment
US20100063059A1 (en) * 2006-07-07 2010-03-11 Gerhard Puerstinger Novel pyridazine compound and use thereof
US20100152444A1 (en) * 2006-07-07 2010-06-17 Gilead Sciences, Inc. Novel pyridazine compound and use thereof
US7754720B2 (en) 2006-07-07 2010-07-13 Gilead Sciences, Inc. Pyridazine compound and use thereof
US20080199427A1 (en) * 2006-07-07 2008-08-21 Bondy Steven S Novel pyridazine compound and use thereof
US7956184B2 (en) 2006-07-07 2011-06-07 Gilead Sciences, Inc. Pyridazine compound and use thereof
US8569487B2 (en) 2006-07-07 2013-10-29 Gilead Sciences, Inc. Pyridazine compound and use thereof
US20090036460A1 (en) * 2007-07-06 2009-02-05 Gilead Sciences, Inc. Crystalline pyridazine compound
US8569488B2 (en) 2007-07-06 2013-10-29 Gilead Sciences, Inc. Crystalline pyridazine compound
US8106054B2 (en) 2007-07-06 2012-01-31 Gilead Sciences, Inc. Crystalline pyridazine compound
CN102427731A (zh) * 2009-02-27 2012-04-25 英安塔制药有限公司 丙型肝炎病毒抑制剂
US8673954B2 (en) 2009-02-27 2014-03-18 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
CN102427731B (zh) * 2009-02-27 2015-05-13 英安塔制药有限公司 丙型肝炎病毒抑制剂
US9765087B2 (en) 2009-02-27 2017-09-19 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
US8927739B2 (en) 2011-05-18 2015-01-06 Enanta Pharmaceuticals, Inc. Processes for the preparation of 5-azaspiro[2.4]heptane-6-carboxylic acid and its derivatives

Also Published As

Publication number Publication date
ES2381890T3 (es) 2012-06-01
NZ548074A (en) 2010-08-27
EP1706403B1 (fr) 2012-02-08
CA2549606C (fr) 2015-10-06
AU2011202214B2 (en) 2012-12-20
EP2546254A1 (fr) 2013-01-16
KR20060132850A (ko) 2006-12-22
EP2161273B1 (fr) 2015-04-15
WO2005063744A2 (fr) 2005-07-14
DK2161273T3 (en) 2015-07-20
KR101131589B1 (ko) 2012-04-13
DK1706403T3 (da) 2012-04-23
PL1706403T3 (pl) 2012-07-31
WO2005063744A3 (fr) 2005-09-01
CY1112733T1 (el) 2016-02-10
AU2011202214A1 (en) 2011-06-16
JP2011148835A (ja) 2011-08-04
IL176298A (en) 2015-06-30
HK1092793A1 (en) 2007-02-16
US20070244148A1 (en) 2007-10-18
AU2004309390A1 (en) 2005-07-14
PT1706403E (pt) 2012-04-23
SG149067A1 (en) 2009-01-29
CA2549606A1 (fr) 2005-07-14
AU2004309390B2 (en) 2011-06-02
US8329727B2 (en) 2012-12-11
EP1706403A2 (fr) 2006-10-04
NZ595000A (en) 2013-03-28
JP5395844B2 (ja) 2014-01-22
JP2013221030A (ja) 2013-10-28
US7648998B2 (en) 2010-01-19
US20100028301A1 (en) 2010-02-04
SI2161273T1 (sl) 2015-10-30
IL176298A0 (en) 2006-10-05
EP1706403B9 (fr) 2012-07-25
JP2007518720A (ja) 2007-07-12
ATE544765T1 (de) 2012-02-15
EP2161273A1 (fr) 2010-03-10
JP4970048B2 (ja) 2012-07-04

Similar Documents

Publication Publication Date Title
US8329727B2 (en) Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment
US7790730B2 (en) Imidazo[4,5-d]pyrimidines, their uses and methods of preparation
US8779141B2 (en) Viral inhibitors
US9242983B2 (en) Viral inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: GILEAD SCIENCES, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BONDY, STEVEN S.;DOWDY, ERIC DAVIS;KIM, CHOUNG U.;AND OTHERS;REEL/FRAME:019272/0061;SIGNING DATES FROM 20070427 TO 20070507

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: K.U. LEUVEN RESEARCH & DEVELOPMENT, BELGIUM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NEYTS, JOHAN;REEL/FRAME:023392/0470

Effective date: 20070521

AS Assignment

Owner name: GILEAD SCIENCES, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GILEAD SCIENCES, INC.;K.U. LEUVEN RESEARCH & DEVELOPMENT;REEL/FRAME:023503/0684;SIGNING DATES FROM 20091029 TO 20091111

Owner name: GILEAD SCIENCES, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PUERSTINGER, GERHARD;REEL/FRAME:023503/0668

Effective date: 20091030

Owner name: K.U. LEUVEN RESEARCH & DEVELOPMENT, BELGIUM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PUERSTINGER, GERHARD;REEL/FRAME:023503/0668

Effective date: 20091030

Owner name: PUERSTINGER, GERHARD, AUSTRIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PUERSTINGER, GERHARD;REEL/FRAME:023503/0668

Effective date: 20091030

Owner name: K.U. LEUVEN RESEARCH & DEVELOPMENT, BELGIUM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GILEAD SCIENCES, INC.;K.U. LEUVEN RESEARCH & DEVELOPMENT;REEL/FRAME:023503/0684;SIGNING DATES FROM 20091029 TO 20091111

Owner name: PUERSTINGER, GERHARD, AUSTRIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GILEAD SCIENCES, INC.;K.U. LEUVEN RESEARCH & DEVELOPMENT;REEL/FRAME:023503/0684;SIGNING DATES FROM 20091029 TO 20091111

AS Assignment

Owner name: K.U. LEUVEN RESEARCH & DEVELOPMENT, BELGIUM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GILEAD SCIENCES, INC.;REEL/FRAME:036495/0004

Effective date: 20150314