WO2005058870A1 - Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication - Google Patents
Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication Download PDFInfo
- Publication number
- WO2005058870A1 WO2005058870A1 PCT/EP2004/053617 EP2004053617W WO2005058870A1 WO 2005058870 A1 WO2005058870 A1 WO 2005058870A1 EP 2004053617 W EP2004053617 W EP 2004053617W WO 2005058870 A1 WO2005058870 A1 WO 2005058870A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- ealkyl
- hydrogen
- hydroxy
- 6alkyl
- Prior art date
Links
- 0 *c(cc1*)cc(*2*=*)c1N=C2N(*)* Chemical compound *c(cc1*)cc(*2*=*)c1N=C2N(*)* 0.000 description 6
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention is concerned with ammo-benzimidazole derivatives having antiviral activity, in particular, having an inhibitory activity on the replication ofthe respiratory syncytial virus (RSV). It further concerns their preparation and compositions comprising them, as well as their use as a medicine.
- RSV respiratory syncytial virus
- Human RSV or Respiratory Syncytial Virus is a large RNA virus, member ofthe family of Paramyxoviridae, subfamily pneumoviridae together with bovine RSV virus.
- Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.
- ribavirin a nucleoside analogue
- the other two drugs, RespiGam ® and paUvizumab, polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way.
- the present invention concerns inhibitors of RSV repHcation, which can be represented by formula (I):
- Q is Ar 2 , C 3-7 cycloalkyl, or Ci- ⁇ alkyl substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1- alkoxy, C 1- alkylthio, Ar 2 -oxy ⁇ , Ar 2 -thio-, Ar 2 (CH 2 ) n oxy, Ar 2 (CH 2 ) n thio, hydroxycarbonyl, aminocarbonyl, C 1- alkyl- carbonyl, C 1- alkoxycarbonyl, aminocarbonyl- oxy, C 1- alkylcarbonyloxy, Ar 2 carbonyloxy, hydroxy- C 2- -alkyloxy, carbonyl, mono- or di(C 1- alkyl)aminocarbonyloxy, aminosulfonyl, mono- or dioxolanyl optionally substituted with one or two Ci- ⁇ alkyl radicals, and a heterocycle selected from the group consist
- R 2a , R 2b , R 3a and R 3 all are hydrogen
- R 4a and R 4b can be the same or can be different relative to one another, and are each independently hydrogen or C ⁇ alkyl; or
- R 4a and R 4b taken together may form a bivalent radical of formula -(CH 2 ) S -;
- R 5 is hydrogen or C ⁇ aU yl; m is 1 or 2; p is 1 or 2; s is 4 or 5 Ar 1 is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from halo, hydroxy, hydroxyC ealkyl, polyhaloC 1-6 alkyl, and Ci- ⁇ alkyloxy;
- Ar 2 is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from the group consisting of halo, hydroxy, amino, cyano, C h alky!, polyhaloCi-ealkyl, aminoC ⁇ -6alkyl, Ci- ⁇ alkyloxy, aminosulfonyl, aminocarbonyl, hydroxycarbonyl, mono- or ch(C ⁇ . ajJ ⁇ yl)amino, mono- or mono- or di(C 1- alkyl)- aminosulfonyl, mono- or and
- the invention relates to the use of a compound of formula (I), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof, for the manufacture of a medicament for inhibiting RSV replication.
- the invention relates to a method of inhibiting RSV replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound of formula (I), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof.
- this invention relates to novel compounds of formula (I) as well as methods for preparing these compounds.
- prodrug' as used throughout this specification and claims means the pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product ofthe derivative is the active drug as defined in the compounds of formula (I).
- the reference by Goodman and Gil an (The
- Prodrugs are characterized by a good aqueous solubility and bioavailability, and are readily metabolized into the active inhibitors in vivo.
- Ci- ⁇ alkyl radicals respectively Ci-inalkanediyl radicals having no, one, two or more substituents, for example no, one, two, three, four, five or six substituents, in particular no, one, two or three substituents, further in particular no, one or two substituents.
- the upper limit of the number of substituents is determined by the number of hydrogen atoms that can be replaced as well as by the general properties ofthe substituents such as their bulkiness, these properties allowing the skilled person to determine said upper limit.
- each of said heterocycle may optionally be substituted with oxo or Ci- ⁇ alkyl' is meant to comprise heterocycles substituted with one or more, such up to 3, or up to 2 substituents or with one s ⁇ bstituent indepently selected from oxo and Ci- ⁇ al yl.
- ' ⁇ olyhaloC 1-6 alkyl' as a group or part of a group, e.g. in polyhaloCi- ⁇ alkyloxy, is defined as mono- or polyhalo substituted
- Ci-ealkyl in particular C ⁇ alkyl substituted with up to one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl.
- perfluoro Ci- ⁇ alkyl groups which are Ci- ⁇ alkyl groups whereion all hydrogen atoms are replaced by fluoro atoms, e.g. pentafluoroethyl. In case more than one halogen atom is attached to an alkyl group within the the halogen atoms may be the same or different.
- Each ofthe monocyclic or bicyclic heterocycles in the definition of R 1 may optionally be substituted with 1 or where possible more substituents, such as 2, 3, 4 or 5, substituents.
- said heterocycles may optionally be substituted with up to 4, up to 3, up to 2 substituents, or up to 1 substituent.
- Each Ar 1 or Ar 2 may be unsubstituted phenyl or phenyl substituted with 1 or more substituents, such as 5 or 4 substituents or, which is preferred, up to 3 substituents, or up to two substituents, or with one substituent.
- a hydroxyCi-ealkyl group when substituted on an oxygen atom or a nitrogen atom preferably is a hydroxyC 2-6 alkyl group wherein the hydroxy group and the oxygen or nitrogen is separated by at least two carbon atoms.
- C 1-3 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1 -methylethyl and the like;
- C 1- alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for C 1-3 alkyl and butyl and the like;
- C 2- alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl, propyl, 1 -methylethyl, butyl and the like;
- Ci-salkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 5 carbon atoms such as the groups defined for andpentyl, 1-methylbutyl, 2-methylbutyL 1-ethy
- C 3 _7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- C 2 5 alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 2 to 5 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl and the like
- C ⁇ alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like
- C ⁇ alkanediyl is meant to include C ⁇ alkanediyl and the higher homologues thereof having from 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like
- halo is generic to fluoro, chloro, bromo and iodo.
- radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable. Radicals used in the definitions ofthe variables include all possible isomers unless otherwise indicated. For instance pyridyl includes 2-pyridyl, 3 -pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.
- each definition is independent.
- the term 'compounds of formula (I)', or 'the present compounds' or s ⁇ nilar term is meant to include the compounds of general formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms.
- An interesting subgroup ofthe compounds of formula (I) or any subgroup thereof are the N-oxides, salts and all the stereoisomeric forms ofthe compounds of formula (I).
- stereochemically isomeric forms as used hereinbefore defines all the possible compounds made up ofthe same atoms bonded by the same sequence of bonds but having different toee-dimensional structures which are not interchangeable, which the compounds of formula (1) may possess.
- the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers ofthe basic molecular structure of said compound. All stereochemically isomeric forms ofthe compounds ofthe present invention both in pure form or in admixture with each other are intended to be embraced within the scope ofthe present invention.
- stereoisomeric forms ofthe compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
- the term 'stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% ofthe other possible isomers) up to a stereoisomeric excess of 100% (i.e.
- Pure stereoisomeric forms ofthe compounds and intermediates of this invention may be obtained by the application of art-known procedures.
- enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl- tartaric acid, ditoluoyltartaric acid and camphosulfonic acid.
- enantiomers may be separated by chromatographic techniques using chiral stationary phases.
- Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occurs stereospecifically.
- a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
- the diastereomeric racemates of formula (I) can be obtained separately by conventional methods.
- Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
- the absolute stereochemical configuration was not experimentally determined.
- a person skilled in the art is able to detetrmdne the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
- the present invention is also intended to include all isotopes of atoms occurring on the present compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- isotopes of carbon include C-13 and C-14.
- salts ofthe compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable.
- salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included wilMn the ambit ofthe present invention.
- the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
- the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
- Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
- hydrochloric or hydrobromic acid sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane- dioic acid), maleic, fumaric, malic (i.e.
- hydroxybutanedioic acid tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, j3-toluenesulfonic, cyclamic, salicyHc, )-aminosalicylic, pamoic and the like acids.
- salt forms can be converted by treatment with an appropriate base into the free base form.
- the compounds of formula (1) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
- Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzatnine, N-memyl-D-glucamine, hydrabarnine salts, and salts with amino acids such as, for example, arginirie, lysine and the like.
- addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form.
- solvates are for example hydrates, alcoholates and the like.
- quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (1) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.
- Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
- a quaternary amine has a positively charged nitrogen.
- Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
- N-oxide forms ofthe present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
- the compounds of formula (I) may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates.
- metalated derivatives ofthe compounds of formula (I) are intended to be included within the scope ofthe present invention.
- any subgroup of compounds of formula (I) specified herein is meant to also comprise the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of this subgroup of compounds of formula (I).
- One embodiment of the present invention concerns compounds of formula (I-a) :
- R 5 , G and R 1 are as specified above or as in any ofthe subgroups of compounds specified herein; and R 2a is C 1-6 alkyl; R 2b is hydrogen or Ci-ealkyl.
- Another embodiment ofthe present invention concerns compounds of formula (I-b):
- R 3a is C 1-6 alkyl
- R 3b is hydrogen or
- Another embodiment ofthe present invention concerns compounds of formula (I-c): wherein Q, R 5 , G and R 1 are as specified above or as in any ofthe subgroups of compounds specified herein.
- Particular subgroups of the compounds of formula (1) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein G is Ci-ioalkanediyl, more in particular wherein G is methylene.
- R 1 is other than Ar 1 ;
- R 1 is Ar 1 or a monocyclic heterocycle, which is as specified in the definitions ofthe compounds of formula (I) or any ofthe subgroups thereof.
- R 1 is pyridyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, carboxyl, Ci- ⁇ alkyl, Ci- ⁇ alkyloxy, oxy, hydroxyC ⁇ .
- R 1 is pyridyl substituted with hydroxy and Ci-ealkyl; or more preferably wherein (h) R 1 is pyridyl substituted with hydroxy and methyl; or wherein
- R 1 is 3-hydroxy-6-methylpyrid-2-yl.
- R 1 is Ar 1 , quinolinyl, benzimidazolyl, a radical of formula
- R 1 is Ar 1 , quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl, or pyridyl;
- each ofthe radicals in (j) and (k) may optionally be substituted with the substituents specified in the definition ofthe compounds of formula (I) and in particular pyridyl may be substituted as specified above in (a) to (i).
- R 1 is Ar 1 , quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl, or pyridyl, wherein each of these radicals may optionally be substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, Ci-ealkyl, Ci- ⁇ alkyloxy, (C 1- 6alkyloxy)C 1-6 alkyloxy; or more specifically wherein
- R 1 is Ar 1 , quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl, or pyridyl, wherein each of these radicals may optionally be substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, Ci-ealkyl, C ⁇ _ 6 alkyloxy, benzyloxy; or more specifically wherein (n) R 1 is phenyl optionally substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, Ci-ealkyl, Ci-ealkyloxy; quinolinyl; a radical (c-4) wherein m is 2, optionally substituted with up to two radicals selected from Ci- ⁇ aikyl; benzimidazolyl optionally substituted with C 1-6 alkyl; pyridyl optionally substituted with one or two radicals selected from hydroxy, halo, Ci-6alkyl
- R 1 is a radical (c-4) wherein m is 2, optionally substituted with up to two radicals selected from Ci-ealkyl; or (r) R 1 is benzimidazolyl optionally substituted with Ci-ealkyl; pyridyl optionally substituted with one or two radicals selected from hydroxy, halo, Ci-ealkyl, benzyloxy and C ⁇ _6alkyloxy; or
- R 1 is pyrazinyl optionally substituted with up to three radicals selected from Ci- 6 alkyl.
- Preferred subgroups of compounds of formula (I) or any ofthe subgroups of compounds of formula (I) are those wherein G is a direct bond or methylene and R 1 is as specified above in (a) - (s). Further preferred are the compounds of formula (I) or any ofthe subgroups specified herein wherein G is a direct bond and R 1 is a radical (c-4), in particular wherein m is 2, optionally substituted with up to two radicals selected from Ci- 6 alkyl. Further preferred are the compounds of formula (I) or any of the subgroups specified herein wherein or G is methylene and R 1 is as specified above in (a) - (s), but is other than a radical (c-4).
- Q is Ar 2 , C 3 . 7 cycloalkyl or Ci_ 6 alkyl substituted with one or two substituents each independently selected from the group consisting of substituents mentioned in the definition of the compounds of formula (I) or of any subgroup thereof; or in particular
- Q is Ar 2 , C 3 . 7 cycloalkyl or Ci_ 6 alkyl substituted with one substituent selected from the group consisting of substituents mentioned in the definition ofthe compounds of formula (I) or of any subgroup thereof, and said Ci-ealkyl is optionally further substituted with one hydroxy; or
- Q is Ar 2 , C 3 - 7 cycloalkyl, or C ⁇ -6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of trifluoromethyl, Ar 2 , hydroxy, Cwalkylthio, Ar 2 -oxy-, Ar 2 (CH 2 ) n oxy, hydroxy- carbonyl, a inocarbonyl, Ar 2 carbonyl, mono- or ⁇ (Ci alkyl)amino- carbonyl, dioxolanyl optionally substituted with one or two C ⁇ -6alkyl radicals, and a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, indolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with
- cycloalkyl, or C h alk ! optionally substituted with one substituent selected from trifluoromethyl, Ar 2 , hydroxy, Ar 2 -oxy-, Ar 2 (CH 2 ) n oxy, hydroxycarbonyl, aminocarbonyl, d ⁇ alkylcarbonyl, Arcarbonyl, hydroxy-C 2 - -alkyloxy, mono- or dioxolanyl optionally substituted with one or two Ci-ealkyl radicals, and a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, indolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with up to two substituents independently selected from oxo and C h alky-, and said C ⁇ -6al
- Ci-ealkyl optionally substituted with one or two substituents each independently selected from the group consisting of Ar 2 , hydroxy, C 1 - alkoxy, ar inocarbonyl, hydroxy- C ⁇ -alkyloxy, dioxolanyl substituted with two Ci-ealkyl radicals, and a heterocycle selected from the group consisting of pyrrolidinyl, indolyl, imidazolyl, piperidinyl, piperazinyl, and pyridyl, wherein each of said heterocycle may optionally be substituted with up to two substituents independently selected from oxo and Ci- 6 alkyl; or (f) Q is Ar 2 , C 3 .
- Ci- 6 alkyl optionally substituted with Ar 2 , hydroxy, hydroxy- C ⁇ -alkyloxy, dioxolanyl substituted with two Ci-6alkyl radicals, or a heterocycle selected from pyrrolidinyl, indolyl, imidazolyl, piperidinyl, piperazinyl, and pyridyl, wherein each of said heterocycle may optionally be substituted with up to two substituents independently selected from oxo and Ci-ealkyl, and said d-ealkyl is optionally further substituted with one hydroxy; or (g) Q is Ar 2 , C 3 .
- Ci-ealkyl optionally substituted with Ar 2 , with one or two hydroxyl groups, with aminocarbonyl, carbonyl, hydroxy-C 2- -alkyloxy, dioxolanyl substituted with two Ci-ealkyl radicals, or a heterocycle selected from pyrrolidinyl, indolyl, imidazolyl, piperidinyl, piperazinyl, and pyridyl, wherein each of said heterocycle may optionally be substituted with two substituents independently selected from oxo and Ci-ealkyl; or
- (h Q is Ci-ealkyl optionally substituted with Ar 2 , with one or two hydroxyl groups, with C ⁇ -4alkoxy, or a heterocycle selected from pyrrolidinyl, imidazolyl, piperidinyl and piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or Ci-ealkyl, or with oxo and Ci- 6 alkyl; or
- Ar 2 is phenyl or phenyl substituted with 1, 2 or 3 substituents or with 1 or 2 substituents, or preferably with one substituent selected from halo, hydroxy, amino, cyano, hydroxyCi- 6 alkyl, aminoCi-ealkyl, Ci- 6 alkyloxy and aminosulfonyl.
- Ar 2 is phenyl or phenyl substituted with 1, 2 or 3 substituents or with 1 or 2 substituents, or preferably with one substituent selected from amino, cyano, hydroxyCi-ealkyl, aminoCi-6alkyl and aminosulfonyl.
- Ar 1 is phenyl or phenyl substituted with 1, 2, 3 substituents or with 1, 2 substituents selected from those mentioned in the definition ofthe compounds of formula (1) or of any subgroup thereof.
- Ar 2 is phenyl or phenyl substituted with 1, 2, 3 substituents or with 1, 2 substituents selected from the group consisting of those mentioned in the definition ofthe compounds of formula (I) or of any subgroup thereof.
- Ar 1 preferably is phenyl or phenyl substituted with up to 3 substituents, or with up to 2 substituents, or with one substituent, selected from halo, hydroxy, Ci-6alkyl, hydroxyCi- 6 alkyl, trifluormethyl, and d ⁇ aUcyloxy;
- Ar 1 more preferably is phenyl or phenyl substituted with up to 3 substituents, or with up to 2 substituents, or with one substituent, selected from halo, hydroxy, Ci- 6 alkyl and d-ealkyloxy;
- Ar 1 more preferably is phenyl or phenyl substituted with up to 3 substituents, or with up to 2 substituents, or with one substituent, selected from halo and d-ealkyl.
- Further particular subgroups ofthe compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Ar 2 is as defined for Ar 1 .
- subgroups ofthe compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein one of R 2a andR 3a is d-ealkyl and the other one of R 2a andR 3a is hydrogen; in case R 2a is different from hydrogen then R 2b is and R 3b is hydrogen; in case R 3a is different from hydrogen then R 3 is Ci-ealkyl, and R 2b is hydrogen.
- Preferred compounds are those compounds listed in tables 1 through 3, more in particular the compound numbers 1 to 11 and 25 to 28.
- R 1 , R a , R 2b , R 3a , R 3 , R 5 have the meanings defined above for the compounds of formula (I) or of any of the subgroups thereof.
- W is an appropriate leaving group, preferably it is chloro or bromo.
- the reactions of these schemes can be typically conducted in a suitable solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichoromethane, CHC1 3 , toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like.
- a base may be added to pick up the acid that is liberated during the reaction.
- a (Haminobenzene (VI) is cyclized with urea, preferably in a suitable solvent, e.g. xylene, to yield a benzimidazolone (VII).
- a suitable solvent e.g. xylene
- the latter is converted to a benzimidazole derivative (VETi) wherein W is a leaving group as specified above, in particular by reaction of (VII) with a suitable halogenating agent, for example POCl 3 .
- a suitable halogenating agent for example POCl 3 .
- the resulting intermediate (VUI) is reacted with an amine derivative (LX) in an N-alkylation reaction to obtain an intermediate (II).
- the compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form.
- Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
- Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
- appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboper- oxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
- 3-chlorobenzenecarbo- peroxoic acid peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tbutyl hydro-peroxide.
- Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
- Pure stereochemically isomeric forms ofthe compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter- current distribution, liquid chromatography and the like.
- the compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
- the racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base.
- Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid.
- An alternative manner of separating the enantiomeric forms ofthe compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
- Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occurs stereospecifically.
- the present invention concerns a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any ofthe subgroups of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier.
- a therapeutically effective amount in this context is an amount sufficient to prophylaxictically act against, to stabilize or to reduce viral infection, and in particular RSV viral infection, in infected subjects or subjects being at risk of being infected.
- this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises mtimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any ofthe subgroups of compounds of formula (I) as specified herein.
- the compounds ofthe present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes.
- compositions there may be cited all compositions usually employed for systemically administering drugs.
- an effective amount ofthe particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in mtimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for adniinistration.
- a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for adniinistration.
- These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
- any ofthe usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in a ⁇ mnistration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a rnixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
- the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
- the compounds ofthe present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for adniinistration via this way.
- the compounds ofthe present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the acmiinistration ofthe present compounds.
- the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
- a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
- the compounds of the present invention are adtrnnistered via inhalation of a solution in nebulized or aerosolized doses.
- Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
- the compounds of formula (I) show antiviral properties.
- Viral infections treatable using the compounds and methods ofthe present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV).
- RSV human and bovine respiratory syncytial virus
- a number ofthe compounds of this invention moreover are active against mutated strains of RSV.
- many ofthe compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
- the in vitro antiviral activity against RSV ofthe present compounds was tested in a test as described in the experimental part ofthe description, and may also be demonstrated in a virus yield reduction assay.
- the in vivo antiviral activity against RSV ofthe present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. (Antiviral Research (1998), 38, 31 -42).
- the compounds of formula (I) or any subgroup thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms are useful in the treatment of individuals experiencing a viral infection, particularly a RSV infection, and for the prophylaxis of these infections.
- the compounds ofthe present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular the respiratory syncytial virus.
- the compounds of the present invention or any subgroup thereof may therefore be used as medicines.
- Said use as a medicine or method of treatment comprises the systemic administration to viral infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the RSV infection.
- the present invention also relates to the use ofthe present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly RSV infection.
- the present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by RSV, said method comprising the aclmimstration of an anti-virally effective amount of a compound of formula (I), as specified herein, or of a compound of any ofthe subgroups of compounds of formula (I), as specified herein.
- an antiviral effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
- the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response ofthe treated subject and/or depending on the evaluation ofthe physician prescribing the compounds ofthe instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
- the combination of another antiviral agent and a compound of formula (I) can be used as a medicine.
- the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment.
- the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
- the compounds ofthe present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections.
- the compounds were identified by LC/MS using the following equipment: LCT: electrospray ionisation in positive mode, scanning mode from 100 to 900 amu; Xterra MS C18 (Waters, Milford, MA) 5 ⁇ m, 3.9 x 150 mm); flow rate 1 n ⁇ Vmin.
- Two mobile phases (mobile phase A: 85% 6.5mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) were employed to run a gradient from 100 % A for 3 min to 100% B in 5 min., 100% B for 6 min to 100 % A in 3 min, and equilibrate again with 100 % A for 3 min).
- ZQ electrospray ionisation in both positive and negative (pulsed) mode scanning from 100 to 1000 amu; Xterra RP C18 (Waters, Milford, MA) 5 ⁇ m, 3.9 x 150 mm); flow rate 1 rn min.
- Two mobile phases (mobile phase A: 85% 6.5mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) were employed to run a gradient condition from 100 % A for 3 min to 100% B in 5 min., 100% B for 6 min to 100 % A in 3 min, and equilibrate again with 100 % A for 3 min).
- LiAfflU (0.0003 mol) was added portion wise at 5°C to a mixture of 3-[l-(3-hydroxy-6- methyl-pyridm-2-ylmemyl)-4,6- ⁇ - ⁇ ethyl ester (0.0001 mol) in tetiahydrofuran (10ml) under N 2 flow. The mixture was stirred at 5°C for 1 hour, then at room temperature for 3 hours. Ethylacetate and H 2 O were added. The mixture was extracted with ethylacetate. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue was crystallized from 2-propanone/CH 3 CN/ diisopropylether.
- intermediate f-3 was prepared analogous to the procedure described for intermediate e-3.
- Example 7 In vitro screening for activity against Respiratory Syncytial Virus.
- the percent protection against cytopathology caused by viruses (antiviral activity or EC50) achieved by tested compounds and their cytotoxicity (CC50) are both calculated from dose-response curves.
- the selectivity ofthe antiviral effect is represented by the selectivity index (SI), calculated by dividing the CC50 (cytotoxic dose for 50% ofthe cells) by the EC50 (antiviral activity for 50 % ofthe cells).
- SI selectivity index
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004298458A AU2004298458B2 (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
JP2006544464A JP2007514718A (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazole derivatives as inhibitors of respiratory syncytium virus replication |
AT04804953T ATE431344T1 (en) | 2003-12-18 | 2004-12-20 | AMINOBENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF REPLICATION OF THE RESPIRATORY SYNCYTIAL VIRUS |
PL04804953T PL1711485T3 (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
US10/596,500 US20090036466A1 (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
CA2548666A CA2548666C (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
BRPI0417808-4A BRPI0417808A (en) | 2003-12-18 | 2004-12-20 | amino benzimidazole derivatives as respiratory syndication virus replication inhibitors |
MXPA06007110A MXPA06007110A (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication. |
DE602004021135T DE602004021135D1 (en) | 2003-12-18 | 2004-12-20 | AMINOBENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF THE REPLICATION OF THE RESPIRATORY SYNCYTIAL VIRUS |
CN2004800372812A CN1894236B (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
EP04804953A EP1711485B1 (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
KR1020067013072A KR101074333B1 (en) | 2003-12-18 | 2006-06-29 | - amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03104804.4 | 2003-12-18 | ||
EP03104804 | 2003-12-18 | ||
US56718104P | 2004-04-30 | 2004-04-30 | |
US60/567,181 | 2004-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005058870A1 true WO2005058870A1 (en) | 2005-06-30 |
Family
ID=34702357
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/053617 WO2005058870A1 (en) | 2003-12-18 | 2004-12-20 | Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication |
Country Status (15)
Country | Link |
---|---|
US (1) | US20090036466A1 (en) |
EP (1) | EP1711485B1 (en) |
JP (1) | JP2007514718A (en) |
KR (1) | KR101074333B1 (en) |
AT (1) | ATE431344T1 (en) |
AU (1) | AU2004298458B2 (en) |
BR (1) | BRPI0417808A (en) |
CA (1) | CA2548666C (en) |
DE (1) | DE602004021135D1 (en) |
ES (1) | ES2326813T3 (en) |
MX (1) | MXPA06007110A (en) |
PL (1) | PL1711485T3 (en) |
PT (1) | PT1711485E (en) |
RU (1) | RU2332414C2 (en) |
WO (1) | WO2005058870A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011019781A1 (en) * | 2009-08-11 | 2011-02-17 | Sanofi-Aventis U.S. Llc | Process for preparing 2-arylamino or heteroarylamino substituted benzimidazole compounds |
US8163935B2 (en) | 2005-04-27 | 2012-04-24 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compounds |
US9738652B2 (en) | 2014-04-14 | 2017-08-22 | Janssen Sciences Ireland Uc | Spiro urea compounds as RSV antiviral compounds |
US11001588B2 (en) | 2018-09-19 | 2021-05-11 | Forma Therapeutics, Inc. | Activating pyruvate kinase R and mutants thereof |
US11014927B2 (en) | 2017-03-20 | 2021-05-25 | Forma Therapeutics, Inc. | Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators |
US11071725B2 (en) | 2018-09-19 | 2021-07-27 | Forma Therapeutics, Inc. | Activating pyruvate kinase R |
KR20210122024A (en) | 2020-03-30 | 2021-10-08 | (주)바이오메트릭스 테크놀로지 | Novel benzimidazole derivatives, preparation thereof and use thereof as anti-cancer agent comprising the same |
EP3907230A1 (en) | 2020-03-30 | 2021-11-10 | Biometrix Technology Inc. | Novel benzimidazole derivatives, preparation method thereof and use thereof as anti-cancer agent comprising the same |
KR102342313B1 (en) | 2021-08-27 | 2021-12-24 | (주)바이오메트릭스 테크놀로지 | Micelle comprising benzimidazole-carbohydrate conjugate compound, preparation thereof and use thereof as anti-cancer agent or anti-virus agent comprising the same |
WO2021261663A1 (en) | 2020-06-23 | 2021-12-30 | (주)바이오메트릭스 테크놀로지 | Novel benzimidazole derivative, preparation method therefor, and use thereof as anticancer or antiviral agent |
US12043644B2 (en) | 2020-06-23 | 2024-07-23 | Biometrix Technology Inc | Benzimidazole derivatives, preparation method thereof and use thereof as anti-cancer agent or anti-virus agent comprising the same |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2731707A1 (en) * | 1995-03-13 | 1996-09-20 | Synthelabo | Novel 2-imidazolyl alkylamino benzimidazole(s) |
WO2001000615A1 (en) * | 1999-06-28 | 2001-01-04 | Janssen Pharmaceutica N.V. | Respiratory syncytial virus replication inhibitors |
WO2001000612A2 (en) * | 1999-06-28 | 2001-01-04 | Janssen Pharmaceutica N.V. | Respiratory syncytial virus replication inhibitors |
WO2001000611A1 (en) * | 1999-06-28 | 2001-01-04 | Janssen Pharmaceutica N.V. | Respiratory syncytial virus replication inhibitors |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179505A (en) * | 1977-03-30 | 1979-12-18 | Janssen Pharmaceutica N.V. | 5-[4-(Diarylmethyl)-1-piperazinylalkyl]benzimidazole derivatives |
IT1214609B (en) * | 1985-05-17 | 1990-01-18 | Opocrin Spa | HEXOSAMINOGLICANS DEPOLYMERIZED SULPHATES FOR ANTI-THROMBOTIC, FIBRINOLITHIC, ANTI-INFLAMMATORY ACTIVITIES, THEIR PREPARATION PROCEDURE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
CA2227688C (en) * | 1998-01-16 | 2007-07-31 | James W. Critchfield | Methods and compositions for inhibition of viral replication |
-
2004
- 2004-12-20 US US10/596,500 patent/US20090036466A1/en not_active Abandoned
- 2004-12-20 MX MXPA06007110A patent/MXPA06007110A/en active IP Right Grant
- 2004-12-20 AT AT04804953T patent/ATE431344T1/en not_active IP Right Cessation
- 2004-12-20 ES ES04804953T patent/ES2326813T3/en active Active
- 2004-12-20 AU AU2004298458A patent/AU2004298458B2/en not_active Ceased
- 2004-12-20 WO PCT/EP2004/053617 patent/WO2005058870A1/en active Application Filing
- 2004-12-20 EP EP04804953A patent/EP1711485B1/en active Active
- 2004-12-20 DE DE602004021135T patent/DE602004021135D1/en active Active
- 2004-12-20 BR BRPI0417808-4A patent/BRPI0417808A/en not_active IP Right Cessation
- 2004-12-20 PL PL04804953T patent/PL1711485T3/en unknown
- 2004-12-20 CA CA2548666A patent/CA2548666C/en not_active Expired - Fee Related
- 2004-12-20 RU RU2006125729/04A patent/RU2332414C2/en not_active IP Right Cessation
- 2004-12-20 PT PT04804953T patent/PT1711485E/en unknown
- 2004-12-20 JP JP2006544464A patent/JP2007514718A/en not_active Withdrawn
-
2006
- 2006-06-29 KR KR1020067013072A patent/KR101074333B1/en not_active IP Right Cessation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2731707A1 (en) * | 1995-03-13 | 1996-09-20 | Synthelabo | Novel 2-imidazolyl alkylamino benzimidazole(s) |
WO2001000615A1 (en) * | 1999-06-28 | 2001-01-04 | Janssen Pharmaceutica N.V. | Respiratory syncytial virus replication inhibitors |
WO2001000612A2 (en) * | 1999-06-28 | 2001-01-04 | Janssen Pharmaceutica N.V. | Respiratory syncytial virus replication inhibitors |
WO2001000611A1 (en) * | 1999-06-28 | 2001-01-04 | Janssen Pharmaceutica N.V. | Respiratory syncytial virus replication inhibitors |
Non-Patent Citations (13)
Title |
---|
ANISIMOVA ET AL., KHIM. GETEROTSIKL. SOEDIN., vol. 23, no. 1, 1987, pages 59 - 63 * |
DA SETTIMO ANTONIO ET AL: "Synthesis of 2-methylaminobenzimidazole derivatives tested for antiinflammatory activity", IL FARMACO, ROME, IT, vol. 49, no. 12, 1994, pages 829 - 834, XP002954490, ISSN: 0014-827X * |
DATABASE BEILSTEIN XP002321512 * |
DATABASE BEILSTEIN XP002321513 * |
DATABASE BEILSTEIN XP002321514 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HUNGER, A. ET AL: "Benzimidazole and related heterocycles. VII. New 2-aminobenzimidazoles", XP002321511, retrieved from STN Database accession no. 1962:12985 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KOVALEV, G. V. ET AL: "Effects of condensed derivatives of benzimidazole on gastric secretion", XP002321510, retrieved from STN Database accession no. 1990:210542 * |
EUR. J. MED. CHEM., vol. 27, no. 4, 1992, pages 395 - 400, XP009029532 * |
HELVETICA CHIMICA ACTA , 44, 1273-82 CODEN: HCACAV; ISSN: 0018-019X, 1961 * |
KHIMIKO-FARMATSEVTICHESKII ZHURNAL , 24(2), 127-30 CODEN: KHFZAN; ISSN: 0023-1134, 1990 * |
MOLINA ET AL., CHEMISCHE BERICHTE, vol. 127, no. 9, 1994, pages 1641 - 52, XP009045299 * |
SIMONOV ET AL., KHIM. GETEROTSIKL. SOEDIN., vol. 5, 1969, pages 184 * |
ZVEZDINA ET AL., KHIM. GETEROTSIKL. SOEDIN., vol. 6, 1970, pages 419 * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8163935B2 (en) | 2005-04-27 | 2012-04-24 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compounds |
WO2011019781A1 (en) * | 2009-08-11 | 2011-02-17 | Sanofi-Aventis U.S. Llc | Process for preparing 2-arylamino or heteroarylamino substituted benzimidazole compounds |
US9738652B2 (en) | 2014-04-14 | 2017-08-22 | Janssen Sciences Ireland Uc | Spiro urea compounds as RSV antiviral compounds |
US11396513B2 (en) | 2017-03-20 | 2022-07-26 | Forma Therapeutics, Inc. | Compositions for activating pyruvate kinase |
US12071440B2 (en) | 2017-03-20 | 2024-08-27 | Novo Nordisk Health Care Ag | Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators |
US11014927B2 (en) | 2017-03-20 | 2021-05-25 | Forma Therapeutics, Inc. | Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators |
US11649242B2 (en) | 2017-03-20 | 2023-05-16 | Forma Therapeutics, Inc. | Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators |
US11071725B2 (en) | 2018-09-19 | 2021-07-27 | Forma Therapeutics, Inc. | Activating pyruvate kinase R |
US11844787B2 (en) | 2018-09-19 | 2023-12-19 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
US11980611B2 (en) | 2018-09-19 | 2024-05-14 | Novo Nordisk Health Care Ag | Treating sickle cell disease with a pyruvate kinase R activating compound |
US12053458B2 (en) | 2018-09-19 | 2024-08-06 | Novo Nordisk Health Care Ag | Treating sickle cell disease with a pyruvate kinase R activating compound |
US11001588B2 (en) | 2018-09-19 | 2021-05-11 | Forma Therapeutics, Inc. | Activating pyruvate kinase R and mutants thereof |
EP3907230A1 (en) | 2020-03-30 | 2021-11-10 | Biometrix Technology Inc. | Novel benzimidazole derivatives, preparation method thereof and use thereof as anti-cancer agent comprising the same |
KR20210122024A (en) | 2020-03-30 | 2021-10-08 | (주)바이오메트릭스 테크놀로지 | Novel benzimidazole derivatives, preparation thereof and use thereof as anti-cancer agent comprising the same |
US11667661B2 (en) | 2020-03-30 | 2023-06-06 | Biometrix Technology Inc | Benzimidazole derivatives, preparation method thereof and use thereof as anti-cancer agent comprising the same |
WO2021261663A1 (en) | 2020-06-23 | 2021-12-30 | (주)바이오메트릭스 테크놀로지 | Novel benzimidazole derivative, preparation method therefor, and use thereof as anticancer or antiviral agent |
US12043644B2 (en) | 2020-06-23 | 2024-07-23 | Biometrix Technology Inc | Benzimidazole derivatives, preparation method thereof and use thereof as anti-cancer agent or anti-virus agent comprising the same |
KR102342313B1 (en) | 2021-08-27 | 2021-12-24 | (주)바이오메트릭스 테크놀로지 | Micelle comprising benzimidazole-carbohydrate conjugate compound, preparation thereof and use thereof as anti-cancer agent or anti-virus agent comprising the same |
EP4140504A1 (en) | 2021-08-27 | 2023-03-01 | Biometrix Technology Inc. | Micelle comprising benzimidazole-carbohydrate conjugate compound, preparation method thereof and use thereof as anticancer agent or antiviral agent comprising the same |
US11998530B2 (en) | 2021-08-27 | 2024-06-04 | Biometrix Technology Inc. | Micelle comprising benzimidazole-carbohydrate conjugate compound, preparation method thereof and use thereof as anticancer agent or antiviral agent comprising the same |
Also Published As
Publication number | Publication date |
---|---|
ATE431344T1 (en) | 2009-05-15 |
RU2006125729A (en) | 2008-01-27 |
KR101074333B1 (en) | 2011-10-17 |
RU2332414C2 (en) | 2008-08-27 |
AU2004298458A1 (en) | 2005-06-30 |
CA2548666A1 (en) | 2005-06-30 |
CA2548666C (en) | 2012-08-07 |
AU2004298458B2 (en) | 2010-05-20 |
MXPA06007110A (en) | 2006-08-23 |
ES2326813T3 (en) | 2009-10-20 |
BRPI0417808A (en) | 2007-04-10 |
EP1711485A1 (en) | 2006-10-18 |
PT1711485E (en) | 2009-07-31 |
EP1711485B1 (en) | 2009-05-13 |
US20090036466A1 (en) | 2009-02-05 |
PL1711485T3 (en) | 2009-11-30 |
KR20060118568A (en) | 2006-11-23 |
JP2007514718A (en) | 2007-06-07 |
DE602004021135D1 (en) | 2009-06-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7355051B2 (en) | Piperdine-amino-benzimidazole derivatives as inhibitors of respiratory syncytial virus replication | |
KR101074333B1 (en) | - amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication | |
US8278455B2 (en) | 5- or 6-substituted benzimidazole derivatives as inhibitors of respiratory syncytial virus replication | |
US8034835B2 (en) | 1-[[2-amino-3-(substituted alkyl)-3H-benzimidazolyl[methyl]-3-substituted-1,3-dihydro-benzoimidazol-2-ones and structural analogs | |
US8044073B2 (en) | Aminobenzimidazoles and benzimidazoles as inhibitors of respiratory syncytial virus replication | |
US8178694B2 (en) | Heterocyclylaminoalkyl substituted benzimidazoles | |
EP1896450B1 (en) | 2-substituted benzimidazoles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200480037281.2 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2972/DELNP/2006 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004298458 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2548666 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2004298458 Country of ref document: AU Date of ref document: 20041220 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10596500 Country of ref document: US Ref document number: 2006544464 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2004298458 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2006/007110 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020067013072 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004804953 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006125729 Country of ref document: RU |
|
WWP | Wipo information: published in national office |
Ref document number: 2004804953 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020067013072 Country of ref document: KR |
|
ENP | Entry into the national phase |
Ref document number: PI0417808 Country of ref document: BR |